Episodes Archives - Cardionerds

CardioNerds (Amit Goyal & Daniel Ambinder) join Boston University cardiology fellows (Yuliya Mints, Anshul Srivastava, and Michel Ibrahim) for some hotdogs at Fenway Park in Boston, MA. They discuss an educational case of carcinoid heart disease with severe tricuspid regurgitation. Program director, Dr. Omar Siddiqi provides the E-CPR and APD Dr. Katy Bockstall provides a message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident Bibin Varghese with mentorship from University of Maryland cardiology fellow Karan Desai.   

Jump to: Patient summary – Case media – Case teaching – References

The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus.

We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director.

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A woman in her mid 60s with history of neuroendocrine tumor (NET) presented to the cardio-oncology clinic with chronic progressive SOB and fatigue. She was diagnosed with NET after presenting with a small bowel obstruction (SBO) several years prior. At the time, she was found to have liver and pulmonary metastasis with MR enterography showing thickening of the terminal ileum. Ileocecetomy and biopsy of the liver lesions confirmed metastatic NET. Despite treatment with octreotide and everolimus, follow up CT showed progression of liver lesions and she was eventually started on telotristat and enrolled in a clinical trial. On presentation, she was not tachycardiac, hypotensive or requiring oxygen supplementation (KD: Correct?). On exam, she demonstrated elevated JVP with a positive hepato-jugular reflex and a 3/6 holosytolic murmur loudest at the LLSB that increased with inspiration. Lab work revealed urinary 5-HIAA was 212 (nl < 6mg/24 hours). TTE showed moderately dilated RV and severely dilated RA. Furthermore, there was a thickened, calcified and retracted TV with severe TR which was consistent with carcinoid heart disease. She was treated with diuretics and was continued on systemic therapies to help achieve control of her NET before surgical intervention for her valvular disease was considered.  

• A
• B

A. ECG
B. TTE: CW Doppler through tricuspid valve

1. The patient had an NET history and presented with shortness of breath. Under what circumstances do patients with NETs present with cardiac symptoms? 
   1. Amongst patients with neuroendocrine tumors (NETs), carcinoid tumors refer classically to gastrointestinal NETs. Around 30 to 40% of these patients will presents with features of carcinoid syndrome, including vasomotor symptoms (e.g., flushing), diarrhea, and bronchospasm. The majority of patients with carcinoid syndrome have metastases to the liver and the vasoactive substances (e.g., 5-hydroxytryptamine [5-HT]) reach the systemic circulation via the hepatic vein bypassing degradation in the liver.  
   2. Similarly, cardiac involvement occurs after metastasis to the liver and exposure of the heart to vasoactive substances. Generally, symptoms are limited to the right heart as the lungs clear carcinoid-related substances. Left-sided involvement may occur, however, in a patient with carcinoid heart disease and an intracardiac right to left shunt is present.  
   3. In addition to the symptoms of carcinoid syndrome, patients with carcinoid heart disease including severe dyspnea, fatigue, and signs and symptoms of right heart failure (e.g., ascites, peripheral edema).  

1.  The patient was diagnosed with carcinoid heart disease. What are the typical echocardiographic findings of carcinoid heart disease?   
   1. The echocardiographic findings of carcinoid heart disease are heterogeneous from mild thickening of a single valve leaflet to advanced disease with significant thickening and retraction of multiple valves. The vasoactive substances of carcinoid can specifically cause valvular thickening (5-HT receptors being most prevalent on heart valves) and restricted leaflet motion that can result in a “club-like” appearance of the leaflets. This occurs on the right-sided heart valves (unless an intracardiac shunt exists), with TV involvement being most common.  
   2. Specifically, in mild cases, the normal concave curvature of the tricuspid leaflets is reduced and the leaflets straighten, This affects its motion during diastole leading to valve dysfunction. Eventually there is progressive thickening of the valve leaflets, chordae and papillary muscle leading to significant leaflet retraction and reduced leaflet motion. When carcinoid heart disease becomes severe, the leaflets can be fixed and fail to coapt leading to severe tricuspid regurgitation, tricuspid stenosis, and signs and symptoms of right heart failure.  
   3. As with the tricuspid valve, carcinoid heart disease can also affect the pulmonary valve leading to diffuse thickening and the formation of typical “carcinoid plaques.” This similarly can result in retraction of the valve cusps and mixed pulmonic regurgitation and pulmonic stenosis. Note pulmonic stenosis secondary to carcinoid has an extremely poor prognosis (with median survival typically less than 2 years) and is often not responsive to balloon vavuloplasty.  

3 . What is the typical diagnostic evaluation of carcinoid heart disease in patients with NET? 

• In patients with NET and subsequently carcinoid syndrome, there should be monitoring for the development of heart failure, right-sided symptoms and new murmurs. Nonetheless, high index of suspicion is necessary as up to 57% of patients with moderate to severe TR can be asymptomatic or have mild symptoms and one-third of patients can lack a cardiac murmur.  
• NT-proBNP is a useful biomarker of carcinoid heart disease, and a cutoff level of 260 pg/ml (31 pmol/l) and has been used as a screening tool for carcinoid heart disease (sensitivity 60-92%, specificity 80-91%). Furthermore, plasma and urinary levels of 5-HIAA are significantly higher in patients with carcinoid heart disease compared with those without cardiac involvement. 5-HIAA levels >300 mmol/24 h conferred a 2- to 3-fold increased risk for developing or progression of carcinoid heart disease  
• TTE is the imaging modality of choice for patients with signs and/or symptoms of carcinoid heart disease, in patients with elevated NT-proBNP , and any patient undergoing surgical liver or abdominal intervention. The findings of carcinoid heart disease are on a spectrum, but there are some characteristic findings as outlined above. TEE can be an additional test to fully characterize valvular involvement and/or for surgical planning. Furthermore, cardiac CT and CMR may be valuable as adjuncts 

4. How do you manage carcinoid heart disease? 

• The only definitive and effective therapy for carcinoid heart disease is valve intervention. Diuretics and aldosterone antagonists can be helpful to relieve symptoms, but typically only have temporary effectiveness. Telotristat ethyl, an oral tryptophan hydroxylase inhibitor used in combination with a somatostatin analog for management of diarrhea associated with carcinoid syndrome, has been used to try to prevent the development and progression of carcinoid heart disease.  
• Surgical valve intervention should be considered in patients with severe valvular disease and/or signs of right heart failure, with at least 12 months of anticipated post-operative survival fromt heir NET disease.  
• Symptomatic management primarily involves loops diuretics and aldosterone antagonists for relieving symptoms associated with RHF. Digoxin, vasodilators, and ACEi have no proven efficacy in this population. Bioprosthetic valves may be preferred over mechanical valves due to the inherent increased risk of bleeding in patients with advanced liver disease and hepatic dysfunction from carcinoid disease. However, bioprosthetic valves may be more prone to premature dysfunction and degeneration due to the underlying carcinoid process and thrombosis formation. A careful multi-disciplinary team and approach is needed to individualize valve choice for each patient.  
• Transcatheter valve replacement has been undertaken for pulmonic valve involvement, but transcatheter tricuspid valve replacement is not common.  

5. What is the overall prognosis of patients with carcinoid heart disease with and without surgical management?  

• Carcinoid heart disease with NYHA III or IV symptoms have a poor prognosis and median survival is only 11 months. In carcinoid patients with cardiac symptoms and controlled systemic disease, cardiac valve replacement surgery alleviates otherwise intractable symptoms and appears to improve survival. 

References

• JACC 2017 – Carcinoid Heart Disease 
• JACC 2017 – Carcinoid Heart Disease – ACC Review 
• https://www.uptodate.com/contents/carcinoid-heart-disease#H14 

• Bibin Varghese, MD
• Rick Ferraro, MD
• Tommy Das, MD
• Eunice Dugan, MD
• Evelyn Song, MD
• Colin Blumenthal, MD
• Karan Desai, MD
• Amit Goyal, MD
• Daniel Ambinder, MD

CardioNerds (Amit Goyal & Daniel Ambinder) join Cleveland Clinic cardiology fellows (Ben Alencherry, Erika Hutt, Zach Il’Giovine, Kara Denby) for some delicious craft beer at Platform Brewery! They discuss a challenging case of Ehlers Danlos Syndrome with Papillary Muscle Rupture. Dr. Vidyasagar Kalahasti provides the E-CPR and program director Dr. Venu Menon provides a message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident, Eunice Dugan, with mentorship from University of Maryland cardiology fellow Karan Desai.  

This case has been published in JACC Case Reports: CardioNerds Corner!

Jump to: Patient summary – Case media – Case teaching – References

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A pregnant woman at 29 weeks gestation presents with postpartum pulmonary edema, found to have papillary muscle rupture, is ultimately diagnosed with vascular Ehlers Danlos Syndrome. For a detailed course, enjoy the JACC case report.

Visit the JACC Case Reports: CardioNerds Corner to review the case media!

Coming soon!

1. What is Ehlers-Danlos Syndrome?  

• Ehlers-Danlos Syndrome (EDS) is a clinically and genetically heterogenous group of heritable connective tissue disorders due to altered collagen metabolism. The inheritance pattern is variable, but is mostly autosomal dominant, with a range of mechanisms including deficiency of collagen-processing enzymes, mutant collagen chains, and haploinsufficiency.    
• Although the syndrome has varying and overlapping clinical manifestations based on subtype (per the 2017 International ED Consortium there are 17 subtypes) it is largely characterized by hyperextensibility of the skin, hypermobility of joints, atrophic scarring, and tissue fragility.  The cardiovascular system is involved in the vascular and cardio-valvular subtypes. 
• The incidence is estimated to be 1 in 2500 to 5000, however this is likely an underestimation since mild presentations may not be clinically diagnosed nor sent for genetic testing.   
• The differential diagnosis for suspected EDS includes osteogenesis imperfecta, Marfan syndrome, and Loeys-Dietz syndrome. Those with joint symptoms may be incorrectly diagnosed with fibromyalgia, chronic fatigue syndrome etc.   

1. What is vascular EDS?  

• There are many subtypes of EDS. Type IV or vascular EDS (vEDS) is an autosomal dominant disorder that affects Type III procollagen protein synthesis. The incidence is rare – 1 in 50,000 to 250,000 people and is ~5% of all EDS cases.   
• It is commonly caused by a defect in the COL3A1 gene, most of which are single base substitutions, but more than 700 different mutations have been identified. Missense mutations at the C-terminal end of the molecule results in a more severe form of the disease. 
• Feared vascular manifestations include arterial dissection, rupture, and aneurysm formation. Death is most frequently secondary to complications from arterial dissection or hollow organ rupture. 70% of patients experience a first major event by age 20. Note, surgical repair of a ruptured aneurysm or dissection can be complicated by poor wound healing or hemorrhage because tissue in Ehlers-Danlos is friable. 
  • In this subtype, the usual manifestations of joint hypermobility and skin hyperextensibility may not be as apparent. 
  • The vascular type has the worst prognosis with median expectancy between 40-50 years of age.  

1. How is vEDS diagnosed?  

• Vascular EDS should be considered in anyone with unexplained arterial or hollow viscus rupture, commonly the sigmoid colon, especially at a young age. 
• Diagnosis is confirmed by either finding of structurally abnormal type III procollagen in a culture of dermal fibroblasts or COL3A1 gene mutation. Clinical criteria can aid in the decision to pursue testing.   
• Molecular testing is recommended when meeting one or more major clinical criteria or several minor criteria. Major criteria include family history of vEDS, unexplained arterial rupture at young age, spontaneous intestinal  perforation (in absence of risk factors), uterine rupture during pregnancy and labor, or carotid-cavernous sinus fistula formation.   
• Some minor criteria include bruising without trauma (especially in unusual locations), spontaneous pneumothorax, tendon/muscle rupture, gingival recession, early onset varicose veins, and characteristic facial appearance amongst other criteria. Characteristic facial features include presence of prominent eyes due to lack of adipose tissue around the orbit, thin punched nose, small lips, hollow cheeks, and lobeless ears.  

1. How should patients with vEDS be managed?  

• Management of patients with vEDS requires a multidisciplinary team including a clinical geneticist. Baseline arterial imaging is needed but recommendations for follow-up imaging are not well defined. TTE should be performed at least every 3 years, to screen for cardiac complications.   
• Contact sports should be avoided, as should anti-platelet and anti-coagulation therapy to minimize bleeding risks. Arterial and intramuscular punctures, arteriography, and routine colonoscopy should also be avoided. Surgical or endovascular management of complications can be challenging due to tissue friability.  
• Ascorbic acid is a co-factor for collagen fibrils and may reduce bruising. Desmopressin, vasopressin, and recombinant factor 8a have also been shown to reduce bleeding complications.  
• Patients with vEDS have decreased intima media thickness which imposes additional mechanical stress onto already fragile tissue. Celiprolol is a cardio-selective beta blocker and beta-2 partial agonist which has been showing to prevent arterial complications. However, this drug lacks FDA approval and is not available in the USA.  
• Importantly, cascade genetic testing should be offered to all first-degree relatives.  

1. How can pregnancy–related complications be avoided?  

• Pregnancy in women with vEDS is considered high risk with maternal death rates over 10%. Pregnancy increases risks in two major ways: (1) increased risk of complications related to the gravid uterus and hypermobility (e.g., premature rupture of membranes, ligament laxity and rupture) or uterine/vascular rupture; (2) worsening of pre-existing pathology such as mitral valve prolapse of aortic dilation due to physiologic changes during pregnancy.   
• Pre-pregnancy risk stratification and counseling is recommended for those with known vEDS. Some recommend termination of pregnancy in patients with known vEDS, but one study suggests that pregnancy does not influence life-expectancy. Current guidelines recommend a risk-benefit discussion with the patient and their family.   
• In a patient with vEDS who becomes pregnant, care should involve a multidisciplinary team at a specialized center with vascular surgery, general surgery, and high-risk obstetrics. It is uncertain which mode of delivery improves the risk-benefit ratio for the patient and fetus. Furthermore, spinal or epidural anesthesia can have increased risk of complications in patients with vEDS. 

The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus.

We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director.

References

Hutt, Erika, Celeste Santos-Martins, Jose Aguilera, Per Wierup, Vidyasagar Kalahasti, and Carmela Tan. “A 27-Year-Old Woman With Postpartum Papillary Muscle Rupture.” JACC: Case Reports, October 2020, S2666084920311748.  

M.J. Eagleton. Arterial complications of vascular Ehlers-Danlos syndrome. J Vasc Surg, 64 (2016), pp. 1869-1880 

Miklovic, Tyler, and Vanessa C. Sieg. “Ehlers Danlos Syndrome.” In StatPearls. Treasure Island (FL): StatPearls Publishing, 2020. 

• Bibin Varghese, MD
• Rick Ferraro, MD
• Tommy Das, MD
• Eunice Dugan, MD
• Evelyn Song, MD
• Colin Blumenthal, MD
• Karan Desai, MD
• Amit Goyal, MD
• Daniel Ambinder, MD

CardioNerds (Amit Goyal & Daniel Ambinder) join UCSF cardiology fellows (Emily Cedarbaum, Matt Durstenfeld, and Ben Kelemen) for some fun in San Francisco! They discuss a informative case of ST-segment elevation (STEMI) due to coronary vasospasm. Dr. Binh An Phan provides the E-CPR and program director Dr. Atif Qasim provides a message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident Evelyn Song with mentorship from University of Maryland cardiology fellow Karan Desai.

Jump to: Patient summary – Case media – Case teaching – References

The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus.

We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director.

CardioNerds Case Reports Page
CardioNerds Episode Page
CardioNerds Academy
Subscribe to our newsletter- The Heartbeat
Support our educational mission by becoming a Patron!
Cardiology Programs Twitter Group created by Dr. Nosheen Reza

A man in his mid-50s with alcohol use disorder, cirrhosis, atrial fibrillation, and alpha thalassemia complicated by iron overload presented with hematemesis. He was tachycardic and hypotensive. Labs were notable for Hgb 8.1 (baseline of 10.2), INR 1.3, lactate 4.2, and ferritin 4660. He was started on IV PPI and octreotide. Course was complicated initially by Afib with RVR with hypotension. Subsequently, the patient developed unstable VT requiring CPR. Post-code EKG showed inferolateral ST elevations. Troponin-I rose from 19 to 225 and his pressor requirement continued to increase despite resolution of his GIB. TTE showed LVEF 42% with new inferolateral wall motion abnormalities, normal RV systolic function, severe mitral regurgitation, and small pericardial effusion. After treatment of his GIB by IR and GI, he underwent an urgent LHC which showed 30% stenosis in proximal LAD, 70% in LADD2, and 95% in distal RCA. Coronary spasm was noted in all vessels. Intracoronary nitroglycerin and nicardipine were administered with significant improvement in spasm and resolution of STE on EKG. Vasopressors were quickly weaned off after. He was eventually stabilized, extubated, and started on an oral nitrate and calcium channel blocker. Repeat TTE showed normalized systolic function without any wall motion abnormalities.  

• A
• B

A. Baseline ECG – atrial fibrillation
B. ECG with inferior STEMI

1. What are the cardiac manifestations of hemochromatosis? 
   • Cardiac hemochromatosis encompasses cardiac dysfunction from either primary or secondary hemochromatosis. Initially, hemochromatosis leads to diastolic dysfunction and arrhythmias. In later stages, it can lead to dilated cardiomyopathy.  
   • Diagnosis of iron overload is established by elevated transferrin saturation (>55%) and elevated serum ferritin (>300 ng/mL). Genetic testing for mutations in the HFE gene should be pursued. 
   • Cardiac MRI with measurement of T2* relaxation times is the diagnostic test of choice as it can both detect and quantify myocardial iron overload. The iron content in the myocardial tissue is inversely proportional to the time constant of decay for relaxation time. Thus the higher the iron content, the shorter T2* relaxation time.  
     
2. What are the causes of ST-segment elevation on EKG besides acute plaque rupture or vasospasm? 
   • Pericarditis: in acute pericarditis, ST elevation can be seen diffusely in all leads, with PR segment depression (except lead aVR +/- V1). The diffuse ST elevations are due to involvement of subepicardial layer of the ventricular wall. The PR depressions are due to involvement of the subepicardial layer of the atrial wall.  
   • Stress CM: The ECG findings of stress cardiomyopathy may be indistinguishable from STEMI secondary to acute plaque rupture. 
   • Brugada syndrome: >2 mm ST-segment elevation in the right precordial leads followed be a negative T wave can be seen in patients with Type 1 Brugada. Type 2 and Type 3 Brugada will have STE as well but with different morphologic criteria.  
   • Electrolyte abnormalities: hyperkalemia can sometimes cause ST elevation. Other EKG findings of hyperkalemia include widened QRS, tall and peaked T waves, low-amplitude or lack of P waves, high grade AV Block, sine wave, and/or ventricular fibrillation or PEA. 
   • Pulmonary embolism: the classic EKG features of PE are S1Q3T3 with signs of RV strain (RBBB, RAD) though these are neither sensitive or specific. Sometimes, ST elevation in aVR and right-sided precordial are seen in massive PE due to RV overload, dilation, and/or ischemia (see the Cedars-Sinai episode for more details!).  
   • Cardioversion: striking ST-segment elevation, often >10mm, can be seen after cardioversion but only lasts 1-2 minutes.  
   • Raised ICP: can mimic acute myocardial infarction with widespread T-wave inversions +/- STE (or depression). Other non-cardiac causes, albeit rare causes, include significant gastrointestinal visceral distension, pneumonia, and pancreatitis.  
     
3. What are the two types of ischemic mitral regurgitation (IMR)? 
   • IMR is often a complication of ischemic heart disease and is associated with a worse prognosis across a variety of settings. Ischemic MR can occur due to a primary cause (e.g., abnormality of the valve apparatus and specifically papillary muscle rupture) or secondary cause (e.g., acutely from ischemia and chronically from a complex pathophysiologic changes).  
   • In chronic IMR, regional and/or global LV systolic dysfunction and ventricular remodeling can cause restricted leaflet motion. There can be outward papillary muscle displacement and when this happens, mitral leaflet coaptation moves apically away from the mitral annulus. Further, scarring of the papillary muscles may produce further mitral leaflet tethering and LV dilation can lead to mitral annular dilation. The posterior mitral annulus may contract less as well (which contributes to as much as 25% of the closure of the mitral orifice during systole). The ultimate results is poor leaflet coaptation and mitral regurgitation.  
   • MR secondary to papillary muscle rupture after an acute MI will almost certainly require surgery; while secondary MR from acute ischemia will often respond to revascularization. The treatment of chronic ischemic MR is a topic for another Cardionerds Episode so stay tuned!  
     
4. What’s the pathogenesis of coronary vasospasm? 
   • In coronary vasospasm, the coronary arteries – and specifically the vascular smooth muscle layer – constricts due to various causes including emotional distress, changes in sympathetic tone, cocaine, or cigarette smoking, leading to myocardial ischemia.  
   • The causes and mechanisms of coronary vasospasms are still poorly understood but there are a few potential mechanisms proposed. 
     • Autonomic nervous system: increase in sympathetic tone can induce coronary vasospasms. Vasospasms more commonly occur at night during rapid eye movement sleep, when a reduction in vagal activity is associated with an increase in adrenergic activity.  
     • Inflammation: chronic inflammation and cigarette smoking are shown to be associated with vasospasm. Patients with vasospasm are found to have elevated hs-CRP, IL-6, and peripheral WBC.  
     • Other mechanisms have also been proposed including smooth muscle cell hypercontractility, oxidative stress, and genetics 
       
5. What’s the treatment for coronary vasospasm? 
   1. Any factor that may precipitate coronary vasospasm, especially smoking, should be avoided. There are additionally certain medications that should be avoided including non-selective beta blockers like propranolol and triptans.  
   2. For medical treatment, long-acting calcium channel blockers can be used, especially taken at nighttime when attacks of coronary vasospasm are frequent 
   3. Long-acting nitrates can also be added to prevent recurrent attacks if calcium channel blockers alone are inadequate 

References

1. Gulati, V., Harikrishnan, P., Palaniswamy, C., Aronow, W. S., Jain, D., & Frishman, W. H. (2014). Cardiac involvement in hemochromatosis. Cardiology in review, 22(2), 56–68. 
2. Wang, K., Asinger, R. W., & Marriott, H. J. (2003). ST-segment elevation in conditions other than acute myocardial infarction. The New England journal of medicine, 349(22), 2128–2135.  
3. Báez-Ferrer, N., Izquierdo-Gómez, M. M., Marí-López, B., Montoto-López, J., Duque-Gómez, A., García-Niebla, J., Miranda-Bacallado, J., de la Rosa Hernández, A., Laynez-Cerdeña, I., & Lacalzada-Almeida, J. (2018). Clinical manifestations, diagnosis, and treatment of ischemic mitral regurgitation: a review. Journal of thoracic disease, 10(12), 6969–6986.  
4. Hung, M. J., Hu, P., & Hung, M. Y. (2014). Coronary artery spasm: review and update. International journal of medical sciences, 11(11), 1161–1171.  
5. Slavich, M., & Patel, R. S. (2016). Coronary artery spasm: Current knowledge and residual uncertainties. International journal of cardiology. Heart & vasculature, 10, 47–53.  

• Bibin Varghese, MD
• Rick Ferraro, MD
• Tommy Das, MD
• Eunice Dugan, MD
• Evelyn Song, MD
• Colin Blumenthal, MD
• Karan Desai, MD
• Amit Goyal, MD
• Daniel Ambinder, MD

CardioNerds (Amit Goyal & Daniel Ambinder) join Summa Health cardiology fellows (Jack Hornick, Phoo Pwint Nandar, and Sideris Facaros) for a hike on the Towpath Trail at Cuyahoga Valley National Park in Akron, Ohio! They discuss an informative case of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) complicated by ventricular tachycardia & cardiogenic shock. Dr. Kenneth Varian provides the E-CPR and program director, Dr. Marc Penn provides a message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident, Eunice Dugan, with mentorship from University of Maryland cardiology fellow Karan Desai.  

Jump to: Patient summary – Case media – Case teaching – References

CardioNerds Case Reports Page
CardioNerds Episode Page
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Subscribe to our newsletter- The Heartbeat
Support our educational mission by becoming a Patron!
Cardiology Programs Twitter Group created by Dr. Nosheen Reza

A female in her 40s with no past medical history presented 6 years prior with acute onset dizziness, palpitations and fatigue without chest pain. She had no family history of arrythmias, SCD, or prior syncope. Her heart rate was 170 bpm and EKG showed wide complex, regular tachycardia felt to be VT. She underwent synchronized cardioversion to sinus rhythm. Her baseline EKG showed sinus bradycardia with low voltage, incomplete RBBB, and ventricular ectopy. Labs were unrevealing, and social history was negative for toxic insults or illicit substance abuse. TTE showed preserved LVEF and normal valves, but RV was dilated with decreased systolic function. LHC was without obstructive coronary disease. She was diagnosed with ARVC and received an ICD for secondary prevention. She was discharged on sotalol for arrythmia management. Her genetic testing later returned positive for uncertain significance in the DSP gene and JUP gene, both commonly implicated in ARVC. She was followed in the outpatient setting for 5 years with no apparent shocks. Six years later, she presented with acute onset dizziness and palpitations similar to her initial presentation. EKG showed a wide complex tachycardia at 170 bpm treated with amiodarone and cardioversion. On ICD interrogation, she was found to have had several episodes of VT, but at a rates below the VT detection zone programmed in the ICD. Subsequent RHC showed significantly depressed cardiac index and RV dysfunction. She underwent successful inpatient VT ablation. She was then discharged home with plans for close follow up; however, 2 days later, she started feeling nauseous with fatigue and abdominal pain. She was sent straight to the nearest transplant-capable hospital where she was found to be in cardiogenic shock. She was admitted to ICU and started on inotropes. Due to refractory shock, she was cannulated for VA ECMO and successfully underwent cardiac transplantation two days later.  

• 1
• 2
• 3

A. Post cardioversion ECG: NSR, low voltage, incomplete RBBB, PVC
B. TTE: RV enlargement
C. TTE: Tissue Doppler velocity (S’) low

1. What is ARVC? 

• Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) is a heritable cardiac muscle disorder that classically involves the RV (though LV involvement is increasingly being recognized) marked by loss of healthy myocardium and replacement with fibrofatty tissue predominantly due to genetic defects in both desmosomal and non-desmosomal proteins. Clinical manifestations include RV dysfunction, ventricular arrhythmias, and sudden cardiac death (SCD). 
• This is a progressive disease that can affect the epicardium and/or mid-myocardium first and then move towards the sub-endocardium.  
• It affects approximately 1 in 5000 individuals and is an important cause of (SCD) in young patients. 50% of patients have a positive family history and it is thought to be inherit in an autosomal dominant fashion, however prevalence is underestimated due to incomplete penetrance. Interestingly, males are more affected than females possibly due to interaction of sex hormones with pathophysiology or historically different levels of participation in competitive sports among men and women. 
• The differential for ARVC should include Uhl’s anomaly, myocarditis, sarcoidosis, and Brugada syndrome among other considerations. 

1. What genes are implicated and what is the pathophysiology? 

• While 20-30% of ARVC is due to non-desmosomal gene variants (e.g., desmin, Titin) and non-genetic causes, 40-50% is due to autosomal dominant gene mutations that encode desmosomal proteins. These include plakophilin 2 PKP2 (in 10 to 45% of patients), followed by desmoplakin DSP (10 to 15%), desmoglein 2 DSG2 (7 to 10%), and desmocollin 2 DSC2 (2%).  Rarely, there can be an autosomal recessive inheritance pattern, including Naxos disease (first recognized in the Cycladian Islands in the Aegean Sea) characterized by ARVC along with “wooly hair” and palmoplantar hyperkeratosis. Our understanding of the genetic underpinnings of ARVC continues to evolve.  
• Desmosomes play a major role in intercellular adhesion and synchronized activation and signaling between myocytes. Defective desmosomes disrupt intercellular junctions which lead to myocyte detachment and myocyte death, and this process is especially exaggerated by mechanical stress like exercise. Athletes often have severe disease, possibly a result of high-intensity mechanical stress during exercise. Other resultant features of defective cardiac myocyte signaling is increased expression of adipogenic and fibrogeneic genes, resulting in the hallmark pathologic correlate of fibrofatty replacement of muscle tissue.  
• The fibrofatty scar tissue that replaces the myocardium slows conduction and allows for formation of macro-entry circuits that lead to the propagation of arrythmias. Furthermore, dysregulation of otherwise synchronized excitability due to abnormal cellular connections increase propensity for fatal arrhythmias. 

1. What EKG findings may be seen in ARVC? 

• EKG is an important tool in screening since 85-90% of patients will have at least one of the findings of ARVC. However, it is important to remember that the findings may evolve over time, including a normal ECG at presentation and thus serial re-assessment is crucial.  
• ECG changes include inverted T-waves in the right precordial leads, which have been correlated with RV enlargement and risk for ventricular arrhythmias. T wave inversions (TWI) are present in up to 87% of adult patients with ARVC, but can be especially challenging to interpret in athletes who may have TWIs as normal variants in 5% of white athletes and 25% of black athletes. The preceding ST-segment may provide a clue as to whether the TWI is abnormal, as ARVC patients with precordial TWI often have an isoelectric ST-segment while athletes have preceding convex ST-segment elevation.  
• Other findings include: 
  •  (1) prolonged S-wave upstroke (≥55 milliseconds) in the absence of a RBBB (~90% of patients w/o a RBBB) 
  • (2) Epsilon wave (~ 5 to 30% of patients) which is a distinct positive deflection at the end of the QRS complex best seen in V1 and/or V2 reflecting delayed activation of some parts to of the RV. Fontaine bipolar precordial leads (repositioning of the limb leads) may help increase the sensitivity for detecting epsilon waves.  
  • Isoproterenol infusion can be used to induce ventricular arrhythmias in suspected patients 

1. How can we diagnose ARVC? 

• In the “concealed phase,” patients are often asymptomatic but are still at risk of sudden cardiac death, especially during exertion. Furthermore, in the early stages of disease, structural changes may be subtle (or even absent) and confined to a focal area of the RV. 
• In the “electrical phase,” patients can present with symptomatic ventricular arrhythmias and RV structural abnormalities that are detected by cardiac imaging. Sports and rigorous exercise increase risk of SCD and contribute to disease progression. Common first symptoms are palpitations and effort-induced syncope, though SCD can also be the first presentation. In the later stages, diffuse disease is possible with biventricular heart failure. 
• In patients in whom there is a clinical suspicion for ARVC (e.g., positive family history, exercise-induced palpitations, unexplained right precordial TWI, patients who present with unexplained ventricular arrhythmias, and/or SCD), the diagnosis frequently requires multiple diagnostic tests.  
• The 2010 revised Task Force Criteria is used to confirm the diagnosis of ARVC, though proposed changes continue to arise as our understanding of ARVC evolves. The criteria require a demonstration of structural, functional, and electrophysiological abnormalities that reflect underlying histological changes. Thus, the criteria include parameters defining  (1) global and/or regional dysfunction and structural changes; (2) tissue characterization of the walls; (3) repolarization abnormalities on ECG; (4) depolarization/conduction abnormalities on ECG; (5) arrhythmias; and (6) family history.  
• Criteria for diagnosis is based on meeting two major, one major and two minor, or four minor criteria. Cardiac MRI is the preferred imaging tool because it can quantitatively assess phenotypic structural and functional abnormalities such as global dilatation and/or systolic akinesia/dyskinesia. In suspected ARVC, late gadolinium enhancement can represent fibrofatty infiltration.  
• It is important to note that endomyocardial biopsy is not indicated as routine testing, but may be considered to aid in securing a diagnosis amongst competing diagnoses. 

1. How is ARVC managed? 

• In patients with suspected and/or confirmed ARVC, there are 5 pillars of management: 
  1. Prevent sudden cardiac death. 
  2. Reduce arrhythmia burden to improve quality of life. 
  3. Treat the ensuing heart failure. 
  4. Screen and protect the family members. 
  5. Develop disease modification therapies (stay tuned!) 
•  Patients with ARVC should not participate in competitive, endurance or high-intensity non-competitive sports due to the association with disease progression and ventricular arrhythmias.  
• Beta-blockers are a critical component of treatment for all symptomatic ARVC patients and is a Grade 2C recommendation to include them as part of treatment for patients without history of sudden cardiac arrest or documented ventricular arrhythmias, as well. There is unclear benefit in asymptomatic genetic carriers. 
• Patients who have suffered a sudden cardiac arrest (i.e., aborted sudden cardiac death) or who have experienced sustained VT which was hemodynamically unstable, secondary prevention ICD implantation is recommended in addition to medical therapy (Grade 1B recommendation). Further, in ARVC patients with suspected arrhythmogenic syncope, moderate to severe RV or LV dysfunction, frequent PVCs and/or NSVT, multiple disease-causing mutations, and/or inducible VT on EP study, ICD implantation for primary prevention is recommended (Grade 2C). For patients with frequent ICD discharges, antiarrhythmic medications are preferred initially over catheter radiofrequency ablation (RFA). RFA can be utilized but due to the patchy and progressive nature of the disease it is often unsuccessful in completely suppressing ventricular arrhythmias.  
• Patients with clinical right, left, or bi-ventricular failure are treated with standard guideline directed pharmacotherapy. For those with refractory arrythmias or end-stage heart failure, cardiac transplant is the curative treatment. Given the typical RV-predominant heart failure, options for durable mechanical circulatory support are limited. 
• Mutation-specific genetic testing is recommended for family members in order to identify and follow affected patients in the pre-clinical phase.  

References

Corrado, Domenico, Mark S. Link, and Hugh Calkins. “Arrhythmogenic Right Ventricular Cardiomyopathy.” New England Journal of Medicine 376, no. 1 (January 5, 2017): 61–72. https://doi.org/10.1056/NEJMra1509267. 

Corrado, Domenico, Peter J. van Tintelen, William J. McKenna, Richard N. W. Hauer, Aris Anastastakis, Angeliki Asimaki, Cristina Basso, et al. “Arrhythmogenic Right Ventricular Cardiomyopathy: Evaluation of the Current Diagnostic Criteria and Differential Diagnosis.” European Heart Journal 41, no. 14 (April 7, 2020): 1414–29. https://doi.org/10.1093/eurheartj/ehz669. 

Gandjbakhch, Estelle, Alban Redheuil, Françoise Pousset, Philippe Charron, and Robert Frank. “Clinical Diagnosis, Imaging, and Genetics of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: JACC State-of-the-Art Review.” Journal of the American College of Cardiology 72, no. 7 (August 14, 2018): 784–804. https://doi.org/10.1016/j.jacc.2018.05.065. 

The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus.

We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director.

• Bibin Varghese, MD
• Rick Ferraro, MD
• Tommy Das, MD
• Eunice Dugan, MD
• Evelyn Song, MD
• Colin Blumenthal, MD
• Karan Desai, MD
• Amit Goyal, MD
• Daniel Ambinder, MD

CardioNerds (Amit Goyal & Daniel Ambinder) join Scripps cardiology fellows (Christine Shen and Andrew Cheng) for some Cardiology and California Burritos in San Diego! They discuss an informative case of Wet Beriberi and Stiff Left Atrial Syndrome. Dr. Thomas Heywood provides the E-CPR and program director Dr. Malhar Patel provides a message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident Tommy Das with mentorship from University of Maryland cardiology fellow Karan Desai.

Jump to: Patient summary – Case media – Case teaching – References

The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus.

We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director.

CardioNerds Case Reports Page
CardioNerds Episode Page
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Support our educational mission by becoming a Patron!
Cardiology Programs Twitter Group created by Dr. Nosheen Reza

A woman in her mid-60s with history of rheumatic mitral stenosis s/p mechanical mitral valve replacement, HFpEF, and paroxysmal atrial fibrillation s/p ablation presents with subacute worsening dyspnea despite escalating diuretic doses. TTE shows an EF of 62%, normal gradients across the mitral valve without mitral regurgitation, and a dilated IVC. She is admitted with a presumed diagnosis of decompensated heart failure, and started given IV furosemide. Her symptoms slightly improve though do not resolve, and her creatinine increases from 1.4 to 2.1.  

In light of the unclear hemodynamic picture, a RHC is done, showing a RA pressure 9, RV pressure of 80/10, PAP 70/25 with mPAP 40, PCWP 30, SVR 872, CO 11 (by thermodilution), and CI 5.2. Notably, large V waves are noted on the RHC. Given concern for mitral regurgitation in the setting of large V waves, a TEE was pursued, which confirmed the lack of MR seen on TTE. Thus, her large V waves were felt to be due to stiff left atrial syndrome, and a cardiac CT showed a severely calcified “coconut left atrium”. Labwork revealed a profoundly low thiamine level (21, with LLN of 70), raising concern for wet beri beri syndrome.  

The patient’s unifying diagnosis was indolent left atrial syndrome that was exacerbated by high outout heart failure due to Wet Beri Beri syndrome. The patient received thiamine supplementation, and was diuresed to euvolemia with dramatic improvement in symptoms. A repeat RHC after thiamine replacement showed a CO of 5.7 and CI of 2.74 by thermodilution, demonstrating resolution of her high output heart failure.  

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A. CXR
B. ECG
C. RHC: large V waves are noted on the RHC
D. CO 11 and CI 5.2 by thermodilution pre-treatment
E. Cardiac CT showed a severely calcified “coconut left atrium”
F. Repeat CO of 5.7 and CI of 2.74 by thermodilution after thiamine replacement

1) This case featured a patient with Stiff Left Atrial Syndrome! Cardionerds, what the heck is that?  

• Stiff Left Atrial Syndrome (SLAS) is fundamentally a disorder of atrial compliance, wherein a non-compliant left atrium (LA) leads to abnormal atrial diastole. During LV systole (atrial diastole), the LA receives blood from the low-resistance pulmonary veins. Under normal conditions, the LA pressures initially fall (x-descent). Then, as the atrium fills from both RV contraction and passive filling from the pulmonary veins, there is a steady and modest rise in LA pressure (v-wave). In patients with decreased LA compliance, the V-wave may be accentuated.  
• In SLAS, left atrial compliance is significantly decreased, leading to very large v-waves that reflect the inability to accommodate LA filling and the steepened slope of the pressure-volume curve (see the below diagram from Urey et al). This leads to dramatically increased LA pressures during LV systole (especially in late LV systole), contributing to post-capillary pulmonary hypertension over time and symptoms of dyspnea on exertion.  

2) Which patients are at risk of developing SLAS, how is it diagnosed, and how is it managed?  

• Stiff Left Atrial Syndrome was first described in the late 1980s as a complication of mitral valve surgery, and has been increasingly recognized as a complication of left atrial ablation procedures leading to atrial fibrosis. While the condition is relatively rare (occurring in ~1.4% of patients following ablation), significant heart failure symptoms and pulmonary hypertension can develop.  
• While no diagnostic criteria exist, SLAS should be considered in patients with HFpEF, a small or calcified LA on imaging, and risk factors including mitral valve surgery and/or prior left atrial ablations. Invasive hemodynamics will show large v-waves in the absence of mitral regurgitation (or disproportionate to the degree of MR) and an elevated PCWP out of proportion to the LVEDP. It is important to exclude pulmonary vein stenosis, another potential complication of ablation.  
• Management consists primarily of diuretics and reducing ventricular afterload as tolerated, though an intra-atrial septostomy could be considered in refractory cases.  
• Notably, SLAS may be asymptomatic in many patients due to the compliance of the pulmonary venous vascular system, which can store blood volume without significant increases in pressure. However, this compliance could become overwhelmed in certain stressed states or exercise. 

3) Our patient experienced a stressor in the form of high output heart failure; what is the pathophysiology of high output heart failure, and what is your differential for high output heart failure? 

• While a number of causes for high output heart failure exist, they share an underlying pathophysiology of excessively decreased systemic vascular resistance and increased metabolic demand. The persistently low SVR leads to decreased ventricular afterload, increased LV emptying and thus increased stroke volume and cardiac output. This subsequently leads to increased preload and symptoms of congestive heart failure. Furthermore, increased oxygen demands requires increased cardiac output. Additionally, the persistently low SVR causes low renal perfusion pressure (renal hypoperfusion) which leads to RAAS activation and volume expansion 
• Diagnosis is based on echocardiographic evaluation, RHC hemodynamics, and an identified cause of a high output state. TTE may show normal or reduced ejection fraction; additional findings may include a dilated IVC, RV enlargement or dysfunction, elevated estimated pulmonary artery pressures, and/or LV enlargement. RHC typically shows a CO > 8 L/min or a CI > 4 L/min/m2, though these cutoffs are not absolute.  
• The differential for high output heart failure includes etiologies secondary to predominantly low SVR (e.g., obesity, cirrhosis, AV fistula) versus those secondary to increased metabolic drive (e.g., hyperthyroidism, myeloproliferative disorders). See the CNCR episode from the Johns Hopkins Hospital for more details!  

4) How does thiamine deficiency lead to high output heart failure?  

• Thiamine is vital to aerobic metabolism in the Krebs cycle and the Pentose Phosphate Pathway. In states of thiamine deficiency, anaerobic metabolism is favored over aerobic metabolism, leading to increased levels of lactate and pyruvate. This leads to a decrease in adenosine triphosphate (ATP) and increase in adenosine monophosphate (AMP), which is released into skeletal muscle as adenosine. This release of adenosine leads to vasodilation and decreased systemic vascular resistance through shunt physiology. 
• Arterial hypoperfusion of the kidneys leads to activation of the RAAS and expansion of plasma volume. Increased oxygen demand lead to an increased cardiac output. 
• Importantly, CO by thermodilution and Fick may be discrepant in Beriberi! This is because mitochondria are unable to utilize O2 by performing aerobic metabolism. Thus, less oxygen is extracted from the blood, and venous oxygen saturations will be relatively elevated. This may leads to an erroneously elevated CO by Fick’s method as compared to thermodilution! 

5) Lets bring it all together! Cardionerds, what is your illness script for Beriberi?  

• Pathophysiology: As detailed above, thiamine deficiency causes an increase in anaerobic metabolism, increased oxygen demand and systemic vasodilation through increased adenosine levels.  
• Epidemiology: Patient populations at risk for severe thiamine deficiency include patients with severe malnutrition, chronic alcohol use, incarceration, social isolation, refugee populations, history of bariatric surgery, or chronic loop diuretic use. Notably, 90% of patients on diuretics can develop some level of thiamine deficiency. 
• Signs/Symptoms: “Dry” beriberi involves symmetrical peripheral neuropathy, primarily in the distal extremities. “Wet” beriberi is characterized by high output heart failure and can lead to shock in severe cases.  
• Diagnosis: Thiamine deficiency is difficult to diagnose. Blood thiamine levels can be low in acute illness and do not reflect total body stores. Erythrocyte transketolase activity and thiamine pyrophosphate effect tests can be used, though these tests have poor specificity and sensitivity. The gold standard is high performance liquid chromatography, though access to this test is expensive and not commonly available.  
  • As a historical note, in 1945, Marion Blankenford developed diagnostic criteria for wet beriberi, which includes evidence of an enlarged heart with normal rhythm, dependent edema, elevated venous pressure, peripheral neuritis or pellagra, nonspecific alternans on ECG, no evidence of other cardiac disease, at least 3 months of thiamine deficiency, and improvement in symptoms and reduction in heart size following thiamine replacement.  
• Treatment: The cornerstone of wet beriberi management is supportive treatment of heart failure while replacing thiamine stores. A rapid and dramatic improvement following thiamine replacement is diagnostic of wet beriberi.  

References

• Bisbal, F., Baranchuk, A., Braunwald, E., et al. (2020). Atrial Failure as a Clinical Entity: JACC Review Topic of the Week. Journal of the American College of Cardiology, 75(2), 222–232.  
• Gibson, D. N., Di Biase, L., Mohanty, P., Patel, J. D., Bai, R., Sanchez, J., Burkhardt, J. D., Heywood, J. T., Johnson, A. D., Rubenson, D. S., Horton, R., et al. (2011). Stiff left atrial syndrome after catheter ablation for atrial fibrillation: clinical characterization, prevalence, and predictors. Heart rhythm, 8(9), 1364–1371.  
• Maeder, M. T., Nägele, R., Rohner, P., & Weilenmann, D. (2018). Pulmonary hypertension in stiff left atrial syndrome: pathogenesis and treatment in one. ESC heart failure, 5(1), 189–192.  
• Urey, M. A., Darden, D., Stoller, D., et al. (2017). Stiff Left Atrial Syndrome After Multiple Percutaneous Catheter Ablations: Role for Invasive Hemodynamic Exercise Testing. Circulation. Heart failure, 10(5), e003885.  
• Durstenfeld, M. S., & Hsue, P. Y. (2020). An Unusual, Reversible Cause of Acute High-Output Heart Failure Complicated by Refractory Shock. Circulation, 142(9), 901–905.  
• Reddy, Y., Melenovsky, V., Redfield, M. M., Nishimura, R. A., et al. (2016). High-Output Heart Failure: A 15-Year Experience. Journal of the American College of Cardiology, 68(5), 473–482.  

• Bibin Varghese, MD
• Rick Ferraro, MD
• Tommy Das, MD
• Eunice Dugan, MD
• Evelyn Song, MD
• Colin Blumenthal, MD
• Karan Desai, MD
• Amit Goyal, MD
• Daniel Ambinder, MD

CardioNerds (Amit Goyal & Karan Desai) join University Hospitals Cleveland Medical Center cardiology fellows (Tarek Chami, Jamal Hajjari, and Haytham Mously) for some amazing pizza and coffee in Cleveland, Ohio! They discuss an important case of effusive constrictive pericarditis. Dr. Brian Hoit provides the E-CPR and assistant program director Dr. Claire Sullivan provides a message for applicants. We are grateful to chief fellow Scott Janus for his leadership in planning this episode! Episode notes were developed by Johns Hopkins internal medicine resident Colin Blumenthal with mentorship from University of Maryland cardiology fellow Karan Desai.

Jump to: Patient summary – Case media – Case teaching – References

The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus.

We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director.

CardioNerds Case Reports Page
CardioNerds Episode Page
CardioNerds Academy
Subscribe to our newsletter- The Heartbeat
Support our educational mission by becoming a Patron!
Cardiology Programs Twitter Group created by Dr. Nosheen Reza

A woman in her mid-70s presented to clinic with subacute onset shortness of breath. Her past medical history includes metastatic breast cancer s/p mastectomy, chemo/radiation, and hormonal therapy. Exam notable for tachycardia without hypoxia, muffled heart sounds, JVD with Kussmaul’s sign, and 1+ LE edema. The patient was sent to the ED for evaluation of possible pericardial effusion. CTA chest in ED did not demonstrate a PE, but did show bilateral pleural effusions, and a moderate pericardial effusion with evidence of metastatic disease extending into the mediastinum. TTE obtained showing normal LVEF, moderate pericardial effusion with thickened pericardium, and significant respirophasic tricuspid and mitral inflow variations. Pulsus paradoxus was manually checked and found to be 16 mmHg. 

Due to concern for cardiac tamponade, she was taken to the cath lab for a RHC and pericardiocentesis. RHC prior to pericardiocentesis showed elevated left and ride sided filling pressures, blunted y decent in the RA, and equalization of diastolic pressures. Pericardiocentesis yielded 200 cc of bloody fluid with improvement, but continued elevation, in her L and R sided pressures. Blunted y decent did give way to a now rapid y descent concerning for constrictive pericarditis. She then underwent a cardiac MRI showing respirophasic septal motion suggestive of interventricular dependence and >1 cm thick pericardium with LGE c/w inflammation. Unfortunately, cytology of pericardial fluid was c/w a malignant effusion and despite treatment with a few months of anti-inflammatory therapy her symptoms did not improve. She then underwent a pericardial stripping with subsequent resolution of her symptoms. As her symptoms and hemodynamics were related to both the effusion and constriction, she was ultimately diagnosed with effusive constrictive pericarditis. 

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A. ECG
B. CXR
C-F. TTE (inflow velocities (mitral and tricuspid), IVC sniff test
G-L: Right heart catheterization tracings
M-N: Post pericardiocentesis TTE: Tissue Doppler
O: Cardiac MRI

1. What is cardiac tamponade, what causes it, and how does it lead to hypotension? 
   • The pericardial cavity typically holds 50 cc of fluid, which acts as a lubricant for the beating heart. Accumulation of additional fluid in this space can increase intrapericardial pressure and cause compression of the cardiac chambers. Rapid accumulation of small amounts of fluid can lead to tamponade as the pericardium will not have time to expand. In instances of a slow accumulation, large volumes might accumulate before tamponade occurs as the pericardium will expand to accommodate the fluid. 
   • Many conditions can cause tamponade. The most common are malignancy (>50% of all cases), infection (viral most common, though TB is common in developing countries), trauma/post procedural (e.g. cardiac surgery, pacemaker placement), uremia, rheumatologic (e.g. SLE, RA), drug induced (e.g. hydralazine, procainamide), and radiation-induced. Note the epidemiology is different from causes of pericarditis without tamponade. 
   • Increasing pericardial pressure leads to a compensatory increase in diastolic pressure in all chambers until they become similar to the pericardial pressure. This happens more rapidly in the right side of the heart due to lower diastolic pressures in these chambers. The elevated intracardiac diastolic pressures reduces the driving pressure for filling (Flow = pressure gradient / resistance and so ↓∆P = ↓Flow ); this reduces diastolic filling (preload) and a causes a compensatory increase in contractility and heart rate to maintain stroke volume and cardiac output (CO = HR x SV so as SV decreases, the HR increases). As diastolic filling continues to decrease the transmural distending pressure of the RA and RV will also decrease and eventually lead to diastolic collapse.  
   • As reviewed in previous posts (Mayo and Tennessee), as ventricular interdependence worsens, left ventricular cardiac output can be further compromised and contribute to hypotension. Enjoy Episodes #58 and #59 discussing constrictive pericarditis. 
     
2. Tamponade can be a difficult clinical diagnosis. How is it diagnosed, what are some of the basic clinical markers of cardiac tamponade, and which are most useful in diagnosis? 
   • Though definitive diagnosis requires pericardiocentesis with hemodynamic and clinical improvement, there are many features that are useful for identifying tamponade. Unfortunately, no one clinical or echocardiographic feature is diagnostic of tamponade and a clinical diagnosis relies on the assimilation of multiple abnormalities. 
   • Beck’s triad of hypotension, jugular venous distension, and muffled heart sounds 
     • Originally described in 1935 by Dr. Claude Beck, it focuses on these signs of tamponade, which were derived from surgical patients and are more characteristic of acute tamponade from trauma or cardiac/aortic rupture. Though ~90% of patients in trauma series have at least one of these findings, only about ~30% have all three. Muffled heart sounds and hypotension are both poorly sensitive findings, making the sensitivity of the overall triad poor. 
   • Tachycardia 
     • Though not specific, tachycardia is a very sensitive marker of cardiac tamponade as in some series it is present in 81-100% of patients with a pooled sensitivity of around 80%. 
   • Elevated JVP 
     • Elevated JVP is one of the key findings in tamponade and is present in almost all cases. Increased early diastolic pressure limits filling during this period, blunting the y descent. Studies show sensitivity ranges from 53-88% with a pooled average of 75%.  
   • Kussmaul’s sign 
     • Kussmaul’s sign is the failure of the JVP to fall during inspiration. This is rarely seen in cardiac tamponade; it is much more common in constrictive pericarditis, where it can be seen in up to 50% of cases. 
   • EKG findings of low voltage or electrical alternans  
     • As fluid builds around the heart it can insulate the heart’s electrical activity from the EKG leads leading to low voltage on the EKG. Additionally, as the heart oscillates within the distended pericardial sack, the QRS amplitude can oscillate, which is called electrical alternans. As low voltage can be seen in a variety of conditions it is poorly specific, but sensitivity is around 70%. Electrical alternans on the other hand is rarely seen in tamponade, but if present it has a PPV > 95%. 
   • Enlarged cardiac silhouette on CXR 
     • The cardiac silhouette on a CXR does not appear enlarged until a pericardial effusion is around 200 mL. Given that many conditions also cause an enlarged silhouette it has both poor sensitivity and specificity. 
       
3. What is a pulsus paradoxus and what is the pathophysiology? How do you measure it and how clinically useful is it in the diagnosis of tamponade? What conditions might cause it to be absent in tamponade? 
   • In a normal heart, inspiration decreases intrathoracic pressure, thus increasing right-sided filling. As the RV stretches to accommodate the volume, the interventricular septum bulges towards the left causing reduced left-sided filling and therefore a drop in blood pressure (this is ventricular interdependence). During expiration the opposite happens and the blood pressure increases. This process is exaggerated in cardiac tamponade as both ventricles are completing for a limited amount of space, which leads to a larger than normal drop in blood pressure during inspiration. This exaggerated drop is called pulsus paradoxus (though pulsus exaggeratus may be a better name!).  
   • Pulsus paradoxus can be measured with a blood pressure cuff while a patient is breathing normally.  First the cuff is inflated until no Korotkoff sounds can be heard and then slowly deflated until Korotkoff sounds can only be heard during expiration (say 120 mmHg). The cuff is further deflated until sounds can be heard throughout the respiratory cycle (say 100 mmHg). If the difference in these two numbers (here 20 mmHg) is ≥ 10 mmHg it is deemed a clinically significant pulsus paradoxus. 
   • Pulsus paradoxus is an important finding in cardiac tamponade as a pulsus > 10 mmHg occurs in almost all patients with tamponade. A cutoff of 12 mmHg improves specificity and is 98% sensitive and 83% specific in patients with a known pericardial effusion. 
   • There are a few situations where a patient might be in tamponade, but might not have pulsus paradoxus. They include extreme hypotension, low pressure tamponade (e.g., dehydration), atrial septal defects, severe AI, loculated/local effusions, and a very poorly compliant LV or RV. 
   • Pulsus can also be present in patients without pericardial disease, including (but not limited to) patients with COPD or asthma, obstructive sleep apnea, and significant obesity.  
     
4. What are the signs of cardiac tamponade on echo and RHC? 
   • Echocardiography is the primary imaging modality to evaluate for signs of tamponade. Consistent with the previously described pathophysiology, signs of tamponade on TTE include early diastolic collapse of the RV free wall, diastolic collapse of the RA, swinging of the heart in the pericardial sac, dilated IVC without collapse, a >60% increase in TV flow and >30% decrease in MV flow during inspiration (more specific for tamponade than the cut-offs of 40% and 25% seen in constriction), and septal deviation into the LV with inspiration. Remember to differentiate the size and composition of the effusion. Of these findings early diastolic collapse of the RV free wall is most specific and dilation of the IVC, and late diastolic collapse of the RA are most sensitive.  
   • Though RHC is not routinely performed for the diagnosis of tamponade, there are a few key findings that are relevant. As discussed above, equalization of diastolic pressures, pulsus paradoxus, and pulsus alternans can all be seen on the pressure tracings and measurements in a RHC. Additionally, the RA waveform can show a blunted y descent as discussed above. 
     
5. What is effusive constrictive pericarditis (ECP) and how does one differentiate it from tamponade or constrictive pericarditis? How is it treated? 
   • Effusive constrictive pericarditis is a clinical entity comprised of both decreased pericardial compliance and a hemodynamically significant pericardial effusion. This is often found when patients undergo pericardiocentesis for suspected tamponade only to reveal continued elevation in RA pressures and constrictive physiology. Some use a cut-off of a failure to fall by 50% or to less than 10 mmHg in the RA.  
   • Though ECP can initially present with some signs of constriction (elevated medial e’ velocities) true constrictive pericarditis should not have signs of a hemodynamically significant effusion (RA/RV diastolic collapse, blunted y descent) and is much less likely to have pulsus paradoxus. 
   • Though there is no uniform consensus on how to treat ECP, it is generally agreed that anti-inflammatory medications are first line. The decision to use NSAIDs or steroids ± colchicine is provider dependent. Prolonged anti-inflammatory therapy may be necessary and escalation versus de-escalation should be guided by symptoms, inflammatory markers, and possibly cardiac MRI. For patients with symptoms refractory to anti-inflammatory medications, pericardiectomy is recommended. Note in effusive-constrictive pericarditis, there tends to be extensive involvement of the visceral pericardium, which requires epicardiectomy, and may need a specialized center.  

References

1. Adler, Y., Charron, P., Imazio, M., Badano, L., Barón-Esquivias, G., Bogaert, J., Brucato, A., Gueret, P., Klingel, K., Lionis, C., Maisch, B., Mayosi, B., Pavie, A., Ristić, A. D., Sabaté Tenas, M., Seferovic, P., Swedberg, K., Tomkowski, W., Group, E. S. D., … Nesukay, E. (2015). 2015 ESC Guidelines for the diagnosis and management of pericardial diseasesThe Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC)Endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS). European Heart Journal, 36(42), 2921–2964. 
2. Ang, K. P., Nordin, R. B., Lee, S. C. Y., Lee, C. Y., & Lu, H. T. (2019). Diagnostic value of electrocardiogram in cardiac tamponade. The Medical Journal of Malaysia, 74(1), 51–56. 
3. Ariyarajah, V., & Spodick, D. H. (2007). Cardiac Tamponade Revisited. Texas Heart Institute Journal, 34(3), 347–351. 
4. Ayan, M., Siraj, A., & Bhatti, S. (2018). Effusive Constrictive Pericarditis. Journal of the American College of Cardiology, 71(11 Supplement), A2383. 
5. BECK, C. S. (1935). TWO CARDIAC COMPRESSION TRIADS. Journal of the American Medical Association, 104(9), 714–716. 
6. Chiabrando, J. G., Bonaventura, A., Vecchié, A., Wohlford, G. F., Mauro, A. G., Jordan, J. H., Grizzard, J. D., Montecucco, F., Berrocal, D. H., Brucato, A., Imazio, M., & Abbate, A. (2020). Management of Acute and Recurrent Pericarditis: JACC State-of-the-Art Review. Journal of the American College of Cardiology, 75(1), 76–92. 
7. Effusive-Constrictive Pericarditis: Maybe Not as Rare and as Bad as We Thought. (n.d.). American College of Cardiology. Retrieved October 13, 2020, from https://www.acc.org/latest-in-cardiology/articles/2019/04/08/10/42/effusive-constrictive-pericarditis
8. Fowler, N. O. (1993). Cardiac tamponade. A clinical or an echocardiographic diagnosis? Circulation, 87(5), 1738–1741. 
9. Guntheroth, W. G. (2007). Sensitivity and specificity of echocardiographic evidence of tamponade: Implications for ventricular interdependence and pulsus paradoxus. Pediatric Cardiology, 28(5), 358–362. 
10. Jesper K., Poulsen, Steen Hvitfeldt, & Mølgaard, Henning. (n.d.). Cardiac tamponade: A clinical challenge. Retrieved October 13, 2020, from https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-15/Cardiac-tamponade-a-clinical-challenge
11. Kearns, M. J., & Walley, K. R. (2018). Tamponade: Hemodynamic and Echocardiographic Diagnosis. Chest, 153(5), 1266–1275. 
12. Klein, A. L., Abbara, S., Agler, D. A., Appleton, C. P., Asher, C. R., Hoit, B., Hung, J., Garcia, M. J., Kronzon, I., Oh, J. K., Rodriguez, E. R., Schaff, H. V., Schoenhagen, P., Tan, C. D., & White, R. D. (2013). American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patients with pericardial disease: Endorsed by the Society for Cardiovascular Magnetic Resonance and Society of Cardiovascular Computed Tomography. Journal of the American Society of Echocardiography: Official Publication of the American Society of Echocardiography, 26(9), 965-1012.e15. https://doi.org/10.1016/j.echo.2013.06.023 
13. Little William C., & Freeman Gregory L. (2006). Pericardial Disease. Circulation, 113(12), 1622–1632. 
14. McGee, S. R. (2018). Evidence-based physical diagnosis (4th edition). Elsevier. 
15. Pérez-Casares, A., Cesar, S., Brunet-Garcia, L., & Sanchez-de-Toledo, J. (2017). Echocardiographic Evaluation of Pericardial Effusion and Cardiac Tamponade. Frontiers in Pediatrics, 5. 
16. Roy, C. L., Minor, M. A., Brookhart, M. A., & Choudhry, N. K. (2007). Does this patient with a pericardial effusion have cardiac tamponade? JAMA, 297(16), 1810–1818. 
17. Spodick, D. H. (2003). Acute cardiac tamponade. The New England Journal of Medicine, 349(7), 684–690. 
18. Stashko, E., & Meer, J. M. (2020). Cardiac Tamponade. In StatPearls. StatPearls Publishing. 
19. Swami, A., & Spodick, D. H. (2003). Pulsus paradoxus in cardiac tamponade: A pathophysiologic continuum. Clinical Cardiology, 26(5), 215–217. 

• Bibin Varghese, MD
• Rick Ferraro, MD
• Tommy Das, MD
• Eunice Dugan, MD
• Evelyn Song, MD
• Colin Blumenthal, MD
• Karan Desai, MD
• Amit Goyal, MD
• Daniel Ambinder, MD

CardioNerds (Amit Goyal & Daniel Ambinder) join University of Michigan cardiology fellows (Apu Chakrabarti, Jessica Guidi, and Amrish Deshmukh) for some craft brews in Ann Arbor! They discuss a challenging case of Ventricular Septal Rupture after acute MI. Dr. Kim Eagle, editor of ACC.org & host of Eagle’s Eye View Podcast, and Dr. Devraj Sukul provide the E-CPR and message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident, Eunice Dugan, with mentorship from University of Maryland cardiology fellow Karan Desai.  

Jump to: Patient summary – Case media – Case teaching – References

The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus.

We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director.

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A male in his 60s with medical history of obesity and GERD presents with five days of progressive chest pressure radiating to bilateral arms and associated with dyspnea on exertion. Due to worsening chest pain with new lightheadedness, he decided to come to the ED. His presentation to the hospital was delayed due to fear of contracting COVID-19. In the ED, patient was afebrile, blood pressure 96/56, HR 137, RR 22, and oxygen saturation 94% on room air. On exam, he was ill appearing, acutely distressed, and altered. He had a 3/6 mid systolic murmur loudest at L sternal border, JVP to 10 cm H2O and had crackles up to mid-lung fields. His extremities were cool to touch. Labs notable for Cr 1.5, High-Sensitivity Troponin-T up to 5756, and lactate 3.9. EKG showed incomplete RBBB, PVCs, and ST elevations in the inferior leads with depressions in lateral and precordial leads. Coronary Angiography showed mid-RCA occlusion with faint L to right collaterals. He underwent PCI with restoration of TIMI 3 flow. After PCI, he continued to be hypotensive requiring IABP and norepinephrine. PA catheter demonstrated (in mmHg): RA 26, RV 63/29 (31), 55/36 (44), PCWP 29, and CO 5 L/min, CI 2.2, and SVR 467. Shunt run of mixed venous O2 saturation showed: SVC 71%, RA 72%, RV 62%, PA 85% with oxygen step up in the R-sided circuit. Left ventriculogram then confirmed septal rupture with contrast extravasation from LV into RV. Due to worsening shock, he was stabilized on VA ECMO which was complicated by hemolysis and acute renal failure requiring CVVHD. On day 7 after presentation, he underwent surgery which revealed a large 6×6 cm ventricular septal defect on the posterior aspect of the septum and repaired with a large bovine pericardial path. He was eventually discharged after a prolonged stay and repeat TTE on follow up showed biventricular dysfunction and residual 1cm VSD.  

• A
• B
• C
• D

A. ECG: Incomplete RBBB, PVCs, and ST elevations in the inferior leads with depressions in lateral and precordial leads.
B. Coronary angiography: mid-RCA occlusion with faint L to right collaterals.
C-D. A large (6x6cm) VSD was found at the posterobasal aspect of the septum.  Infarcted tissues were removed and a large bovine pericardial patch was used to repair the defect (due to the size of the defect, there was very little viable septum remaining and the patch had to be sewn directly into the LV and RV walls).

Classification and Management of Post-AMI VSR 

Why and in whom should we worry about VSR? 

• Ventricular Septal Rupture or VSR is rare in the era of early reperfusion strategies. Historical incidence of VSR after AMI was thought to be 1-2% and has decreased to between 0.17% and 0.3%. It can be attributed to early identification and restoration of flow in the infarct related artery (IRA). Although the incidence has decreased, the mortality remains high (41-80%). 
• Risk factors include older age, female sex, history of heart failure, and chronic kidney disease. If VSR does occur it tends to be in a patients presenting with their first MI with delayed, failed or no reperfusion therapy. The presence of collaterals is likely protective against developing VSR and reducing size of infarct.  

How do we recognize and diagnose VSR after AMI? 

• Abrupt hemodynamic compromise after revascularization or refractory shock with AMI should prompt suspicion for mechanical complications, including VSR. Note: some patients may be stable early in their course.  
• The classic presentation would be recurrent chest pain and hypotension several days after an MI, along with a new harsh holosystolic murmur usually best heard at the left lower sternal border sometimes accompanied by a thrill. Identifying this murmur requires a thorough baseline examination and frequent re-evaluation. Note, the absence of this murmur does not rule out VSR as the murmur may not be audible in a large VSR. 
• In terms of making the diagnosis of VSR, TTE is the starting point. The location of the VSR will likely depend on the infarct related artery (see below), but the two most common locations are basal inferoseptal and anteroapical septal walls. To identify the VSR it is critical to use color doppler in the area of interest and to lower the Nyquist limit to readily identify lower velocity flow with better definition.  
• TTE is also critical to define worsening pulmonary hypertension and/or left and right ventricular dysfunction as these are prognostic factors. When there are poor image quality and the defect cannot be readily identified, TEE may be necessary.  
• If a RHC is available, we can identify a left to right shunt via an oxygen step-up. Normal oxygen saturation in the RV is typically 64 to 68%. When there is an increase in oxygen saturation from RA to RV (or PA) of greater than 5% that can be suggestive of a VSR. Further, we can calculate the shunt fraction to quantify the extent of the shunt. 
• During a left heart catheterization, LV ventriculography can identify the VSR 

When does VSR occur post AMI and how does IRA relate to VSR location? 

• It is historically thought to occur between 3-6 days after AMI, however newer studies show earlier development with one study showing median time of 16 hours after AMI. This may be related to more awareness, increased access to echo, or a change in the presentation of VSR due to earlier reperfusion strategies. 
• The LAD and the RCA are the arteries most commonly implicated in the development of a VSD. Remember, anatomically, the LAD supplies the apical portion of the ventricular septum and the RCA gives posterior septal perforators that supply the basal inferoseptal wall. These areas are the most common locations for VSR after a transmural infarct as they are located at the border zone of a myocardial infarct.  
• Remember the defect can be simple or complex. A complex VSR is associated with multiple areas and various dissection planes that track along the myocardium.  

What is the pathophysiology and classification for VSR 

• We can classify VSR in 2 ways: the Becker and Mantgem system and simple vs. complex.  
• The Becker and Mantgem system was originally made for cardiac free wall rupture, but is also used for pathological classification of VSR. There are 3 mechanisms and pathophysiologic findings that correlate with temporal presentation. 
  • Type 1 : Occurs acutely (<24 hr) and are abrupt slit-like tear associated with infarcts without wall thinning. 
  • Type 2: Occurs sub-acutely (>24 hours) typically shows slow erosion of infarcted myocardium due to neutrophilic infiltration of ischemic/necrotic tissue 
  • Type 3:  Occurs late following an MI and after aneurysm formation and then subsequent rupture 
• In the simple vs. complex VSR classification, we classify VSR as simple if there is a direct connection between the LV and RV. Meanwhile, a complex VSR is a serpiginous connection (multiple planes) and more likely caused by hemorrhage. 

What are the goals of management and definitive therapy? 

• Surgical repair is the ideal definitive treatment, though mortality is very high. Patients with worse outcomes after surgery are female, older, RV dysfunction and have higher level of cardiac circulatory compromise.  
• Newly infarcted tissue is weak and friable, may not hold sutures well, and is prone to repeat defects. Successful repair requires complete debridement of necrotic tissue and sparing of healthy tissue which may be difficult to differentiate in the early stages after infarction. Surgical mortality appear to be higher with basal inferoseptal rupture associated with inferior MI, as these patients may need concomitant mitral valve repair as they often have ischemic MR as well 
• Timing of surgery is a complex issue and there are no clear guidelines for timing of surgery and therefore it is an individualized decision. Studies show that patients who were able to wait >7 days after VSR for repair had a lower mortality compared to <7 days likely due to improved cardiac tissue stability, but survival bias could play a major role here. Although the mortality with repair is high, non-surgical mortality is even higher. Patients who didn’t undergo surgery by day 30 had a 94% mortality rate.   
• While awaiting surgical repair, the goal of medical management is afterload reduction to reduce shunt fraction. This can be accomplished with IV medications (e.g., nitroprusside) or IABP. Other MCS as a bridge can be considered, including ECMO, Tandemheart, and total artificial heart. Percutaneous closure is an option as a bridge or definitive treatment for those with high surgical risk, but need to consider factors such as size of rupture and viable septal muscle.  
• Residual or recurrent VSR after surgical repair can be seen in up to 28% of surviving patients. If asymptomatic, it can be treated conservatively. However, in patients with clinical heart failure or Qp/Qs >2 (significant left to right shunt), repeat repair may improve outcomes. 

References

1. Birnbaum, Yochai, Michael C. Fishbein, Carlos Blanche, and Robert J. Siegel. “Ventricular Septal Rupture after Acute Myocardial Infarction.” New England Journal of Medicine 347, no. 18 (October 31, 2002): 1426–32.
2. Goyal, Amit, Menon, Venu. JACC Expert Analysis. Contemporary Management of Post-MI Ventricular Septal Rupture. July 2018. 
3. Jones, Brandon M., Samir R. Kapadia, Nicholas G. Smedira, Michael Robich, E. Murat Tuzcu, Venu Menon, and Amar Krishnaswamy. “Ventricular Septal Rupture Complicating Acute Myocardial Infarction: A Contemporary Review.” European Heart Journal 35, no. 31 (August 14, 2014): 2060–68.

• Bibin Varghese, MD
• Rick Ferraro, MD
• Tommy Das, MD
• Eunice Dugan, MD
• Evelyn Song, MD
• Colin Blumenthal, MD
• Karan Desai, MD
• Amit Goyal, MD
• Daniel Ambinder, MD

CardioNerds (Amit Goyal & Daniel Ambinder) join University of Connecticut (UCONN) cardiology fellows (Mansour Almnajam, Justice Oranefo, Yasir Adeel, and Srinivas Nadadur) as they enjoy the amazing view from the Heublein tower! They discuss a challenging case of left ventricular free wall rupture & pseudoaneurysm as a complication of a STEMI. Dr. Peter Robinson provides the E-CPR and program director Dr. Joyce Meng provides a message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident Bibin Varghese with mentorship from University of Maryland cardiology fellow Karan Desai.   

Jump to: Patient summary – Case media – Case teaching – References

The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus.

We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director.

CardioNerds Case Reports Page
CardioNerds Episode Page
CardioNerds Academy
Subscribe to our newsletter- The Heartbeat
Support our educational mission by becoming a Patron!
Cardiology Programs Twitter Group created by Dr. Nosheen Reza

A man in his mid 50s with no significant PMH presented with a 10-day history of chest pain that progressed to acute pleuritic pain and shortness of breath in the past 24 hours. On arrival, he was hypothermic, in rapid atrial fibrillation with HR in the 130-150s, and an initial BP was not able to be obtained. He was tachypneic with labored breathing, lethargic, and cyanotic. Exam revealed markedly elevated JVP, cool extremities, and diminished breath sounds with bibasilar rales. Labs demonstrated leukocytosis, significantly elevated liver enzymes, troponin-I at 10.91, elevated NT-proBNP, and lactate at 6. ECG demonstrated tall, broad R-waves in V1-V4 with downsloping STD and upright T-waves concerning for a posterior infarct. He was immediately intubated, cardioverted into NSR, and started on vasopressors. Bedside echocardiogram demonstrated diffuse LV hypokinesis with akinesis of the inferolateral wall, LVEF 25-30%, and pericardial fluid with hyperechoic material adherent to the inferior wall as well as tamponade physiology. Chest CTA was negative for aortic dissection and confirmed hemopericardium. He was taken to the OR where he underwent a subxiphoid pericardial window. They found significant clot burden (both old and new), but no frank rupture. Adherent clot was not removed to prevent further hemodynamic compromise. Intraoperative TEE additionally demonstrated severe eccentric MR with partial posteromedial papillary muscle rupture. An IABP was placed and inotropic and vasoactive support was continued to temporize pending definitive therapy and the patient improved hemodynamically. Repeat TTE prior to surgery demonstrated a large apical and inferolateral pseudoaneurysm. Coronary angiogram revealed proximal occlusion of the LCx and diffuse three vessel coronary disease otherwise. He ultimately underwent CABG, mechanical mitral valve replacement, and pericardial patch repair of the ventricular pseudoaneurysm. Final diagnosis: Free Wall Rupture & Pseudoaneurysm. Thankfully, the patient ultimately made a complete recovery!  

• A
• B
• C
• D
• E
• F

A. ECG: tall, broad R-waves in V1-V4 with downsloping STD and upright T-waves
B. CXR
C. CT angiogram thoracic aorta: Moderate sized hemopericardium with tamponade physiology. Transmural infarction of LV base to mid inferior wall. Circumflex occlusion just beyond the first obtuse marginal. Normal aorta without dissection or aneurysm.
D-F. Coronary angiogram: LCx is occluded proximally, distal vessel fills via faint collaterals from the right, OM1: Fills via right to left collaterals. LAD: 70%, mid; 90%, apical, 1st diagonal: 50%, ostial; 60-70%, proximal; 90% of inferior subdivision, bifurcating vessel. RCA: (Dominant); 50%, mid: 40%, distal. PDA: 60%, proximal, small-caliber vessel. PLV: 60-70%, proximal

1. This patient presented with EKG showing a posterior myocardial infarction. Why was he not taken to the cath lab immediately for revascularization? 
   • Duration of ischemia, its relationship to infarct size, and the mortality benefit from reperfusion therapies are crucially related to time in the very early course of STEMI. However, this relationship breaks down in patients presenting late after a STEMI. 
   • In OAT (Occluded Artery Trial), hemodynamically stable patients who presented late (3-28 days) after a myocardial infarction with high risk features (e.g., proximal LAD occlusion with TIMI 0 to 1 flow) were randomized to PCI + optimal medical therapy (OMT) within 24 hours or OMT alone. There was no difference in the primary endpoint of all-cause mortality, nonfatal MI, or NYHA class III to IV heart failure. These findings are reflected in the ACC/AHA guidelines, where delayed PCI of a totally occluded infract artery >24 hours after STEMI in hemodynamically and electrically stable patients is given a Class III recommendation (no benefit).  
   • Although the patient presented with EKG findings concerning for a posterior STEMI, this was likely 10 days after his acute insult. In addition, his hemodynamic instability and bedside POCUS raised the concern for a mechanical complication of a STEMI. In a patient with suspected mechanical complication of acute MI, such as free wall rupture and acute MR, the priority of therapy is to rapidly identify the mechanical problem and perform emergency surgical therapy. Furthermore, the need for antiplatelet therapy following any PCI would complicate surgical planning.  
   • PCI may be helpful in patients with ischemia induced papillary muscle dysfunction (“ischemic MR”). However there is no role for immediate PCI when the mechanical integrity of the mitral valve has been compromised. 
     
2. This patient presented with hemodynamic instability and bedside POCUS revealed pericardial fluid with tamponade physiology. What are some causes of acute hemorrhagic pericardial effusion? 
   • When thinking about hemorrhagic pericardial effusions, expedited evaluation is critical. While there is overlap with traditional causes of pericardial effusion, some causes may need immediate intervention. Amongst these considerations are iatrogenic complication of cardiac surgery, cardiac catheterization, or electrophysiologic procedures. Other etiologies include complications of myocardial infarction including free wall rupture/pseudoaneurysm, complication of aortic dissection, and trauma. As with serous pericardial effusions, malignancy should remain on the differential, as well as tuberculosis in endemic areas.  
     
3. A CTA of the aorta ruled out dissection but showed a moderate sized hemopericardium raising concern for a mechanical complication of posterior MI, specifically a free wall rupture (FWR). What are the risk factors for a FWR after an MI? 
   • Ventricular free wall rupture is quite uncommon in the reperfusion era; however, if it does occur, mortality rates are high. FWR typically occurs acutely or sub-acutely, occurring within 2 weeks for 90% of patients. Risk factors include first myocardial infarction, poor collateralization of the infarcted territory, older age, female sex, persistent ST elevation and delayed presentation/unsuccessful revascularization. When patients present acutely, patients will typically develop tamponade, rapidly progress to pulseless electrical activity, and/or  sudden cardiac death. When patients develop subacute FWR or contained rupture (i.e., pseudoaneurysm), they may present with signs and symptoms of pericarditis and subacute hypotension. 
   • When FWR occurs, it typically involves the anterior, posterior, or lateral left ventricular wall. The pathophysiology of ventricular free wall rupture is related to the timing of the rupture. Rupture will typically occur at the border of the necrotic and healthy (and often hyperkinetic) myocardium and in areas of the greatest shear stress. In the left ventricle, this tends to be near the anterior and posterior papillary muscles, regardless if they are compromised in the infarct. 
   • Note, pericardial effusions can be a common finding in the setting of an acute MI (~15-25% of patients in the acute setting); however, a rapidly expanding pericardial effusion associated with significant wall thinning along the infarcted region should raise the suspicion for LV free wall rupture.  
     
4. The patient was stabilized after surgical evacuation of pericardial fluid in the OR. When should you consider pericardiocentesis vs surgical management? 
   • In cases of cardiac tamponade with concern for circulatory collapse there are no absolute contraindications to pericardiocentesis. The goal is urgent drainage of pericardial fluid and how we drain the fluid will depend on the etiology, acuity, and available providers. Emergent surgical management should generally be considered first line in patients with traumatic hemopericardium, aortic dissection related hemopericardium, or free wall rupture. In the setting of aortic dissection, controlled drainage of very small amounts of hemopericardium can be considered as a temporizing measure to maintain SBP > 90 mmHg. With purulent or loculated effusions, surgical drainage over pericardiocentesis may be the preference as well.  
   • Supportive measures include ensuring adequate preload, avoiding diuretics and/or vasodilator therapy, and inotropic and vasopressor therapy as needed.  
     
5. The patient was found to have a pseudoaneurysm rather than a frank free wall rupture. What is a pseudoaneurysm and how is it different than a true ventricular aneurysm? 
   • Ventricular pseudoaneurysm is caused by a contained rupture of the LV free wall where the rupture is contained by adherent pericardium, thrombus, or hematoma with no myocardial tissue in the outpouching. In a true ventricular aneurysm, the outer walls are formed by the infarcted myocardium and scar tissue. Pseudoaneurysms have a high propensity to rupture and thus surgical management is recommended.  
   • A small, narrow neck typically connects the ventricular cavity with the contained pericardial space. On echocardiogram, pseudoaneurysm can demonstrated the following differentiating features: (1) neck diameter to maximal aneurysmal diameter < 0.5; (2) color and spectral doppler demonstrating bidirectional flow through the narrowed neck; (3) thrombus and/or spontaneous echo contrast in the pericardial space.  

References

1. Alkhalil Mohammad, Choudhury Robin P. Reperfusion Treatment in Late Presentation Acute Myocardial Infarction. Circ Cardiovasc Interv. 2018;11(9):e007287. doi:10.1161/CIRCINTERVENTIONS.118.007287 
2. Hochman JS, Lamas GA, Buller CE, et al. Coronary Intervention for Persistent Occlusion after Myocardial Infarction. N Engl J Med. 2006;355(23):2395-2407. doi:10.1056/NEJMoa066139 
3. Adler Y, Charron P, Imazio M, et al. 2015 ESC Guidelines for the diagnosis and management of pericardial diseasesThe Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC)Endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2015;36(42):2921-2964. doi:10.1093/eurheartj/ehv318 
4. Hutchins KD, Skurnick J, Lavenhar M, Natarajan GA. Cardiac rupture in acute myocardial infarction: a reassessment. Am J Forensic Med Pathol. 2002 Mar;23(1):78-82. doi: 10.1097/00000433-200203000-00017. PMID: 11953501. 
5. Griffin, Brian P. 2019. Manual of cardiovascular medicine. 

• Bibin Varghese, MD
• Rick Ferraro, MD
• Tommy Das, MD
• Eunice Dugan, MD
• Evelyn Song, MD
• Colin Blumenthal, MD
• Karan Desai, MD
• Amit Goyal, MD
• Daniel Ambinder, MD

CardioNerds (Amit Goyal & Daniel Ambinder) join University of California San Diego (UCSD) cardiology fellows (Harpreet Bhatia, Dan Mangels, and Quan Bui) for a relaxing beach bonfire in the beautiful city of San Diego! They discuss a challenging case of post-transplant cardiac allograft vasculopathy. Dr. Hao (Howie) Tran provides the E-CPR and program director Dr. Daniel Blanchard provides a message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident Richard Ferraro with mentorship from University of Maryland cardiology fellow Karan Desai.  

Jump to: Patient summary – Case media – Case teaching – References

The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus.

We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director.

CardioNerds Case Reports Page
CardioNerds Episode Page
CardioNerds Academy
Subscribe to our newsletter- The Heartbeat
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Cardiology Programs Twitter Group created by Dr. Nosheen Reza

A man in his late 20s with a past medical history of orthotopic heart transplant, presents with one-week of progressive lower extremity edema and dyspnea with NYHA class IV symptoms. 5 years prior, he underwent orthotopic heart transplant for arrhythmogenic right ventricular cardiomyopathy. Subsequently, he has had multiple episodes of rejection or recurrent graft dysfunction. On presentation, he was normotensive and borderline tachycardic. Exam revealed elevated JVP, decreased breath sounds, and pitting edema.  Labs demonstrated leukocytosis, acute kidney injury, and elevated pro-BNP. TTE demonstrated LVEF 35%, apical akinesis, and grade III diastolic dysfunction (all similar to prior). He was initially diuresed and RHC/EMB was performed to evaluate for rejection. Early in his course, the patient unfortunately suffered a PEA arrest with ROSC was quickly achieved after 1 minute of CPR. He was intubated and cannulated for VA ECMO. EMB demonstrated ISHLT Grade 1R cellular rejection and he was ultimately listed for re-transplant. Shortly thereafter, the patient received an OHT. His pathology demonstrated intimal thickening of all his coronaries, consistent with coronary artery vasculopathy, felt to be the major contributor to his presentation.  

• ECG

1. What is CAV?  

• CAV stands for cardiac allograft vasculopathy. Within the transplanted heart, CAV is the proliferation of vascular smooth muscle and intimal thickening in the epicardial coronary arteries and microvasculature leading to diffuse narrowing. CAV is common, present in greater than 30% of patients at 5 years post-transplant. It is a significant contributor to post-transplant mortality after the first year.  
• CAV, in contrast to typical atherosclerotic lesions, is diffuse and concentric while atherosclerosis tends to be focal with eccentric luminal narrowing and heterogenous plaque composition. Patients s/p OHT can still develop typical coronary artery disease, likely developed from pre-existing disease in the donor heart. CAV should be high on the differential for the cause of graft dysfunction, especially after the first year post-transplant.  

2. How and Why Does CAV Occur? 

• CAV has multiple contributing factors. There are immunologic and non-immunologic factors, but it appears the immunologic components play the larger role given that the pan-vasculopathy develops in the donor heart and not in the recipient’s vasculature. In CAV, there is chronic immune-mediated injury creating a persistent inflammatory state in the donor coronary endothelium leading to a neointimal proliferative process in the coronaries. Amongst immunologic factors, it appears the number of episodes of cellular rejection correlates with the development of CAV.  
• CAV occurs when foreign antigens are recognized by the host immune system as “non-self,” a process termed allorecognition.  T-cells are subsequently activated, and release a number of inflammatory cytokines that leads to additional T-cell stimulation, inflammatory cell proliferation, and endothelial cell propagation.  Ultimately this inflammatory cascade leads to smooth muscle cell advancement and intimal growth into the arterial lumen.  
• Other immunologic factors include HLA mismatch and antibody-mediated rejection. There are numerous non-immunologic factors, including older donor age, CMV infection, hyperlipidemia, insulin resistance, donor brain death secondary to intracranial hemorrhage, and prolonged ischemic time.  

3. How Do Patients with CAV Present?  

• Donor hearts are denervated at explantation, and so post-transplant patients typically will not develop classic anginal symptoms as seen with typical atherosclerotic coronary disease. Thus, routine surveillance is necessary (see below).  
• If not diagnosed early, the clinical presentation may include LV dysfunction (with or without symptoms), acute myocardial infarction, heart block, arrhythmias, syncope, or sudden cardiac death.  

4.  How Do We Diagnose CAV? 

• Routine surveillance is necessary because patients are generally asymptomatic and there is a high incidence of CAV posttransplant.  
• The most common method for screening includes coronary angiography, but its sensitivity is reduced compared to traditional atherosclerotic disease as CAV is diffuse. Intravascular ultrasound (IVUS) significantly improves sensitivity and the early the detection of disease.  
• The timing and method of screening will be center-specific. As the patient is farther removed from their transplant date, dobutamine stress echo may be a reasonable method to screen for CAV. Myocardial perfusion imaging, specifically with PET Rest/Stress with absolute myocardial blood flow quantification, and coronary CTA may also be effective methods to diagnose CAV.  
• The ISHLT grading of CAV by angiography is as follows: 
  1. CAV0 (Nonsignificant): No detectable angiographic lesion 
  2. CAV1 (mild): Angiographic LM lesion <50%; or primary vessel with maximum lesion of <70%; or any branch vessel stenosis <70% without allograft dysfunction 
  3. CAV2 (moderate): Angiographic LM <50%; or a single primary vessel ≥70% stenosis; or isolated branch stenosis in 2 systems ≥ 70% without allograft dysfunction 
  4. CAV3 (Severe): Angiographic LM ≥50%; or ≥2 primary vessel ≥70% stenosis; or isolated branch stenosis in all 3 systems ≥70%; CAV1 or CAV2 with allograft dysfunction or evidence of significant restrictive physiology 

5. How Do we Treat CAV?  

• Primary prevention remains key. Statins have been shown prospectively to reduce cardiac allograft vasculopathy and improve survival. Chronic immunosuppression is the foundation of post-transplant care. The mTOR inhibitors, everolimus and sirolimus, harbor antiproliferative properties that may prevent allograft vasculopathy. However, these are generally not first-line immunosuppressive medications in the United States, given the potential for multiple side effects including impaired wound healing in new transplant patients. In patients with documented or progressive CAV, escalation of immunosuppression to sirolimus may be considered. Revascularization for patients may be considered, given the morbidity associated with CAV, though no survival advantage has been shown. In patients with severe CAV, re-transplantation should be considered.  

References

1. Mehra, M. R., Crespo-Leiro, M. G., Dipchand, A., et. al (2010). International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy—2010. 
2. Chih, S., Chong, A. Y., Mielniczuk, L. M. et. al. (2016). Allograft vasculopathy: the Achilles’ heel of heart transplantation. Journal of the American College of Cardiology, 68(1), 80-91. 
3. Schmauss, D., & Weis, M. (2008). Cardiac allograft vasculopathy: recent developments. Circulation, 117(16), 2131-2141. 

• Bibin Varghese, MD
• Rick Ferraro, MD
• Tommy Das, MD
• Eunice Dugan, MD
• Evelyn Song, MD
• Colin Blumenthal, MD
• Karan Desai, MD
• Amit Goyal, MD
• Daniel Ambinder, MD

CardioNerds (Amit Goyal & Daniel Ambinder) join Virginia Commonwealth University (VCU) cardiology fellows (Ajay Pillai, Amar Doshi, and Anna Tomdio) for a delicious skillet breakfast and amazing day in Richmond, VA! They discuss a fascinating case of a patient with Wolff-Parkinson-White (WPW) and hypertrophic cardiomyopathy (HCM). Dr. Keyur Shah provides the E-CPR and program director Dr. Gautham Kalahasty provides a message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident Colin Blumenthal with mentorship from University of Maryland cardiology fellow Karan Desai.

Jump to: Patient summary – Case media – Case teaching – References

The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus.

We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director.

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Cardiology Programs Twitter Group created by Dr. Nosheen Reza

A man in his mid-60s presented to the ED after an episode of unwitnessed syncope while drinking. Patient had suddenly passed out from a seated position with no prodrome or post-ictal state. He had episodes like this in the past, which were thought to be seizures, but otherwise PMHx only notable for alcohol use disorder. He denied any FH of SCD or syncope. In the ED, exam was unremarkable. Labs notable for mild thrombocytopenia, mild hyponatremia with AKI, 2:1 AST/ALT ratio, elevated NT-proBNP, and a very high lactate that rapidly corrected with fluids. EKG was notable for sinus tachycardia, short PR interval, wide QRS, and delta waves consistent with Wolff-Parkinson-White (WPW) pattern. Echo showed preserved LVEF, thickened LV septum (1.6 cm) and posterior wall (1.3 cm) concerning for hypertrophic cardiomyopathy (HCM). No outflow tract gradient was noted at rest or with stress, and the strain pattern demonstrated apical sparing. Evaluation for cardiac amyloid, including plasma cell dyscrasia and PYP scan, was negative. Cardiac MRI confirmed severely thickened LV inferior and inferolateral walls at 1.7 cm with no LVOT obstruction. 25% of the myocardium demonstrated patchy LGE.  

Due to concern for WPW syndrome, the patient underwent an EP study. This revealed a malignant septal accessory pathway that was successfully ablated with resolution of the WPW EKG features. Given large LGE burden in setting of HCM, patient underwent placement of primary prevention ICD. Genetic testing for PRKAG2 mutation is pending given comorbid WPW and HCM. 

• A
• E
• C
• D
• B
• F

A. CXR: Slightly increased interstitial markings in the lung bases, an elevated right hemidiaphragm. No acute airspace disease or pulmonary edema
B. ECG: Sinus tachycardia rate 120bpm, PR interval 80ms, QRS 130ms, WPW pattern.  Arruda algorithm localizes to posterior septum.
C. CMR:  Myocardium nulls before blood pool.
D. CMR:  Delayed gadolinium enhancement
E. Follow up ECG: NSR 78, repolarization abnormalities.  T wave memory inferior leads.
F. CXR status post dual chamber ICD implantation

• Hypertrophic Cardiomyopathy Infographic

1. Our patient was found to have Wolff-Parkinson-White (WPW) pattern. What are the diagnostic criteria for WPW pattern and how does it differ from WPW syndrome? How can you localize the accessory pathway using the EKG? 
   • WPW pattern refers to the presence of the below criteria on a patient’s surface EKG in the absence of symptomatic arrhythmias. If symptomatic arrhythmias related to the accessory pathway occur, then it is WPW syndrome. Symptoms may include palpitations, shortness of breath, presyncope, syncope, and sudden cardiac death (SCD).  
   • Not all patients with accessory pathways have EKG findings as only 60-75% of accessory pathways are “manifest” (meaning they conduct antegrade from atria to ventricles or are bidirectional). Conversely, a “concealed” accessory pathway only conducts retrograde (from ventricles to atria) and would not be apparent on resting sinus EKG; these patients can have WPW diagnosed after a ventricular premature beat, ventricular pacing, or an EP study that shows retrograde conduction through the accessory pathway.  
   • The WPW pattern is diagnosed by the following EKG criteria: 
     • Short PR interval < 120 ms 
     • Signs of pre-excitation: a delta wave (slurred upstroke of QRS complex) and QRS > 120 ms. The degree of pre-excitation on EKG depends on the position (how much of the ventricular myocardium is depolarized by the accessory pathway) and depolarization speed of the accessory pathway (more rapid conduction leading to earlier ventricular depolarization and wider delta wave).  
   • We can use EKG findings to localize accessory pathways using the Arruda Criteria, which has an overall sensitivity of 90% and specificity of 99%. Note, patients who have a left-lateral bypass tract as the antegrade limb may not have delta waves on surface EKG, as the atrial impulse can take longer to reach the bypass tract than the AV node.   
     
2. What are the major mechanisms for WPW and how do they lead to early activation of the ventricles? How can this precipitate arrhythmias? 
   • Accessory pathways are abnormal congenital connections between the atria and ventricles when there is incomplete atrio-ventricular isolation during fetal development. They can be associated with congenital cardiac malformations like Ebstein anomaly. 
   • Depolarization of the ventricles occurs via the AV node and the accessory pathway simultaneously, leading to early depolarization of a portion of the ventricles and the characteristic delta wave. Depolarization through the His Purkinje system reaches the apex first and travels back up the ventricle, meeting the slower cell to cell conduction from the accessory pathway and causing termination of the impulses. The resulting QRS complex is essentially a “fusion beat” between the two sources. 
   • Accessory pathways often have more rapid conduction, but longer refractory periods than the AV node. If a PAC occurs when the accessory pathway is refractory, there will be antegrade conduction solely through the AV node. As the impulse travels through the ventricles it can conduct retrograde through the accessory pathway from V to A. This creates a reentrant pathway that results in atrioventricular reentrant tachycardia (AVRT), which accounts for up to 80% of SVT in WPW. Orthodromic AVRT (antegrade through AV node, retrograde through accessory pathway) accounts for 90-95% of AVRT in WPW.  
   • Other tachycardias can occur where the accessory pathway is a bystander and not required for initiation and maintenance of the arrhythmia like in AVRT. This includes atrial arrhythmias (e.g., atrial fibrillation, atrial flutter), ventricular tachycardia, and ventricular fibrillation. Atrial fibrillation is relatively common (~20%) in WPW syndrome patients. Atrial fibrillation with an accessory pathway can produce rapid ventricular rates due to unencumbered conduction via the accessory pathway. In these situations, QRS width and morphology may vary due to variable conduction via the AV node vs accessory pathway. Depending on the rate of conduction, the patient can degenerate into VF. A shorter refractory period places patients at the highest risk for VF.  
     
3. How do we risk stratify patients with WPW pattern? When would an EP study (EPS) be beneficial? What features are high risk on EPS and would warrant treatment? 
   • Patients who are asymptomatic are typically at low risk of sudden cardiac death. Those who do have SCD typically have symptoms at some point prior to arrest. Patients with intermittent loss of the delta wave on a beat-to-beat basis are likely at lower risk, as it suggests the accessory pathway lacks the ability for rapid AV conduction. However, persistent delta wave in asymptomatic patients may still be at low risk.  
   • The risk for SCD is thought to be due to rapid conduction of Afib down the accessory pathway leading to VF. Accessory pathways with shorter refractory periods are able to conduct at higher rates (shorter R to R intervals). Delta waves disappear when R to R interval is less than the refractory period, at which point the atrial impulse only conducts through AV node. Thus, the lower the HR that delta waves become intermittent, the lower the risk of SCD. 
   • We can start risk stratification in most patients noninvasively with a resting EKG and exercise EKG stress test, unless we clearly demonstrate intermittent delta wave at rest. If preexcitation persists even with maximal sinus heart rates, then an EPS is recommended.  
   • High risk features on EPS include multiple accessory pathways, inducible AVRT or Afib, shortest pre-excited RR interval (SPERRI) < 250 ms, and accessory pathway refractory period < 240 ms 

1. How are high risk WPW pattern and WPW syndrome treated? 
   • For the chronic prevention of arrhythmia: 
     • In patients with high risk WPW pattern, we typically refer for catheter ablation (typically radiofrequency ablation though cryoablation can be utilized) of the accessory pathway to help prevent SCD. Successful ablation is curative.  
     • In patients with WPW syndrome, we can still risk stratify with the above algorithm, but symptomatic patients should receive treatment. Ablation is first line for all patients who are candidates and willing given success rates of 90-95%.  In terms of medical therapy for patients who are not ablation candidates, flecainide and propafenone are reasonable options in the absence of structural heart disease. Dofetilide or sotalol are options in patients with structural heart disease. AV nodal blocking agents can be considered in the setting of orthodromic AVRT. 
   • For WPW patients presenting with an acute arrhythmia and who are hemodynamically unstable, synchronized cardioversion is first line therapy. Pharmacologic therapy in the hemodynamically stable patient depends on the suspected level of involvement of the accessory pathway and type of arrhythmia. For arrhythmias not dependent on the accessory pathway for initiation and maintenance (e.g., atrial fibrillation), AV nodal blocking agents can induce rapid antegrade conduction down the accessory pathway which could degenerate into ventricular fibrillation. In the setting of rapid pre-excited atrial fibrillation, procainamide or ibutilide are the agents of choice.  
   • AVRT requires the accessory pathway for initiation and maintenance of the arrhythmia. Orthodromic AVRT will typically be a narrow complex tachycardia (unless there is aberrancy) and can be managed similarly to other regular narrow complex tachycardias (e.g., use of adenosine). If there is any doubt about the diagnosis, procainamide should be utilized.   
     
2. Where do the diagnostic schema for WPW and HCM overlap and what syndrome should you think of in patients where they coexist? 
   • Familial WPW is rare and characterized by the autosomal dominant inheritance of the combination of WPW syndrome and non-sarcomeric HCM. It is caused by mutations in the PRKAG2 gene, which encodes a portion of 5’AMP-activated protein kinase (AMPK). This mutation leads to cardiac glycogen overload, resulting in ventricular hypertrophy (HCM phenocopy), WPW-like syndrome, AV block, and progressive conduction system disease.  
   • Cardiac myocyte glycogen accumulation is thought to decrease the myocardial activation threshold and so overcomes the insulating properties of the AV annulus fibrosus, resulting in electrical leak between the atria and ventricles. This gives the clinical appearance of an accessory pathway. Given the typical absence of a distinct accessory pathway, EPS with ablation is often not effective.  
   • Other glycogen storage disorders may cause a similar overlap between an HCM phenocopy and WPW mimic like Pompe disease and Danon disease. 

References

1. Aggarwal, V., Dobrolet, N., Fishberger, S., Zablah, J., Jayakar, P., & Ammous, Z. (2015). PRKAG2 mutation: An easily missed cardiac specific non-lysosomal glycogenosis. Annals of Pediatric Cardiology, 8(2), 153. 
2. Arruda, M. S., McCLELLAND, J. H., Wang, X., Beckman, K. J., Widman, L. E., Gonzalez, M. D., Nakagawa, H., Lazzara, R., & Jackman, W. M. (1998). Development and Validation of an ECG Algorithm for Identifying Accessory Pathway Ablation Site in Wolff-Parkinson-White Syndrome. Journal of Cardiovascular Electrophysiology, 9(1), 2–12. 
3. Calkins Hugh, Yong Patrick, Miller John M., Olshansky Brian, Carlson Mark, Saul J. Philip, Huang Shoei K. Stephen, Liem L. Bing, Klein Lawrence S., Moser Suzan A., Bloch Daniel A., Gillette Paul, & Prystowsky Eric. (1999). Catheter Ablation of Accessory Pathways, Atrioventricular Nodal Reentrant Tachycardia, and the Atrioventricular Junction. Circulation, 99(2), 262–270. 
4. Chhabra, L., Goyal, A., & Benham, M. D. (2020). Wolff Parkinson White Syndrome (WPW). In StatPearls. StatPearls Publishing. 
5. Gollob, M. H., Green, M. S., Tang, A. S.-L., Gollob, T., Karibe, A., Hassan, A.-S., Ahmad, F., Lozado, R., Shah, G., Fananapazir, L., Bachinski, L. L., Tapscott, T., Gonzales, O., Begley, D., Mohiddin, S., & Roberts, R. (2001). Identification of a Gene Responsible for Familial Wolff–Parkinson–White Syndrome. New England Journal of Medicine, 344(24), 1823–1831. 
6. Gollob Michael H., Seger John J., Gollob Tanya N., Tapscott Terry, Gonzales Oscar, Bachinski Linda, & Roberts Robert. (2001). Novel PRKAG2 Mutation Responsible for the Genetic Syndrome of Ventricular Preexcitation and Conduction System Disease With Childhood Onset and Absence of Cardiac Hypertrophy. Circulation, 104(25), 3030–3033. 
7. Miyamoto, L. (2018). Molecular Pathogenesis of Familial Wolff-Parkinson-White Syndrome. The Journal of Medical Investigation: JMI, 65(1.2), 1–8. 
8. Page, R. L., Joglar, J. A., Caldwell, M. A., Calkins, H., Conti, J. B., Deal, B. J., Estes III, N. A. M., Field, M. E., Goldberger, Z. D., Hammill, S. C., Indik, J. H., Lindsay, B. D., Olshansky, B., Russo, A. M., Shen, W.-K., Tracy, C. M., & Al-Khatib, S. M. (2016). 2015 ACC/AHA/HRS guideline for the management of adult patients with supraventricular tachycardia. Heart Rhythm, 13(4), e136–e221. 
9. Spector, P., Reynolds, M. R., Calkins, H., Sondhi, M., Xu, Y., Martin, A., Williams, C. J., & Sledge, I. (2009). Meta-Analysis of Ablation of Atrial Flutter and Supraventricular Tachycardia†. American Journal of Cardiology, 104(5), 671–677.
10. Talle, M. A., Buba, F., Bonny, A., & Baba, M. M. (2019). Hypertrophic Cardiomyopathy and Wolff-Parkinson-White Syndrome in a Young African Soldier with Recurrent Syncope. Case Reports in Cardiology, 2019. 

• Bibin Varghese, MD
• Rick Ferraro, MD
• Tommy Das, MD
• Eunice Dugan, MD
• Evelyn Song, MD
• Colin Blumenthal, MD
• Karan Desai, MD
• Amit Goyal, MD
• Daniel Ambinder, MD