Episodes Archives - Cardionerds

CardioNerds (Amit Goyal and Daniel Ambinder), join CardioNerds FIT Ambassador, Dr. Pablo Sanchez, and his co-fellows, Dr. Jimmy Tooley and Dr. Maggie Ning from Stanford University for an important case discussion about an An otherwise healthy young adult presented with fatigue and was found to be in complete heart block due to sarcoidosis. Dr. Ronald Witteles, (Stanford University Program Director for the Stanford Internal Medicine residency program and advanced heart failure specialist who’s particular expertise focuses in the treatment of amyloidosis, sarcoidosis, and cardio-oncology) provides the E-CPR for this episode. 

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Disclosures: Dr. Witteles reports that he has served as an advisor for Pfizer, Alnylam, Eidos, Regerenon Pharmaceuticals, Janssen, and Ionis
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An otherwise healthy young adult presented with fatigue and was found to be in complete heart block. Imaging studies were suspicious for cardiac and pulmonary sarcoidosis. Sarcoidosis was confirmed on biopsy. Given the high risk of future cardiac events our patient underwent a dual chamber ICD implantation. He was started on prednisone and methotrexate for immunosuppression.

1. Cardiac sarcoidosis is a disease characterized by noncaseating granulomas involving the heart that can exist alone or together with other organ system involvement
2. Depending on the sites of cardiac involvement it can present as conduction system disease, ventricular arrhythmia, or heart failure
3. Cardiac sarcoidosis should be considered in patients with history of sarcoidosis involving other organ systems who develop left ventricular dysfunction, wall motion abnormalities, or arrhythmias
4. Cardiac sarcoidosis should be considered in patients who present with otherwise unexplained heart block or ventricular tachycardia (VT)
5.  It is generally recommended that patients with cardiac sarcoidosis with an indication for pacemaker receive an ICD at time of implantation regardless of history of VT

1. What is Sarcoidosis?

Sarcoidosis is a rare disorder of inflammation characterized by the formation of noncaseating granulomas in affected tissues. It most commonly involves the pulmonary system, but other organ systems can be involved including the heart. Sarcoidosis typically affects young adults, and its etiology is still uncertain.

2. What is Cardiac Sarcoidosis and how is it diagnosed?

Cardiac sarcoidosis (CS) can occur alone or with systemic disease and depending on the cardiac sites of involvement, can present as conduction system disease, ventricular arrhythmia, heart failure, or sudden cardiac death.

3. How is Cardiac Sarcoidosis diagnosed?

Diagnosis of CS is challenging as the gold standard is endomyocardial biopsy (EMB), though sensitivity of EMB is low given the often-patchy tissue involvement. Societal guidelines on the diagnosis of CS require either a positive EMB or biopsy-confirmed extracardiac sarcoidosis with evidence of secondary criteria to suggest cardiac involvement – unexplained VT, high grade AV block, third degree AV block, LVEF <40%, or characteristic imaging finding on cardiac MRI and cardiac PET.

The diagnosis of CS must be considered in all patients with a diagnosis of extra cardiac sarcoidosis who develop symptoms to suggest cardiac involvement. Additionally,

screening for CS should be done in all patients <60 years of age presenting with unexplained Mobitz type II block, 3rd degree AV block, or VT.

Our patient was a previously healthy very active gentleman in his 30s with fairly sudden onset of fatigue found to have 100% burden of high-grade AV block and third-degree AV block on ambulatory rhythm monitor. Given his young age and no other explanation for his conduction system disease, he underwent a workup for CS.  Cardiac MRI revealed mesocardial scarring in the mid inferior and anteroseptal walls with prominent mediastinal and hilar lymphadenopathy suggestive of sarcoidosis with pulmonary and cardiac involvement. FDG-PET was also highly suggestive of CS given FDG uptake of the basal septum and lymph nodes. Diagnosis was ultimately confirmed based on FNA of a supraclavicular lymph node, though EMB would have been the appropriate next step if there were no extracardiac sites available for biopsy.

4. What are important considerations of conduction disease associated with cardiac sarcoidosis?

Third degree AV block typically occurs with increased frequency at advanced age and most commonly is due to idiopathic myocardial fibrosis of the conduction system. However, in younger patients, CS is an important cause of AV block that must be considered. In a single-center study, CS was diagnosed in greater than ⅓ of patients <60 years of age with unexplained high grade AV block.

The diagnosis of AV block associated with CS is important to distinguish from idiopathic AV block as it is associated with higher rates of adverse cardiac events. Patients with CS that present with high grade AV block have similar rates of fatal cardiac events – cardiac death, VF, and sustained VT – compared to those who present with VT or HF. In a single center study, >50% of CS patients who presented with AV block experienced a fatal cardiac event at 34 months follow up.

Societal recommendations reflect this increased cardiac risk in CS patients and give a Class IIa recommendation for ICD implantation in CS patients with indication for permanent pacing, unexplained syncope, or inducible VT/VF.

1. Barra, Sérgio Nuno Craveiro, Rui Providência, Luís Paiva, José Nascimento, and António Leitão Marques. “A Review on Advanced Atrioventricular Block in Young or Middle-Aged Adults: ATRIOVENTRICULAR BLOCK IN YOUNG ADULTS.” Pacing and Clinical Electrophysiology 35, no. 11 (November 2012): 1395–1405. https://doi.org/10.1111/j.1540-8159.2012.03489.x.
2. Birnie, David H., William H. Sauer, Frank Bogun, Joshua M. Cooper, Daniel A. Culver, Claire S. Duvernoy, Marc A. Judson, et al. “HRS Expert Consensus Statement on the Diagnosis and Management of Arrhythmias Associated With Cardiac Sarcoidosis.” Heart Rhythm 11, no. 7 (July 2014): 1304–23. https://doi.org/10.1016/j.hrthm.2014.03.043.
3. Kandolin, Riina, Jukka Lehtonen, and Markku Kupari. “Cardiac Sarcoidosis and Giant Cell Myocarditis as Causes of Atrioventricular Block in Young and Middle-Aged Adults.” Circulation: Arrhythmia and Electrophysiology 4, no. 3 (June 2011): 303–9. https://doi.org/10.1161/CIRCEP.110.959254.
4. Nery, Pablo B., Rob S. Beanlands, Girish M. Nair, Martin Green, Jim Yang, Brian A. Mcardle, Darryl Davis, et al. “Atrioventricular Block as the Initial Manifestation of Cardiac Sarcoidosis in Middle-Aged Adults: Cardiac Sarcoidosis Presenting as Atrioventricular Block.” Journal of Cardiovascular Electrophysiology 25, no. 8 (August 2014): 875–81. https://doi.org/10.1111/jce.12401.
5. Takaya, Yoichi, Kengo Fukushima Kusano, Kazufumi Nakamura, and Hiroshi Ito. “Outcomes in Patients With High-Degree Atrioventricular Block as the Initial Manifestation of Cardiac Sarcoidosis.” The American Journal of Cardiology 115, no. 4 (February 2015): 505–9. https://doi.org/10.1016/j.amjcard.2014.11.028.
6. Terasaki, Fumio, Arata Azuma, Toshihisa Anzai, Nobukazu Ishizaka, Yoshio Ishida, Mitsuaki Isobe, Takayuki Inomata, et al. “JCS 2016 Guideline on Diagnosis and Treatment of Cardiac Sarcoidosis ― Digest Version ―.” Circulation Journal 83, no. 11 (October 25, 2019): 2329–88. https://doi.org/10.1253/circj.CJ-19-0508.
7. Uemura, A., S. Morimoto, S. Hiramitsu, Y. Kato, T. Ito, and H. Hishida. “Histologic Diagnostic Rate of Cardiac Sarcoidosis: Evaluation of Endomyocardial Biopsies.” American Heart Journal 138, no. 2 Pt 1 (August 1999): 299–302. https://doi.org/10.1016/s0002-8703(99)70115-8.

• Karan Desai, MD
• Amit Goyal, MD
• Daniel Ambinder, MD

CardioNerds Dan Ambinder, Dr. Tommy Das (Program Director of the CardioNerds Academy and cardiology fellow at Cleveland Clinic), and episode lead, Dr. Teodora Donisan (CardioNerds Academy fellow and incoming Chief fellow and Beaumont Health Internal Medicine resident) join Dr. Matthew Budoff (professor of medicine at David Geffen School of Medicine at UCLA and the Endowed Chair of Preventive Cardiology at Harbor-UCLA Medical Center) for a discussion about triglycerides from pathophysiology to clinical outcomes. This episode is part of the CardioNerds Lipids Series which is a comprehensive series lead by co-chairs Dr. Rick Ferraro and Dr. Tommy Das and is developed in collaboration with the American Society For Preventive Cardiology (ASPC).

Triglyceride (TG) metabolism can produce a by-product called remnant lipoproteins, which can be atherogenic. Most guidelines consider hypertriglyceridemia to start at values ≥ 150 mg/dl. It is the most common dyslipidemia, as it can occur in 30% of the general population. Although fasting levels are usually obtained per the current US protocol, there is evidence that non-fasting TG levels might be a better indicator of cardiovascular (CV) risk as these levels may better reflect the usual levels that the body is exposed to. There are multiple primary (genetic) causes of elevated TG, but these are rarer than lifestyle factors, medical conditions, or medications. Genetic association studies are helping better define the level of CV risk stemming from elevated TG-levels, which will impact how we target lifestyle and treatment interventions in the future.

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Relevant disclosures: Dr. Matthew Budoff has funding from General Electric.

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1. In the process of metabolizing TG, remnant lipoproteins are formed, which have been shown to promote atherogenesis. TG themselves have not been directly linked to this process and have not been studied in large population studies, and so are considered risk enhancing factors, and not risk factors per se. Elevated triglyceride levels measured on our traditional lipid panels act as a proxy for the Apo-B rich lipoproteins, such as VLDL, which directly cause atherogenesis.
2. Hypertriglyceridemia is defined as TG values of ≥150 mg/dl, although there is emerging evidence that even high-normal values (100-140 mg/dl) can still be associated with increased CV risk. You can think of TG in a similar fashion to glucose values (patients with prediabetes are still at higher CV risk than those with normal glycemic level). These are continuous and not binary variables!
3. Fasting lipid levels are not necessarily a better predictor of CV events than non-fasting lipid levels. A non-fasting TG level can potentially provide information on the body’s metabolism similarly to how we interpret glucose tolerance tests, although there isn’t such a standardized approach in the lipid world yet.
4. Before testing for genetic causes, make sure you review secondary causes of elevated TG. Don’t forget to evaluate for lifestyle factors and medical causes (diabetes, alcohol abuse, hypothyroidism, pregnancy) and to review the medication list (pay attention to thiazides, non-selective beta blockers, antipsychotics and others).
5. TG values of ≥ 175 mg/dl are considered a risk enhancing factor and can aid in the decision to be more aggressive with lifestyle changes or starting treatment.
6. Although treatment will be reviewed in depth in future episodes, Dr. Budoff suggests we “back away from using fibrates for CV event protection.” Even though they are efficient at lowering TG levels, they haven’t been shown to have a beneficial impact on ASCVD. New trials are exploring the role of pemafibrate for CV outcomes (1). Furthermore, EPA treatment can be considered for TG < 500 mg/dl with the goal of CV risk reduction. We should remember that omega-3 dietary supplements are impure, may be stored in improper conditions, and may be unsafe, even though more affordable to patients.

1. What is the basic biochemical structure of triglycerides (TG), and how are they metabolized by the body?

TG are hydrophobic substances packed into the core of lipoproteins. Lipoproteins are made up of a lipid rich core bound to proteins called apolipoproteins and can travel freely through the extracellular environments inside the body. The main way to transport dietary and endogenous TG to the tissues is through 2 types of TG-rich lipoproteins secreted by the intestine and the liver: chylomicrons and very low-density lipoproteins (VLDL). In order to unpack these TG-rich lipoproteins, the body produces lipoprotein lipase, which releases free fatty acids (FFA) and remnant lipoproteins.

The main places in the body where this process occurs is in adipose tissue, where FFA are used for storage, and in the muscle tissue, where FFA are used for energy production. Both skeletal muscle and cardiac muscle use FFA as an energy source for contraction. Remnant chylomicrons and VLDL are then mostly taken up by the liver using low-density lipoproteins (LDL) receptors and they are then used to produce VLDL or LDL which return to the circulation. Some of the remnant lipoproteins can be taken up by the vessel wall, thereby leading to endothelial dysfunction, vascular inflammation, and atherogenesis (2-4).

2. What is the epidemiology of hypertriglyceridemia? How prevalent is hypertriglyceridemia in the general population?

The normal TG levels in American men and women are 128 mg/dl and 110 mg/dl respectively (5). Hypertriglyceridemia is defined as fasting TG levels of ≥ 150 mg/dl by most guidelines and expert committees (6-9). Emerging evidence indicates that high-normal TG values (100-149 mg/dl) may still be associated with increased risk of cardiovascular events (10). Similar to how we regard glucose values and the increased risk people can have even as prediabetics, so too are TG a continuous variable.

Hypertriglyceridemia is the most common form of dyslipidemia in the general population. An estimated 53% of American adults have dyslipidemia, 27% have elevated LDL levels, 23% have low HDL levels, and 30% have elevated TG levels (12). Of these, men have a higher prevalence of hypertriglyceridemia than women (28.7% and 21.5% respectively). The age distribution is different between the genders as well (highest prevalence in men ages 40-59 years old and women over 60 years old) (13). Some of these differences mainly stem from lifestyle – dietary habits and exercise levels.

3. What is the best way to measure TG values in the blood and what is the clinical significance of fasting vs non-fasting values?

Fasting lipid levels are not necessarily a better predictor of cardiovascular events than non-fasting lipid levels. To the contrary, there is evidence that non-fasting TG levels might actually be a better indicator of increased cardiovascular risk (14,15). The European guidelines recommend obtaining a fasting sample when non-fasting TG levels are greater that 440mg/dL (16). 

The convention in the US is to obtain fasting lipid panels and TG levels, as the fasting TG value can be used to calculate LDL through the Friedewald equation. To continue building on the analogy with glucose values above, a non-fasting TG level can potentially provide information on the body’s metabolism similarly to how we interpret glucose tolerance tests, although there isn’t such a standardized approach in the lipid world yet.

4. What are some of the main causes of elevated TG?

Causes that we more frequently encounter in our clinical practice include lifestyle factors (i.e., diet, alcohol, decreased physical activity, and smoking) or medical conditions (i.e., obesity, metabolic syndrome, uncontrolled diabetes, pregnancy, Cushing’s, hypothyroidism, or nephrotic syndrome) (11). We must not forget that there are medications which can cause mild to moderate elevations (e.g., thiazides, non-selective BB, atypical antipsychotics, glucocorticoids), or ones that can cause severe TG elevations (e.g., estrogen and estrogen receptor blockers, propofol, interferon, and various cancer therapies such as isotretinoin, ciclosporin, sirolimus, capecitabine, and protease inhibitors) (11).

We can consider primary genetic abnormalities if secondary causes have been excluded. Primary genetic causes more frequently encountered include familial hypertriglyceridemia and familial combined hyperlipidemia (which are polygenic with environmental influences), followed by familial dysbetalipoproteinemia (which is usually autosomal recessive, but can be autosomal dominant), and familial chylomicronemia syndrome (which is AR and extremely rare) (11). Genetic screening would be considered if TG levels are ≥ 500 mg/dl or even ≥ 1000 mg/dl, for family risk stratification.

5. What is the clinical significance of hypertriglyceridemia? What is the difference between “risk factors” and “risk enhancing factors?”

The consequences associated with hypertriglyceridemia include acute pancreatitis and increased CV risk. As discussed above, the biochemical components that contribute to atherosclerosis formation are remnant lipoproteins that are able to enter the arterial intima and lead to atherogenesis. Because of this, hypertriglyceridemia is considered a “risk enhancing factor,” as it is not a direct causal agent for CV morbidity and mortality. Furthermore, original risk factor studies focused mostly on LDL and HDL and did not include TG. Of note, recent guidelines consider TG as risk enhancing factors if repeated non-fasting measurements are ≥175 mg/dl (17). The importance of reviewing TG as a risk enhancing factor is to aid in the decision about being more aggressive with preventive management, when the indications are not clear.

6. How have genome-wide association studies helped identify hypertriglyceridemia as a causative agent in the development of ASCVD?

Hypertriglyceridemia is commonly associated with other dyslipidemias, making a direct causal relationship between elevated TG and atherogenesis difficult. Genetic association studies have tried to elucidate the role of elevated TG as an independent CV risk factor (18). Recent large-scale meta-analyses and population-based sequencing studies show that TG-raising variant alleles have strong associations with CV endpoints. Additionally, patients with loss of function variants in the gene encoding apo-C III, which inhibits the lipoprotein lipase, have reduced TG levels and decreased ASCVD risk (18). Such emerging evidence will play a significant role in better defining the CV risk profile in patients with dyslipidemia and in helping us target specific lifestyle and treatment interventions.

1. Pradhan AD, Paynter NP, Everett BM et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J 2018;206:80-93.
2. Doi H, Kugiyama K, Oka H et al. Remnant lipoproteins induce proatherothrombogenic molecules in endothelial cells through a redox-sensitive mechanism. Circulation 2000;102:670-6.
3. Chait A, Ginsberg HN, Vaisar T, Heinecke JW, Goldberg IJ, Bornfeldt KE. Remnants of the Triglyceride-Rich Lipoproteins, Diabetes, and Cardiovascular Disease. Diabetes 2020;69:508-516.
4. Zheng XY, Liu L. Remnant-like lipoprotein particles impair endothelial function: direct and indirect effects on nitric oxide synthase. J Lipid Res 2007;48:1673-80.
5. Miller M, Stone NJ, Ballantyne C et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2011;123:2292-333.
6. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-421.
7. Grundy SM, Stone NJ, Bailey AL et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139:e1082-e1143.
8. Berglund L, Brunzell JD, Goldberg AC et al. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97:2969-89.
9. Catapano AL, Graham I, De Backer G et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J 2016;37:2999-3058.
10. Kajikawa M, Maruhashi T, Kishimoto S et al. Target of Triglycerides as Residual Risk for Cardiovascular Events in Patients With Coronary Artery Disease　- Post Hoc Analysis of the FMD-J Study A. Circ J 2019;83:1064-1071.
11. Simha V. Management of hypertriglyceridemia. Bmj 2020;371:m3109.
12. Tóth PP, Potter D, Ming EE. Prevalence of lipid abnormalities in the United States: the National Health and Nutrition Examination Survey 2003-2006. J Clin Lipidol 2012;6:325-30.
13. Fan W, Philip S, Granowitz C, Toth PP, Wong ND. Prevalence of US Adults with Triglycerides ≥ 150 mg/dl: NHANES 2007-2014. Cardiol Ther 2020;9:207-213.
14. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. Jama 2007;298:309-16.
15. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. Jama 2007;298:299-308.
16. Parhofer KG, Laufs U. The Diagnosis and Treatment of Hypertriglyceridemia. Dtsch Arztebl Int 2019;116:825-832.
17. Arnett DK, Blumenthal RS, Albert MA et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;74:1376-1414.
18. Dron JS, Hegele RA. Genetics of Triglycerides and the Risk of Atherosclerosis. Curr Atheroscler Rep 2017;19:31.

Matthew Jay Budoff, MD, FACC, FAHA, is a professor of medicine at David Geffen School of Medicine at UCLA and the Endowed Chair of Preventive Cardiology at Harbor-UCLA Medical Center. Dr. Budoff is a graduate of University of California at Riverside (BS) and graduated a member of Alpha Omega Alpha from George Washington University School of Medicine (MD). He completed his training in internal medicine and his cardiology fellowship at Harbor-UCLA Medical Center. Dr. Budoff is on the editorial boards of several cardiology journals, including Clinical Cardiology, Journal of Invasive Cardiology, JACC: Cardiovascular Imaging, and Cardiovascular Diabetology. Dr. Budoff has served on a number of association committees, including as secretary and executive committee member for LA BioMed (2018–current), foundation board member of the American College of Cardiology (ACC; 2014–current), and member of the ACC Annual Scientific Session program committee (2013–2015). He also serves on the executive committee of the ACC Center of Excellence on Cardiovascular Risk Reduction (2018-2020).

Dr. Budoff has author or coauthored more than 50 books and book chapters and more than 2000 articles and abstracts. He has received numerous research grants from the National Institutes of Health and has been invited to lecture at cardiology conferences around the world. In addition to his 2015 appointment as the Endowed Chair of Preventive Cardiology at Harbor-UCLA Medical Center, he has been recognized for his work by the Society of Cardiovascular Computed Tomography, from which he received the Gold Medal Award and recently designated as Master of the Society of Cardiovascular Computed Tomography (MSCCT), and has been inducted into the European Academy of Sciences. Dr. Budoff has been named to “America’s Top Doctors” for each of the past 9 years. In 2011, he was named a US News Top Doctor for cardiology, was awarded the Albert Nelson Marquis Lifetime Achievement Award in 2018 and named to “The world’s most influential scientific researchers” in 2018 and 2019.

• Tommy Das, MD
• Dr. Rick Ferraro
• Amit Goyal, MD
• Daniel Ambinder, MD

CardioNerds (Amit Goyal and Josh Saef) join ACHD fellow Dr. Prashanth Venkatesh and ACHD program director Dr. Jeannette Lin, both from the University of California, Los Angeles, for a deep dive into the complex disease entity that is Ebstein anomaly. They discuss the anatomic features of the dysplastic tricuspid valve as well as the right ventricle in patients with Ebstein anomaly, and how these structural features affect cardiovascular physiology and clinical presentation. This is followed by an in-depth discussion into associated entities including arrhythmias and atrial-level shunts as well as the appropriate multimodality evaluation. Finally, they tackle the difficult question of when and how to intervene, delving into the various interventional treatments and exploring their outcomes using illustrative case-based examples. Audio editing CardioNerds Academy Intern, Pace Wetstein.

The CardioNerds Adult Congenital Heart Disease (ACHD) series provides a comprehensive curriculum to dive deep into the labyrinthine world of congenital heart disease with the aim of empowering every CardioNerd to help improve the lives of people living with congenital heart disease. This series is multi-institutional collaborative project made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Josh Saef, Dr. Agnes Koczo, and Dr. Dan Clark.

The CardioNerds Adult Congenital Heart Disease Series is developed in collaboration with the Adult Congenital Heart Association, The CHiP Network, and Heart University. See more

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1. Ebstein anomaly is characterized by an inherent myopathy which is often more clinically consequential than the more obvious tricuspid valvulopathy. This can affect not only the right ventricle due to ‘atrialization’ and severe tricuspid regurgitation (TR) but also the left ventricle that is often small due to chronic preload deprivation from reduced RV outflow (no flow, no grow)!
2. Diagnosing severe TR on echocardiography in patients with Ebstein anomaly is challenging, due to the frequent absence of a clearly defined vena contracta and lack of hepatic vein systolic flow reversal. Be on the lookout for severe low gradient TR, which may manifest as a triangular doppler signal rather than the normal parabolic profile.
3. If an electrocardiogram of a patient with Ebstein anomaly suggests prior inferior myocardial infarction, be very suspicious for a right-sided accessory pathway! These are seen in nearly a third of patients with Ebstein anomaly, and manifest as negative delta waves in the inferior leads, leading to a pseudo-infarct pattern. NOTE: infarction, aberrancy, and ventricular hypertrophy should not be coded in the presence of an accessory pathway (i.e., WPW pattern).
4. Patients with Ebstein anomaly who are planned for tricuspid valve replacement should undergo an electrophysiology study preoperatively, since the cavo-tricuspid isthmus responsible for atrial flutter that plagues a large number (>20%) of these patients will be covered by a tricuspid prosthetic valve ring and be inaccessible for future catheter ablation.
5. Certain patients with Ebstein anomaly with significant baseline RV dysfunction who require tricuspid valve surgery may benefit from a concomitant Glenn shunt, which is a surgical anastomosis of the superior vena cava to the right pulmonary artery. This relieves the dysfunctional RV of a third of its baseline preload, potentially enabling it to recover effectively from the stress of cardiopulmonary bypass.

1. What is Ebstein anomaly and why does it occur?

• Ebstein anomaly is a rare congenital heart defect of the tricuspid valve (TV) and the myocardium. It occurs in approximately 1 in 200,000 live births.
• Ebstein anomaly occurs because of defective delamination of the TV. Delamination is the process by which the TV leaflets form from tissue that peels away from the endocardium and myocardium of the right ventricle.
• Specifically, the septal and posterior leaflets of the TV are inadequately delaminated in Ebstein anomaly. Since they didn’t peel away sufficiently from the myocardium to form the TV at the valve annulus, these leaflets are small, dysplastic and attach significantly more apical to the true tricuspid valve annulus.
• The anterior TV leaflet is attached to the true TV annulus, but is long, redundant, and floppy, hence often described as ‘sail-like’. It may have fenestrations and can have fibrous attachments to the free wall of the RV. It may also be non-restricted and prolapse into the RV outflow tract, causing outflow obstruction.

2. How is the myocardium affected in Ebstein anomaly and what are the hemodynamic sequelae?

• Ebstein anomaly is characterized by an inherent ventricular myopathy which often is more clinically important than the tricuspid valve dysfunction.
• The apically displaced tricuspid valve resulting from inadequate delamination causes the RV to be partitioned into a ‘functional RV’ which is responsible for generating RV outflow and an ‘atrialized RV’ which is a redundant chamber anterior to the true TV annulus but posterior to the septal and posterior leaflets.
• The atrialized RV is redundant since it does not contribute to RV output, and hence takes out a lot of the RV contractile reserve, especially in cases of severe apical displacement of the TV. In these cases, the functional RV chamber generating the output may be small and can get dysfunctional due to the superimposed severe TR.
• Also, since the RV output is reduced, the left ventricle (LV) is chronically deprived of preload and is often smaller than normal (remember – no flow, no grow). The LV may also have features of noncompaction cardiomyopathy, further contributing to myocardial dysfunction.

3. What are the major clinical findings in Ebstein anomaly?

• Look for clubbing, cyanosis, and hypoxemia at rest or on exertion, which may occur due to interatrial shunting.
• Extra heart sounds are common in Ebstein anomaly, due to flow across the abnormal TV. It has been memorably described as sounding like someone falling down the stairs.
• A TR murmur may or may not be heard and may be suppressed due to the presence of laminar rather than turbulent flow, through a very wide regurgitant valve orifice.
• A CV wave, usually seen in patients with acquired severe TR, are usually absent in patients with Ebstein anomaly despite having severe TR, since the severely dilated RA typically absorbs the regurgitant flow and blunts the transmission of pressure into the internal jugular vein during systole.
• Manifestations of RV failure including ascites, leg edema, and exertional dyspnea are often seen in cases of severe RV dysfunction.

4. What are some of the key echocardiographic features of Ebstein anomaly?

• The key finding that you need to identify immediately on an apical 4 chamber view is the abnormal apical position of the septal attachment of the TV. NOTE that the tricuspid valve normally attaches more apically than the mitral valve. To meet echocardiographic criteria for Ebstein anomaly, the attachment of the septal leaflet of the TV should be >8mm/m2 (normalized for body surface area) apical from the septal attachment of the anterior mitral valve leaflet.
• The right atrium is usually severely dilated and comprises both the anatomic right atrium (posterior to the true TV annulus) and the ‘atrialized RV’.
• Tricuspid regurgitation is seen in essentially all cases of Ebstein anomaly and is commonly severe or torrential. However, this may not be obvious because the malcoaptation of the leaflets is often so severe that a vena contracta may not be seen.
• Hepatic vein flow reversal in systole from severe TR is usually absent because the extra flow of the TR is absorbed by the severely dilated RA and does not cause high pressure in the hepatic vein.
• A sharp, triangular profile of the TR jet on continuous wave doppler rather than its usual parabolic form may be the only indication of severe low gradient TR seen in Ebstein anomaly.
• RV myopathy can lead to interventricular dyssynchrony that can manifest as abnormal motion of the interventricular septum.

5. What conditions are associated with Ebstein anomaly and how are they best diagnosed?

• Up to 90% of Patients with Ebstein anomaly have an atrial level shunt, which is either an atrial septal defect or patent foramen ovale, best seen on transesophageal echocardiography. Right-to-left interatrial shunting can cause exertional hypoxia that is detected on cardiopulmonary exercise testing. These defects may also predispose to paradoxical emboli.
• One-third of Patients with Ebstein anomaly have associated Wolff-Parkinson-White syndrome from accessory pathways. Two-thirds of these are right-sided pathways and can be diagnosed on electrocardiography, where they manifest as negative delta waves in the inferior limb leads, often mimicking a Q-wave myocardial infarction. These can be definitively diagnosed with an electrophysiology study.
• Additional arrhythmias include AV nodal re-entrant tachycardia and focal atrial tachycardia in up to 20% of patients, as well as atrial flutter in approximately 20% of patients.
• Markedly tall P-waves with amplitude > 2.5 mm are seen in nearly all Ebstein’s patients, due to severe (often massive) right atrial enlargement. The P-waves are classically known as ‘Himalayan’ P-waves due to their markedly peaked morphology. Most Patients with Ebstein anomaly have right bundle branch block on ECG.
• Left ventricular noncompaction can be seen in up to 40% of patients with Ebstein anomaly on echocardiography.

6. What are some of the main considerations for tricuspid valve surgery in Ebstein patients?

• The timing for surgery is a nuanced decision since some patients will remain well compensated for decades. Clear indications for surgical referral would be exercise intolerance, refractory arrhythmias, and progressive RV dilation or dysfunction.
• The RV myopathy in Ebstein anomaly can lead to significant postoperative RV dysfunction, arrhythmias, and failure. The goal is to wait as long as we can to minimize the number of surgeries/interventions these patients will need in their lifetime, but not to wait so long as to increase morbidity and mortality from progressive RV dysfunction from uncorrected severe valvulopathy +/- myopathy and associated end organ injury.
• In experienced centers, tricuspid valve repair has been and remains the preferred approach in patients with suitable anatomy. The hope is that a good tricuspid valve repair will last at least 15-20 years, though it is not uncommon to eventually need reoperation for tricuspid valve replacement.
• The most common type of repair performed is called the Cone repair, in which the septal and posterior leaflets are mobilized, detached from their apical attachment and sewn together with the anterior leaflet to create a single, monocusp tricuspid valve that is shaped like a cone, and attached to the true anatomic TV annulus.
• Tricuspid valve replacement is also commonly performed, and a bioprosthetic valve is favored over a mechanical valve due to superior long-term outcomes.
• Patients with Ebstein anomaly heading for tricuspid valve replacement should undergo an electrophysiology study preoperatively, since the cavo-tricuspid isthmus responsible for atrial flutter that plagues a large number (> 20%) of these patients will be covered by a tricuspid prosthetic valve ring and be inaccessible for future catheter ablation.
• Ebstein surgery should not only address the TV but should also address interatrial shunting by suture/ patch closure, and arrhythmia substrate in the form of right sided MAZE procedure that should be performed concomitantly in the appropriate patient.
• For patients with restrictive right ventricles or those with poor contractility, a Glenn shunt, in which the SVC is anastomosed to the right pulmonary artery, can volume unload the right ventricle and improve hemodynamics especially in the postoperative period.
• Patients with Ebstein anomaly with severe TR and severe RV failure not expected to tolerate valve surgery should be referred to an advanced heart failure cardiologist either for consideration of a perioperative/postoperative ventricular assist device, or for cardiac transplantation.

1. Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. Apr 2 2019;139(14):e698-e800. https://www.ahajournals.org/doi/10.1161/CIR.0000000000000603
2. European Society of G, Association for European Paediatric C, German Society for Gender M, et al. ESC Guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). European heart journal. Dec 2011;32(24):3147-3197. https://academic.oup.com/eurheartj/article/39/34/3165/5078465
3. Pierpont ME, Brueckner M, Chung WK, et al. Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association. Circulation. Nov 20 2018;138(21):e653-e711. https://www.ahajournals.org/doi/10.1161/CIR.0000000000000606
4. Elkayam U, Goland S, Pieper PG, Silversides CK. High-Risk Cardiac Disease in Pregnancy: Part II. Journal of the American College of Cardiology. Aug 2 2016;68(5):502-516. https://www.jacc.org/doi/full/10.1016/j.jacc.2016.05.048

Adult Congenital Heart Association
Founded in 1998, the Adult Congenital Heart Association is an organization begun by and dedicated to supporting individuals and families living with congenital heart disease and advancing the care and treatment available to our community. Our mission is to empower the congenital heart disease community by advancing access to resources and specialized care that improve patient-centered outcomes. Visit their website (https://www.achaheart.org/) for information on their patient advocacy efforts, educational material, and membership for patients and providers

CHiP Network

The CHiP network is a non-profit organization aiming to connect congenital heart professionals around the world. Visit their website (thechipnetwork.org) and become a member to access free high-quality educational material, upcoming news and events, and the fantastic monthly Journal Watch, keeping you up to date with congenital scientific releases. Visit their website (https://thechipnetwork.org/) for more information.

Heart University
Heart University aims to be “the go-to online resource” for e-learning in CHD and paediatric-acquired heart disease. It is a carefully curated open access library of educational material for all providers of care to children and adults with CHD or children with acquired heart disease, whether a trainee or a practicing provider. The site provides free content to a global audience in two broad domains: 1. A comprehensive curriculum of training modules and associated testing for trainees. 2. A curated library of conference and grand rounds recordings for continuing medical education. Learn more at www.heartuniversity.org/

Dr. Jeannette Lin is an adult congenital heart disease specialist at UCLA. Her interests are in echocardiographic imaging and medical education. She serves as the Program Director for the Adult Congenital Heart Disease Fellowship at UCLA, where she has the privilege of helping train the next generation of ACHD cardiologists. She is co-director of the American College of Cardiology’s ACHD Training Directors Workgroup, and has served on the writing committee for the revised ACGME Milestones for ACHD, and is also a lecturer for the ACHD section of the ACCSAP Board Review.

Dr. Prashanth Venkatesh is a first year ACHD fellow at UCLA. He did his medical school at Weill Cornell Medicine in Doha, Qatar; his internal medicine residency in New York-Presbyterian Hospital/ Weill Cornell Medicine in New York City and his cardiovascular disease fellowship at UCLA, where he has stayed on to pursue his ACHD training.

• Amit Goyal, MD
• Daniel Ambinder, MD

CardioNerds, Amit Goyal and Daniel Ambinder, join Duke University CardioNerds Ambassador and Correspondent, Dr. Kelly Arps for the diuretic showdown of a lifetime. Join us for this Cardiology vs. Nephrology discussion and respective approach to volume overload and diuretic strategies with Dr. Michael Felker (Professor of Medicine with tenure in the Division of Cardiology at Duke University School of Medicine), and Dr. Matt Sparks (Founding member of the Nephrology Social Medial Collective and #NephJC and Associate Professor of Medicine and Program Director for the Nephrology Fellowship Program at Duke University School of Medicine). Episode introduction, audio editing and Approach to Diuretic Resistance infographic by Dr. Gurleen Kaur (Director of the CardioNerds Internship).

Volume overload is a common indication for hospitalization in patients with heart failure. Loop diuretics are first line therapy for volume overload in heart failure, with assessment for adequate response within 3-6 hours after administration. Elevation in creatinine is common with venous congestion as well as during decongestion. While other causes of renal injury should be considered, an elevated creatinine in this context should not automatically trigger avoidance or cessation of diuresis. Diuretic resistance is an exaggerated form of natural safety mechanisms in the face of diuresis. Strategies for addressing diuretic resistance include optimizing dose and frequency of loop diuretic administration, adding adjunctive medication for sequential nephron blockade (i.e., thiazide diuretic, potassium sparing diuretic, acetazolamide, tolvaptan, SGLT2 inhibitor), and, in refractory cases, hemodialysis with ultrafiltration. In the outpatient setting, transition to a more potent loop diuretic (i.e., torsemide or bumetanide from furosemide), addition of a mineralocorticoid antagonist, or intermittent dosing of thiazide diuretic may augment maintenance diuretic therapy for patients with diminished response to loop diuretics. 

Check out the CardioNerds Failure Heart Success Series Page for more heart success episodes and content!

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The CardioNerds Heart Success Series is developed in collaboration with the Heart Failure Society of America. The Heart Failure Society of America is a multidisciplinary organization working to improve and expand heart failure care through collaboration, education, research, innovation, and advocacy. Its members include physicians, scientists, nurses, nurse practitioners, and pharmacists. Learn more at hfsa.org.

1. Elevation in creatinine is expected in both congested states and during diuresis. Do not avoid or stop diuresis in a patient who is clearly volume overloaded based on an elevated creatinine. There may be a role for right heart catheterization if the fluid and/or hemodynamic status is unclear. 
2. Alkalosis in the setting of loop diuretic administration and diuretic resistance may represent a natural response to loop diuretics and not volume depletion. Ensure adequate potassium repletion and try using a mineralocorticoid antagonist to correct this alkalosis. Acetazolamide is rarely necessary but may be of use.
3. Currently available evidence does not support extreme fluid or salt restriction in hospitalized patients with volume overload. Consider permissive restrictions and focus on choosing appropriate diuretic dosing for each individual patient. 
4. Diuretic resistance is an exaggerated form of diuretic braking, the kidney’s natural response to prevent dangerous degrees of sodium loss from the NKCC2-blocking effects of loop diuretics. 
5. Torsemide has improved bioavailability and duration of action compared to furosemide and may be a good choice for outpatient therapy in patients with limited diuretic response.  

Permissive hypercreatinemia 

Eventually the…body recognizes that, Hey, if we’re going to live without this very important, cotransporter in KCC2, we’re going to have to kick on things in the distal nephron to basically have a steady state. – Dr. Sparks

I would rather the patient feel good with a creatinine of 2 than terrible with creatinine of 1 and a half. – Dr. Felker

I think it’s pretty clear that in the long run, if they’re accompanied by effective decongestion, [minor elevations in creatinine] are actually if anything, a favorable prognostic indicator in terms of heart failure, prognosis, as opposed to an adverse one. – Dr. Felker

I think we hit a record for that. The most number of times a cardiologist has mentioned urine and measuring something in the urine. – Dr. Sparks

I can tell you my experience and it’s biased because I take care of people with pretty bad heart failure, but nine times out of 10, if we do a right-heart cath, because we’re not sure if the patient is still volume overloaded, they still are. – Dr. Felker

The more, when you look at the data, the more high quality, the study design, so randomized versus non-randomized, uh, the worst sodium and fluid restriction look. The one thing we are guaranteed to do though, is create unhappy patients. – Dr. Felker

1. Approach to diuretic therapy for inpatients with volume overload

• Evaluate for non-cardiac sources of edema (nephrotic syndrome, hepatic dysfunction, VTE, etc).
• Choose a starting dose of loop diuretic. The effective home dose is a helpful guide.
• Evaluate diuretic response within 2-3 hours of each dose. 
• If inadequate response, double the next dose of loop diuretic
• If inadequate or diminishing response to high-dose loop diuretic, consider additional pharmacotherapies (discussed below) 
• Consider right heart catheterization when
  • Concerned for low output state 
  • Exam is unclear for volume status

2. Initial dose of diuretic therapy for hospitalized patients 

The kidney alters its compensatory mechanisms to avoid being poisoned by too much blockade of important transporters like NKCC-2 (loop diuretic) and NCC (thiazide diuretics). 

• Start with at least double the patient’s maintenance dose of diuretic 
• Patients on chronic high-dose diuretics need higher initial IV doses
• Patients with CKD need higher doses of diuretic

3. Evaluating for adequate response to diuretic in a hospitalized patient

• 2-3 hours after the dose: 
  • Urine output: should be >150 mL / hour in the 2-3 hours after an adequate diuretic dose. 
  • Spot urine sodium: should be >50-70 mmol/L after an adequate diuretic dose 

• Daily: assess for improvement in jugular venous distension, lower extremity edema, weight, calculated ratio of fluid intake to output, and symptoms (orthopnea, dyspnea on exertion).

4. Approach to elevated creatinine in a volume overloaded patient

• Evaluate for alternative causes of hypercreatinemia: urinary obstruction, nephrotoxic agents (i.e. IV contrast, antibiotics, NSAIDs). 

• If exam and/or invasive hemodynamic data are consistent with volume overload, renal vascular congestion may be contributing to elevated creatinine, and is expected to improve with euvolemia. 

5. Approach to ‘contraction alkalosis’ in a patient undergoing diuresis

Alkalosis in the setting of loop diuretic administration and diuretic resistance may not indicate volume depletion.

• Diuretics increase delivery of sodium to the distal nephron, which accelerates potassium and proton secretion and results in bicarbonate reclamation, resulting in hypokalemic metabolic alkalosis. 
• Diuresis triggers activation of the renin-angiotensin system, which increases apical ATPase activity, increasing hydrogen ion secretion into the urine. 
• Repleting potassium (with potassium chloride, not potassium citrate) can correct metabolic alkalosis. 
• Use of mineralocorticoid receptor antagonists can improve this metabolic alkalosis.
• Acetazolamide may be used in refractory cases with severe metabolic alkalosis. 

6. Approach to hyponatremia in heart failure

• Consider reasonable degree of fluid restriction (available evidence does not support extreme fluid restriction. 
• Pharmacotherapy options for extreme hyponatremia includes urea and tolvaptan.

7. Causes of diuretic resistance

• Processes outside the nephron: venous congestion, low-output heart failure, hypoalbuminemia, increased intraabdominal pressure
• Intra-renal causes (response to sodium loss, caused by NKCC2 blockade by loop diuretics): reflexive upregulation of sodium intake in the proximal tubule, increased expression of sodium reabsorption channels (e.g., ENAC, NCC, pendrin)

8. Treatment options for diuretic resistance

• Increase dose +/- frequency of loop diuretic
• Thiazide diuretic (and monitor electrolytes closely)
• Potassium sparing diuretic (i.e., spironolactone, amiloride)
• Tolvaptan 
• SGLT2 inhibitor (“a diuretic enabler”)

Oral loop diuretics

Reviews

Ellison DH, Felker GM. Diuretic Treatment in Heart Failure [published correction appears in N Engl J Med. 2018 Feb 1;378(5):492]. N Engl J Med. 2017;377(20):1964-1975. doi:10.1056/NEJMra1703100 

Felker GM, Ellison DH, Mullens W, Cox ZL, Testani JM. Diuretic Therapy for Patients With Heart Failure: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75(10):1178-1195. doi:10.1016/j.jacc.2019.12.059

Trials

3T trial: Cox ZL, Hung R, Lenihan DJ, Testani JM. Diuretic Strategies for Loop Diuretic Resistance in Acute Heart Failure: The 3T Trial. JACC Heart Fail. 2020;8(3):157-168. doi:10.1016/j.jchf.2019.09.012

ASCEND-HF trial: O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure [published correction appears in N Engl J Med. 2011 Aug 25;365(8):773. Wilson, W H [corrected to Tang, W H W]]. N Engl J Med. 2011;365(1):32-43. doi:10.1056/NEJMoa1100171

ATHENA trial: Butler J, Anstrom KJ, Felker GM, et al. Efficacy and Safety of Spironolactone in Acute Heart Failure: The ATHENA-HF Randomized Clinical Trial. JAMA Cardiol. 2017;2(9):950-958. doi:10.1001/jamacardio.2017.2198

BNP trial: McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation. 2002;106(4):416-422. doi:10.1161/01.cir.0000025242.79963.4c

DOSE trial: Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364(9):797-805. doi:10.1056/NEJMoa1005419

EVEREST trial: Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007;297(12):1319-1331. doi:10.1001/jama.297.12.1319

ROPA-DOP trial: Sharma K, Vaishnav J, Kalathiya R, et al. Randomized Evaluation of Heart Failure With Preserved Ejection Fraction Patients With Acute Heart Failure and Dopamine: The ROPA-DOP Trial. JACC Heart Fail. 2018;6(10):859-870. doi:10.1016/j.jchf.2018.04.008

ROSE trial: Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA. 2013;310(23):2533-2543. doi:10.1001/jama.2013.282190

TRANSFORM-HF trial: Greene SJ, Velazquez EJ, Anstrom KJ, et al. Pragmatic Design of Randomized Clinical Trials for Heart Failure: Rationale and Design of the TRANSFORM-HF Trial [published online ahead of print, 2021 Mar 10]. JACC Heart Fail. 2021;S2213-1779(21)00061-5. doi:10.1016/j.jchf.2021.01.013

Dr. Michael Felker is a Professor of Medicine in the Division of Cardiology at Duke University and head of Cardiovascular Research at the Duke Clinical Research Institute. Dr. Felker obtained his medical degree from Duke University School of Medicine, completed internal medicine residency training at the Johns Hopkins Osler program where he served as ACS, and finally cardiology fellowship at Duke University where he remained for an illustrious career including having served as Chief of the Heart Failure Section and numerous other roles.

Dr. Matt Sparks is the Nephrology Fellowship Program and Director of medical student research at Duke University. In addition to clinical, research, and educational roles locally at Duke University, Dr. Sparks is internationally recognized as a founding member of the Nephrology Social Media Collective (NSMC) and the widely popular nephrology journal club (#NephJC) with the goals of leveraging social media to enhance free online medical education. In addition to the NephJC, they’ve created several impactful education projects including the AJKD nephrology blog, NephMadness, the Renal Fellow Network.

• Amit Goyal, MD
• Daniel Ambinder, MD

CardioNerds (Amit Goyal and Daniel Ambinder), join Dr. Anjali Wagle (Internal medicine resident, Johns Hopkins Hospital) and Dr. Nick Smith (Cardiology fellow, Johns Hopkins Hospital) for an important discussion involving a patient with non-ischemic dilated cardiomyopathy and biventricular heart failure who had developed diuretic resistance. They discuss the role for invasive hemodynamic assessment of volume overload, initial strategies in managing a patient with volume overload, the role of guideline directed therapy in the management of patients with recurrent volume overload, and advanced strategies for diuretic resistance. Dr. Nisha Gilotra (Director of the Cardiac Sarcoidosis Program and assistant professor of medicine, Johns Hopkins Hospital) provides the E-CPR for this episode. Audio editing and Approach to Diuretic Resistance infographic by Dr. Gurleen Kaur (Director of the CardioNerds Internship).

This episode is made possible with support from Panacea Financial. Panacea Financial is a national digital bank built for doctors by doctors. Visit panaceafinancial.com today to open your free account and join the growing community of physicians nationwide who expect more from their bank. Panacea Financial is a division of Primis, member FDIC.

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A young woman in her 20s with non-ischemic dilated cardiomyopathy and NYHA class IV ACC stage D biventricular heart failure with an LV ejection fraction of 30-35% on palliative inotropic therapy complicated by cardiogenic cirrhosis and stage IIIb chronic kidney disease presented with acute decompensated heart failure with volume overload. During her hospitalization she exhibited profound signs of diuretic resistance with minimal improvement after increasing inotropes, increasing IV loop diuretics, adding IV thiazides, and trialing continuous IV furosemide. She was given high dose mineralocorticoids, IV acetazolamide, and hypertonic saline paired with IV furosemide and had a durable treatment response.

1. Diuretic resistance is a complex clinical problem defined as inadequate natriuresis despite an adequate diuretic regimen. However, the practitioner cannot overlook low output heart failure and/or insufficient renal perfusion as the causes for inadequate diuretic response. In cases of inadequate urine output due to low cardiac output, increased inotropic or mechanical support would be the first objective.
2. Confirming adequate cardiac output to support renal perfusion and/or confirming high filling pressures may require invasive hemodynamic assessment.
3. Sodium avidity is most effectively blunted by treating the patient with maximally tolerated guideline directed therapy. This includes but is not limited to a backbone of ARNI (or ACE or ARB), mineralocorticoid receptor antagonists, beta-blockers, and SGLT-2 inhibitors.
4. In cases of advanced diuretic resistance, hypertonic saline paired with high dose IV furosemide can be an effective strategy.
5. In cases of diuretic resistance combined with cirrhosis and heart failure there is a synergistic hyperaldosteronism that can be targeted with higher doses of mineralocorticoid receptors as is seen in the treatment of cirrhosis with ascites.

1. What is the role for invasive hemodynamic assessment in acute decompensated heart failure?

• Cases where intracardiac filling pressures are in question: right heart catheterization (RHC) can give insight into the presence and degree of right versus left sided filling pressures. We discussed the concepts of “RV equalizer” vs “RV compensated” groups in Episode 142 with Dr. Mark Drazner.
• Cases where cardiac output is in question, especially to guide vasoactive infusions during low flow states: RHC can assess cardiac output and cardiac power output.
• Cases with rising creatinine during diuresis despite a clinical exam suggesting volume overload.
• Cases where body habitus prevents optimal evaluation.

2. What are the initial strategies in managing a patient with volume overload?

• Initial furosemide dosing: The patient’s home dose, renal function, and reason for decompensation all help decide the initial IV diuretic dosing. However, in general if a patient has an outpatient furosemide regimen, the initial diuretic dose should 2.5 times the oral dosing for intermittent IV doses. For example, if a patient is taking 40 mg PO daily as an outpatient, a starting dose of 100 mg IV as a starting dose is appropriate.
• Furosemide escalation
  • IV dosing: constantly assess the appropriateness of each furosemide dose by monitoring hourly urine output and daily standing weight changes. Post-dose urine sodium is another option. If the patient has not made 300 cc/hr after their last furosemide dose, you may need to escalate the dose. Due to the furosemide threshold effect, the patient may need to double the prior dose for every uptitration. Additionally, even though furosemide lasts for 6 hours, if the diuretic effect is minimal, immediately prescribe double the last dose of furosemide.
  • Continuous infusion vs bolus: The DOSE trial, or Diuretic Optimization Strategies Evaluation, randomized 308 patients to either IV furosemide q12 or an equivalent dose as a continuous infusion and found no difference in secondary endpoints of change in weight or net fluid loses. There may be a role for continuous infusion furosemide in patients who are sensitive to large fluid shifts, such as patients with right heart failure.
• Adjunctive diuretics
  • Thiazide diuretics: when high dose IV furosemide is failing, thiazide diuretics are commonly the first adjunct use. When given in combination with loop diuretics, they allow blockade of both the sodium-potassium-chloride channels in the loop as well as the sodium chloride channels distally to allow increased blockade of the ability to reabsorb sodium and potassium.
  • Potassium sparing diuretics: the addition of potassium-sparing diuretics (i.e., mineralocorticoid receptor antagonists or ENaC inhibitors like amiloride or triamterene) may be especially helpful for hypokalemia caused by loop +/- thiazide diuretics.
  • Acetazolamide: is a carbonic anhydrase inhibitor and acts in the proximal convoluted tubule. It aids in the excretion of sodium and bicarbonate. It is commonly, but not always, used in situations where serum bicarbonates become elevated.

3. What is the role of guideline directed therapy in the management of patients with recurrent volume overload?

• In short, maximally tolerated guideline directed therapy blunts sodium retention through multiple mechanisms, but none more so than blockers of the renin-angiotensin-aldosterone-system. By blocking aspects of this pathway, the kidneys’ propensity to reabsorb sodium is blunted upstream of the nephron, preventing some of the need for high dose diuretics. Individual GDMT therapies and some of their effects on diuretic dosing are explained below.
• ARNI (angiotensin receptor neprilysin inhibitor): post-hoc analysis of the PARADIGM trial demonstrated that patients were more likely to decrease diuretic dosing on ARNI compared to placebo. Other single center studies have demonstrated similar effects, finding that loop diuretic dosing decrease was achieved in 1/3 of patients with a mean reduction of 10±38 mg furosemide equivalent across the entire population. Conversely, be cautious of diuretic dosing when initiating a patient on an ARNI agent. Enjoy Episode 148 with Dr. Milton Packer discussing the history of ARNI!
• MRA: Post-hoc analysis of EPHESUS demonstrated that the mineralocorticoid receptor antagonist Eplerenone led to a mean furosemide equivalent dose reduction of −2.2 mg/day (−2.9 to −1.6) throughout the follow-up
• MADIT-CRT: A post-hoc analysis of the MADIT-CRT trial showed that CRT implant led to diuretic cessation in 9.7% of patients. In a subsequent retrospective study of 352 subjects on baseline diuretics, 36% of patients tolerated a down-titration of loop diuretic dose following CRT-implant. These effects appeared sustained and were associated with both an improved hemodynamic performance and decreased probability of HF or death.
• SGLT-2 inhibitors: SGLT-2 inhibitors have a modest diuretic effect through glycosuria. Post-hoc analysis of the DAPA-HF trial did not show reduction in diuretic requirements over the 18-month trial, however SGLT-2 inhibitors have been shown to lead to reduction in diuretic requirements when used in combination when used in combination with MRA, BB, and ARNI therapy as part of a GDMT regimen.

4. What are some advanced strategies for diuretic resistance?

• Dopamine: The ROPA-DOP trial was a small single center trial performed in hospitalized patients with acute decompensated heart failure with preserved ejection fraction. It showed that continuous low dose dopamine infusion had no significant impact on renal function or decongestion.
• High Dose Spironolactone: Post-hoc analyses of trials involving spironolactone have not demonstrated reductions in diuretic dosing. However, in patients with a combination of cirrhosis and heart failure the hyperaldosteronism that results can be profound. For these patients, natriuretic doses of aldosterone antagonists (spironolactone >50 mg/day) may be a potential option and have been studied in small proof-of-principle studies. The competitive natriuretic response of aldosterone antagonists is related to activity of the renin-angiotensin-aldosterone system: the higher the renin-angiotensin-aldosterone system activity, the higher the dose of aldosterone antagonist required to produce natriuresis.
• Hypertonic saline: Hypertonic saline combined with high-dose loop diuretics has been studied and shown to produce greater natriuresis than diuretics alone, particularly in patients with diuretic resistance. The proposed mechanism of hypertonic saline’s diuretic effect has been the instantaneous mobilization of extravascular fluid into the intravascular space through the osmotic action of hypertonic saline.

1) Felker GM, Institute DCR, Ellison DH, et al. Diuretic Therapy for Patients With Heart Failure: JACC 2020 Mar, 75 (10) 1178-195

2) DOSE Trial: Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364(9):797-805

3) Athena-HF: Butler J, Anstrom KJ, Felker GM, et al. Efficacy and Safety of Spironolactone in Acute Heart Failure. JAMA Cardiol. 2017;2(9):950–958

4) Wan S-H, Stevens SR, et al. Differential Response to Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Reduced or Preserved Ejection Fraction. Circulation: Heart Failure. 2016;9:e002593

5) Bansal S, Lindenfeld J, Schrier RW. Sodium retention in heart failure and cirrhosis: potential role of natriuretic doses of mineralocorticoid antagonist?. Circ Heart Fail. 2009;2(4):370-376.

6) ROPA-DOP Trial: Sharma K, Vaishnav J, Kalathiya R, et al. Randomized Evaluation of Heart Failure With Preserved Ejection Fraction Patients With Acute Heart Failure and Dopamine. JACC Heart Fail. 2018;6(10):859-870.

7) RALES trial: Pitt B, et al. “The effect of spironolactone on morbidity and mortality in patients with severe heart failure”. New England Journal of Medicine. 1999. 341(10):709-717.

8) PARADIGM Trial: McMurray JJV, et al. “Angiotensin-neprilysin inhibition versus enalapril in heart failure”. The New England Journal of Medicine. 2014. 371(11):993-1004.

9) Vardeny O, Claggett B, Kachadourian J, et al. Reduced loop diuretic use in patients taking sacubitril/ valsartan compared with enalapril: the PARADIGM-HF trial. Eur J Heart Fail 2019;21:337-41.

10) Kerr B, Mcdonald K, Angiotensin Receptor Neprilysin Inhibitors in HFrEF: Is This the First Disease Modifying Therapy Drug Class Leading to a Substantial Reduction in Diuretic Need? Int J Heart Fail. 2021 Apr;3(2):106-116

• Karan Desai, MD
• Amit Goyal, MD
• Daniel Ambinder, MD

CardioNerds (Amit Goyal and Daniel Ambinder), Cardio-OB series co-chair and University of Texas Southwestern Cardiology Fellow, Dr. Sonia Shah, episode lead fellow, Dr. Kaitlyn Ibrahim (Temple University now practicing with Lankenau Heart Group), join Dr. Afshan Hameed (Maternal-Fetal Medicine, Obstetrics & Gynecology, UC Irvine), Dr. Paul Forfia (Co-Director, Pulmonary Hypertension, Right Heart Failure & CTEPH Program, Temple University Hospital), and Dr. Marie-Louise Meng (Obstetric and Cardiothoracic Anesthesiology, Duke University) to discuss pregnancy and multidisciplinary critical care.

Three experts from varied subspecialties including Cardiology, Pulmonary Hypertension, Maternal Fetal Medicine, Cardiac Anesthesia and Obstetrical Anesthesia guide listeners through a case of a patient with a congenital conotruncal ventricular septal defect, Eisenmenger physiology, and pulmonary hypertension who becomes pregnant. The discussion touches on pre-conception risk assessment, pulmonary hypertension medical therapy in pregnancy, maternal monitoring during pregnancy, development of detailed multidisciplinary delivery plans and accessibility of such plans, and peri- and post-partum multidisciplinary management of high-risk patients.

Audio editing and episode introduction by CardioNerds Academy Intern, Christian Faaborg-Andersen.

Pearls • Notes • References • Guest Profiles • Production Team

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1. Cyanotic congenital heart disease presents multiple risks to the fetus, the most significant being intrauterine growth restriction. In a patient with Eisenmenger physiology, maternal oxygenation should be monitored closely throughout pregnancy, as hypoxia is often a marker of increased right to left shunting in these patients.
2. In patients with pulmonary hypertension, the RV-PA coupling relationship is the best indicator of maternal cardiovascular reserve through the pregnancy and post-partum period. The goal of therapy is to get the pulmonary vascular resistance down to a point where the right heart can adapt to that load and function either at a normal or a near-normal level.
3. When a high-risk patient meets with Anesthesia, it is important to consider the A’s: 1. Airway (anticipating any potential difficulties); 2. Access (whether this may present a challenge at the time of delivery); 3. Anxiety (specifically differentiating true hemodynamic changes in high-risk patients versus physiologic changes from anxiety); 4. Anticoagulation (knowledge of what agent the patient is on to determine safety of neuraxial anesthesia); 5. Availability (determining who else needs to be in the room, i.e. CT surgery, cardiothoracic anesthesia, ECMO team); 6. Arena (where is the safest place for this patient to deliver).
4. In patients with a shunt who undergo a Cesarean section, the uterus should not be exteriorized due to risk of venous micro air emboli.
5. As Dr. Forfia says, “panic is more dangerous sometimes than pulmonary hypertension!” Meaning, it is important to meet as a multidisciplinary team to develop a clear, easily accessible delivery plan for the patient. It is also prudent to have “everyone functioning in the environment they function best” like delivering the baby on the labor and delivery floor where all the necessary equipment and team members are available and bringing in other experts if needed rather than a cardiac operating room.

For a deep dive into Pregnancy & Pulmonary Hypertension, enjoy:

• Episode #124 with Dr. Candice Silversides.
• Episode #144 – Case Report: A Mother with Shortness of Breath

1. How does a multidisciplinary team play a role in the care for a high risk cardio-obstetrics patient, particularly one with congenital heart disease and pulmonary hypertension?

• According to the 2018 ESC guidelines, a multidisciplinary team is required to care for the pregnant patient with PH. This should include a PH expert at an experienced center for pregnancy and cardiac disease. Maternal outcomes in patients with PH have improved with targeted therapies as well as a multidisciplinary, team-based approach.
• A multidisciplinary team for a high-risk cardio-obstetrics patient should have representation from several subspecialties, typically including Cardiology (and in patients with PH, a PH expert should be included), Maternal Fetal Medicine, and Anesthesiology. Additional subspecialities can be added depending on the underlying diagnosis of the patient and any potential challenges anticipated at the time of delivery. (i.e. CT Surgery if ECMO may be needed).
• The key is consistent membership within the group for optimal team dynamics, working relationships, and continuity of patient care. Familiarity among group members helps to facilitate improved communication.
• Team members should be experienced in the care of high-risk cardio-obstetrics patients. As Dr. Forfia mentions during the podcast, panic can be the downfall of a well-functioning team in a high stake setting and is often dangerous to the patient.
• Frequent meetings should happen amongst group members to discuss patients and to form individualized, multidisciplinary delivery plans. The delivery plan should detail each aspect of labor and delivery, include the names and contact information of providers involved in the patient’s care, and should be easily accessible (ideally in a prominent location in the patient’s electronic medical record).
• If possible, providers should be allowed to work in their usual environment. For example, a high-risk patient should deliver on the L&D floor/L&D OR with OB/MFM and other members of the multidisciplinary team should come to that area. This ensures all necessary equipment and experienced staff will be present during the delivery.

2. What are the important considerations during the Anesthesia evaluation of a high-risk pregnant patient?

• When a high-risk patient meets with Anesthesia during pregnancy, the A’s should be considered, listed below:
• Airway: It is important to perform an assessment of the patient’s airway prior to delivery to anticipate any potential difficulties and to ensure that the appropriate equipment is available at the time of delivery if a difficult airway is anticipated.
• Access: Potential intravenous access sites should be assessed prior to delivery to determine whether access may present a challenge at the time of delivery.
• Anxiety: An Anesthesiologist for a high-risk patient should be adept at differentiating true hemodynamic alterations versus physiologic changes from anxiety to provide appropriate therapy and counseling.
• Anticoagulation: A subset of high-risk cardiac patients will be on chronic anticoagulation therapy during pregnancy. Knowledge of a patient’s anticoagulant is critical in determining the safety of neuraxial anesthesia. It is also important to highlight that Eisenmenger’s can lead to thrombocytopenia, which (if severe enough) can be a contraindication to neuraxial anesthesia.
• Availability: It is vital to determine who will need to be available for a high-risk patient’s delivery, particularly which specialists, but also which subspecialists (i.e. cardiac anesthesia, cardiologists with expertise in pulmonary hypertension, ECMO team etc.). This allows adequate planning and staffing at the time of delivery.
• Arena: The multidisciplinary team should discuss the best place for the patient to deliver (i.e. the L&D floor, L&D OR, cardiac OR) depending on the expected course of delivery. Often, it is best to have the patient delivery on a dedicated obstetrical floor and bring any necessary consultants there to ensure all necessary equipment for the delivery and experienced obstetrical staff are present.

3. What are some pearls for the multidisciplinary management of high-risk cardio-obstetrics patients and specifically those with pulmonary hypertension and a shunt lesion during delivery?

• As mentioned previously, a detailed delivery plan should be created in advance of delivery with input from the multidisciplinary team caring for the patient. This should be easily accessible by all team members at the time of delivery.
• Most of these patients should deliver by 37 weeks gestation at a center with cardiology and intensive care unit support if needed.
• Patients with pulmonary hypertension should avoid Valsalva/pushing as much as possible. This is accomplished by an assisted second stage of labor.
• Patients with uncorrected cyanotic congenital heart disease should be considered for antibiotic prophylaxis for endocarditis at the time of delivery.
• In patients with an intracardiac shunt, all intravenous lines should have filters to prevent paradoxical air embolism. Additionally, the OB team should avoid “exteriorizing” the uterus during a C-section due to risk of paradoxical air embolism. This is particularly important in right-to-left shunt lesions.
• Fetal heart rate can serve as the “5th vital sign” of the mother during the time of delivery and can add to the overall assessment of the mother and fetus.
• Specialized Anesthesia care may involve the insertion of a central line and/or arterial line for close hemodynamic monitoring during delivery and in the immediate post-partum period.

4. What are the interdisciplinary critical care considerations in the post-partum period for high-risk patients, and specifically those with pulmonary hypertension and shunt lesions?

• According to the 2018 ESC guidelines, the highest risk period is during puerperium and early post-partum where fluid shifts and hemodynamic changes are the greatest. As part of the delivery plan, immediate post-partum care should also be specified. Often high-risk patients may need to be monitored and managed in an ICU setting or on a Cardiology primary service with the OB/MFM, Anesthesiology, and Cardiology/PH teams participating in co-management.
• Meticulous fluid balance and optimization of RV function are important determinants of an optimal outcome in patients with PH who are post-partum.
• Frequent monitoring of volume status and oxygenation by experts in Cardiology and Pulmonary Hypertension is key in the early post-partum period in these patients. If progressive volume overload is seen, diuretics should be administered.
• Fluid mobilization in the early post-partum period is a cause of right ventricular volume overload and right heart failure and may lead to increased shunting.

5. If the unexpected happens, what are pearls for cardiac arrest in a pregnant patient?

• Cardiac arrest in the pregnant patient can have many possible causes. Initial steps including establishing IV access above the diaphragm, administering 100% oxygen, and relieving aortocaval compression with continuous left lateral displacement of the gravid uterus. This helps to improve maternal hemodynamics during compressions.
• The gravid uterus causes upward displacement of the internal organs. According to the AHA guidelines, chest compressions should be delivered with the patient supine, with constant left lateral displacement of the gravid uterus to relieve aortocaval compression. In the past, a 30-degree left lateral decubitus tilt was recommended, however it has been shown that this decreases the effectiveness of chest compressions and is therefore no longer recommended.
• If the patient was receiving IV Magnesium pre-arrest, this should be stopped, and IV/IO Calcium Chloride or Calcium Gluconate given.
• The pregnant patient’s airway undergoes significant changes during pregnancy, with increased friability and mucosal secretion. The upward displacement of internal organs also increases the risk of aspiration. The upward shift of the diaphragm leads to decreased functional residual capacity, increased metabolic demand, and potentially faster desaturation.
• Defibrillation doses and standard ACLS medication doses remain the same in the pregnant patient. During a cardiac arrest, no medications should be withheld for concerns of teratogenicity.
• If the pregnant patient does not respond to intervention and lacks return of spontaneous circulation, Cesarean section must be considered immediately within the first 4-5 minutes of CPR for optimal maternal and fetal outcomes. This should be done at the site of the cardiac arrest if it was an in-hospital cardiac arrest.

1. Li Q, Dimopoulos K, Liu T, et al. Peripartum outcomes in a large population of women with pulmonary arterial hypertension associated with congenital heart disease. Eur J Prev Cardiol. 2019; 26:1067-1076.

2. Presbitero P, Somerville J, Stone S, Aruta E, Spiegelhalter D, Rabajoli F. Pregnancy in cyanotic congenital heart disease. Outcome of mother and fetus. Circulation. 1994; 89:2673 – 2676.

3. Regitz-Zagrosek V, Roos-Hesselink J.W., Bauersachs J, et al. 2018 ESC guidelines for the management of cardiovascular diseases during pregnancy: the task force for the management of cardiovascular diseases during pregnancy of the European Society of Cardiology (ESC). Eur Hear J. 2018; 39:3165-3241.

4. Jeejeebhoy FM, et al. Cardiac arrest in pregnancy. A scientific statement from the American Heart Association. Circulation. 2015; 132: 1747-1773.

Dr. Kaitlyn Ibrahim has graduated cardiology fellowship from Temple University Hospital. She is currently a non-invasive cardiologist with a focus on women’s health as part of the Lankenau Heart Group.

Dr. Afshan Hameed is a Clinical Professor of both Cardiology and Maternal Fetal Medicine at the University of California, Irvine.  Dr. Hameed has served on multiple guideline committees on heart disease and pregnancy for the American College of Obstetrics and Gynecology and serves on the California Maternal Quality Care Collaborative (CMQCC) Pregnancy Associated Mortality Review Advisory Committee (PAMR) that reviews all cases of maternal mortality to identify gaps in care for quality improvement opportunities. She also serves on the writing committee for the Heart Rhythm Society’s “Arrhythmias in Pregnancy Guidelines” and as an expert to help create an Obstetrics Basic Life Support curriculum to integrate into the American Heart Association Life Support Program.

Dr. Paul Forfia is a Professor of Medicine at Temple University Hospital and Co-Director of the Pulmonary Hypertension, Right Heart Failure, and CTEPH Program at Temple University Hospital. He is a renowned expert in the management of patients with right heart failure and PH and has grown the program at Temple to one of the largest in the country.

Dr. Marie-Louise Meng is an assistant professor of anesthesiology at Duke University who has completed additional fellowships in both obstetrical anesthesia and cardiothoracic anesthesia. She is also a physician-scientist researching the role of echocardiography and biomarkers in identifying women at risk of cardiovascular complications after pregnancies complicated by preeclampsia.

• Natalie Stokes, MD
• Sonia Shah, MD
• Amit Goyal, MD
• Daniel Ambinder, MD

CardioNerds (Amit Goyal, Daniel Ambinder) and Dr. Mark Belkin, (CardioNerds Correspondent) and Dr. Shirlene Obuobi (CardioNerds Ambassador) from University of Chicago are honored to bring to you the Dr. Milton Packer perspective on the evolution of the neurohormonal hypothesis as part of The CardioNerds Heart Success Series.

In part 6 Dr. Packer reflects on a conversation he had with Dr. Eugene Braunwald about mentorship and its role in immortality. This episode is particularly meaningful to the CardioNerds team as mentorship and sponsorship is such an important part of the CardioNerds mission.

Check out the CardioNerds Heart Failure Success Series Page for more heart success episodes and content!

This is a non CME episode. Disclosures: Milton Packer reports receiving consulting fees from Abbvie, Actavis, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson & Johnson Health Care Systems Inc., Eli Lilly and Company, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, Teva Pharmaceuticals USA Inc. and Theravance Biopharma Inc.

CardioNerds Heart Failure Success Series Page
CardioNerds Episode Page
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CardioNerds Journal Club
Subscribe to The Heartbeat Newsletter!
Check out CardioNerds SWAG!
Become a CardioNerds Patron!

This CardioNerds Heart Failure Success Series was created in memory of Dr. David Taylor. We thank our partners at the Heart Failure Society of America which is a multidisciplinary organization working to improve and expand heart failure care through collaboration, education, research, innovation, and advocacy. Its members include physicians, scientists, nurses, nurse practitioners, and pharmacists. Learn more at hfsa.org.

CardioNerds (Amit Goyal, Daniel Ambinder) and Dr. Mark Belkin, (CardioNerds Correspondent) and Dr. Shirlene Obuobi (CardioNerds Ambassador) from University of Chicago are honored to bring to you the Dr. Milton Packer perspective on the evolution of the neurohormonal hypothesis as part of The CardioNerds Heart Success Series.

In part 5, Dr. Packer shares his thoughts on the term “guideline directed medical therapy,” guidelines in general, and the challenges of using the ejection fraction to measure systolic function.

Check out the CardioNerds Heart Failure Success Series Page for more heart success episodes and content!

This is a non CME episode. Disclosures: Milton Packer reports receiving consulting fees from Abbvie, Actavis, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson & Johnson Health Care Systems Inc., Eli Lilly and Company, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, Teva Pharmaceuticals USA Inc. and Theravance Biopharma Inc.

CardioNerds Heart Failure Success Series Page
CardioNerds Episode Page
CardioNerds Academy
Cardionerds Healy Honor Roll

CardioNerds Journal Club
Subscribe to The Heartbeat Newsletter!
Check out CardioNerds SWAG!
Become a CardioNerds Patron!

This CardioNerds Heart Failure Success Series was created in memory of Dr. David Taylor. We thank our partners at the Heart Failure Society of America which is a multidisciplinary organization working to improve and expand heart failure care through collaboration, education, research, innovation, and advocacy. Its members include physicians, scientists, nurses, nurse practitioners, and pharmacists. Learn more at hfsa.org.

CardioNerds (Amit Goyal, Daniel Ambinder) and Dr. Mark Belkin, (CardioNerds Correspondent) and Dr. Shirlene Obuobi (CardioNerds Ambassador) from University of Chicago are honored to bring to you the Dr. Milton Packer perspective on the evolution of the neurohormonal hypothesis as part of The CardioNerds Heart Success Series.

In part 4, Dr. Packer shares his perspective on the revolutionary SGLT2 inhibors. We discuss the mechanisms of action and the data regarding their role in the care of heart failure patients. This episode is particularly historic in that Dr. Packer shares his thoughts about the EMPEROR-PRESERVED trial well before the data was available. Also see Dr. Mark Belkin’s DocWire News article EMPEROR’s New Groove? Empagliflozin Provides Long-Awaited Treatment for HFpEF where Dr. Packer is quoted as saying “we are pleased to have the first trial in patients with HFpEF that shows an unequivocally positive and clinically important result. We are looking forward to many secondary papers that will provide detailed information about what we have found, and what it means for patients.”

Check out the CardioNerds Heart Failure Success Series Page for more heart success episodes and content!

This is a non CME episode. Disclosures: Milton Packer reports receiving consulting fees from Abbvie, Actavis, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson & Johnson Health Care Systems Inc., Eli Lilly and Company, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, Teva Pharmaceuticals USA Inc. and Theravance Biopharma Inc.

CardioNerds Heart Failure Success Series Page
CardioNerds Episode Page
CardioNerds Academy
Cardionerds Healy Honor Roll

CardioNerds Journal Club
Subscribe to The Heartbeat Newsletter!
Check out CardioNerds SWAG!
Become a CardioNerds Patron!

This CardioNerds Heart Failure Success Series was created in memory of Dr. David Taylor. We thank our partners at the Heart Failure Society of America which is a multidisciplinary organization working to improve and expand heart failure care through collaboration, education, research, innovation, and advocacy. Its members include physicians, scientists, nurses, nurse practitioners, and pharmacists. Learn more at hfsa.org.

CardioNerds (Amit Goyal, Daniel Ambinder) and Dr. Mark Belkin, (CardioNerds Correspondent) and Dr. Shirlene Obuobi (CardioNerds Ambassador) from University of Chicago are honored to bring to you the Dr. Milton Packer perspective on the evolution of the neurohormonal hypothesis as part of The CardioNerds Heart Success Series. In part 3 Dr. Packer reflects on the value of neutral trials and recounts the journey that led to the PARADIGM Trial

Check out the CardioNerds Heart Failure Success Series Page for more heart success episodes and content!

This is a non CME episode. Disclosures: Milton Packer reports receiving consulting fees from Abbvie, Actavis, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson & Johnson Health Care Systems Inc., Eli Lilly and Company, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, Teva Pharmaceuticals USA Inc. and Theravance Biopharma Inc.

CardioNerds Heart Failure Success Series Page
CardioNerds Episode Page
CardioNerds Academy
Cardionerds Healy Honor Roll

CardioNerds Journal Club
Subscribe to The Heartbeat Newsletter!
Check out CardioNerds SWAG!
Become a CardioNerds Patron!

This CardioNerds Heart Failure Success Series was created in memory of Dr. David Taylor. We thank our partners at the Heart Failure Society of America which is a multidisciplinary organization working to improve and expand heart failure care through collaboration, education, research, innovation, and advocacy. Its members include physicians, scientists, nurses, nurse practitioners, and pharmacists. Learn more at hfsa.org.