#150 HFpEF Update with Dr Clyde Yancy MD

May 20, 2019 | By Beth Garbitelli

Best practices update and the future of heart failure with preserved EF

Update on current best practices and the future of HFpEF (heart failure with preserved ejection fraction) with master cardiologist, Dr Clyde Yancy MD, Chief of Cardiology and Professor of Medicine (Cardiology) and Medical Social Sciences, Northwestern, Feinberg School of Medicine. Topics include: pathophysiology, HFpEF phenotypes, how to interpret a borderline ejection fraction, evidence based therapies, diuretics, and future directions (pulmonary artery monitors, interatrial shunts, ARNI compounds), and more!

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Credits

Written and produced by: Paul Williams MD, FACP; Sarah Phoebe Roberts MPH

Hosts: Matthew Watto MD, FACP; Paul Williams MD, FACP; Stuart Brigham MD

Show Notes: Justin Berk MD, MPH, MBA; and Beth Garbitelli MS1

Infographics: Beth Garbitelli MS1

Editor: Matthew Watto MD, FACP

Guest: Clyde Yancy MD, MSc, MACC, FAHA, MACP, FHFSA

Time Stamps

• 00:00 Thanks to our producers Sarah Phoebe Roberts, Beth Garbitelli and Justin Berk
• 00:50 Intro and guest bio
• 04:00 Guest one liner, career advice
• 08:20 Ms Diana Stolic has HFpEF. What’s the difference in HFpEF and diastolic dysfunction?  
• 11:33 How should we think about borderline ejection fraction?
• 15:24 Pathophysiology and Phenotypes of HFpEF
• 18:57 More on the pathophysiology of HFpEF (nitric oxide, fibrosis, inflammatory signaling)
• 21:00 Are there morbidity and mortality differences for HFpEF versus HFrEF?
• 24:45 What historical factors are most important in HFpEF?
• 27:50 Pulmonary artery monitors for HFpEF
• 29:00 Does Diuretic therapy differ in HFpEF and HFrEF?
• 33:44 Ischemic workup for new HFpEF
• 35:33 Right heart cath for HFpEF
• 36:53 Future of HFpEF
• 41:04 Will ARNI compounds work for HFpEF? What are the current medications for HFpEF?
• 45:20 SGLT2 inhibitors for heart failure
• 46:30 Outro

HFpEF Pearls

The first discrimination point in CHF is preserved vs. reduced ejection fraction.

There are multiple phenotypes of HFpEF and they may have different therapeutic strategies.  

The mortality rate of HFpEF is lower than HFrEF, but the morbidity may be worse.

There are no significant differences in physical exam findings between HFpEF and HFrEF.

For new HFpEF, there should be a coronary work-up. This may be initially done with coronary CT rather than catheterization.

New imaging strategies of the LAD may help predict which patients will have HFpEF.

New evidence suggests interatrial shunts may offer symptomatic and mortality benefit.

Basic treatment plan should include: diuresis for dyspnea, spironolactone (if elevated proBNP), SGLT2i if diabetes.

Future research is underway to evaluate SGLT2i in non-diabetics and sacubitril/valsartan (an ARNI compound) in HFpEF.

HFpEF Show Notes

Definitions

Heart Failure  – The syndrome of shortness of breath, volume overload, and elevated natriuretic peptide.

Heart Failure with Preserved Ejection Fraction (HFpEF) – The first discrimination point in the heart failure syndrome. EF is considered ‘preserved’ if normal (i.e. >50%).

Ejection Fraction: How much blood is emitted with each contraction of the ventricle in comparison to how much blood is in the heart

Global Longitudinal Strain: Measures the deformation of the myocardium during systole. Less load dependent and more reflective of intrinsic ventricular functioning, contractility.

Diastolic Dysfunction – Specific hemodynamic consequences associated with valvular disease or ischemia.

Heart Failure with Preserved EF (HFpEF)

The Heart Failure Clinical Syndrome

Heart failure is the syndrome of shortness of breath, volume overload, and elevated natriuretic peptide often requiring hospital admission. The first discrimination point is the ejection fraction (EF). If the EF < 40%, this is Heart Failure with Reduced Ejection Fraction (HFrEF). If the EF is normal (i.e. >50%), this is HFpEF. In low EF with preserved strain, the ventricle may improve. Low EF and low strain is less favorable (Int J Cardiol Heart Vasc 2019).  Up to 50% of patients with heart failure have preserved ejection fraction.

The “Gray Zone” EF

There is also a “gray zone” with a measured EF of 40 – 50%. Dr. Yancy suggests that this should be interpreted in context: e.g. a patient with known HFrEF and now has some improvement in ejection fraction may be different than a patient with HFpEF with worsening cardiac remodeling/ventricular weakening and lower ejection fraction.  

Multiple phenotypes

HFpEF is an amalgam of different cardiac metabolic profiles and phenotypes that require unique approaches and need to be addressed with different prescribed therapies (i.e. Diabetes, AFib, HTN, Hyperlipidemia). For volume redistribution issues occurring in diabetic patients with obesity and a degree of renal insufficiency, physicians should take care not to over-diurese. SGLT2 inhibitors may be helpful for patients with diabetes/obesity/renal insufficiency. Patients with pulmonary hypertension may be more responsive to anti-ANP (ie: sacubitril) or antifibrotic therapy, like spironolactone. For patients with cardiorenal issues, it may be most important to optimize renal function.

Pathophysiology of HFpEF

Hypertension can lead to both HFrEF and HFpEF. Left ventricular hypertrophy (LVH) is not a required part of the pathophysiology.  It may also be driven by a genetic predilection.

Research indicates that the pathophysiology of heart failure may be caused by a deficiency in nitric oxide and impairment in nitric oxide (NO) signaling. Obesity-driven upregulation of inflammatory markers may be one of the underlying etiologies in HFpEF.  These inflammatory markers reduce cyclic GMP signaling activity, decreasing NO creation which leads to increasing reactive oxygen species, vascular compartment stiffness, damage, and fibrosis.

A 45 year old person with DM, hypertension, and obesity is 4 – 5 times more likely to develop heart failure than someone without these risk factors.

Outcomes in HFpEF vs HFrEF

Outcomes for HFpEF are driven less by pump failure and cardiovascular death than by sudden cardiac death or acute coronary syndrome (JACC 2017; .

Many therapies for HFrEF have been successful in reducing hospitalizations, but this has not been the case for HFpEF: there are limited evidence-based therapies for reducing hospitalizations. Previous data is outdated: there has been improvement in outcomes, and mortality in HFpEF is lower than in HFrEF. Elevated natriuretic peptide levels are similary predictive of death in all CHF phenotypes.

HFpEF Treatment

Manage the underlying diabetes (if present) with comprehensive diet/lifestyle modification and adequate metformin therapy. Initiate discussion about SGLT2 inhibitors if indicated.  Weight loss is associated with is associated with beneficial effects on cardiac structure and decreased hospitalization utilization.

Statin therapy is not indicated unless for other reasons (e.g. diabetes, CAD). This is true for beta-blocker treatment as well.  ARB (ESC 2017) and spironolactone therapy have shown a small signal for improvement in HFpEF hospitalizations (see WikiJournal Club entry on TOPCAT).

New monitoring includes a wireless pulmonary arterial monitor that can help calibrate diuretic therapy, predict volume overload, and reduce future episodes of acute decompensated heart failure hospitalizations.

Diuresis in HFpEF vs. HFrEF

For HFpEF: Because ventricular volume is preserved, the pressure and volume differences in HFpEF are different. For any unit change in volume, there is a larger delta on pressure. This can significantly compromise renal blood flow if there is overdiuresis.  

Dr Yancy points out that for patients with HFrEF, we often don’t augment diuresis nearly enough.  Decompensation is not just symptoms, but causes a release of inflammatory cytokines and apoptotic signals. If not corrected quickly, the additional time spent exposed to adverse stimuli (cytokine environment) may make treatment more challenging.

Trials from the NHBLI Clinical Trial Network provided good evidence for initiating inpatient diuresis for congestion. Based on this work, Dr Yancy recommends doubling a patient’s home dose of furosemide and administering it IV two-three times daily. (Example:If the patient takes 60 mg QD of furosemide, they should start on 120mg IV furosemide 2-3 times a day for the first 48 – 72 hours).

Work-up for New Diagnosis

Patients with new HFpEF need a workup for ischemic heart disease, as they have high likelihood of coronary artery disease (CAD). This could, but does not necessarily mean catheterization (which can increase renal insufficiency), as coronary CT may provide a simple, lower impact, binary answer to ‘Yes’ or ‘No’ on CAD.

For patients with exercise-induced symptoms of heart failure who are asymptomatic at rest, a right heart catheterization can identify the specific etiology.

Future HFpEF Therapies

Novel technology can now use transthoracic echocardiogram (TTE) to image left anterior descending artery and can then test for flow-mediated dysfunction and endothelial dysfunction (Eur Heart J Cardiovasc Imaging 2015).  HFpEF is uniquely associated with endothelial flow mediated dysfunction. By non-invasively imaging the LAD to see flow pathologies, it may be possible to see if patient is at risk for complications of HFpEF.

Interatrial Shunts

Creating LA to RA shunts in patients with pHTN and HFpEF can help decompress left atrial hypertension. Elevated LA pressure causes the pulmonary hypertension and symptoms of heart failure. Preliminary data suggests a possible 33% reduction in mortality. Dr. Yancy notes that the study had limitations and further data is needed.

Evidence-Based Treatments

Diuretics relieve dyspnea, but do not alter the natural history of HFpEF. In HFpEF patients with elevated BNP, spironolactone might have a small reduction in HF hospitalizations (see foot note for 7.3.3 of 2017 ACC/AHA Focused Update).

Sacubitril / Valsartan (Entresto) was studied in PARAGON-HF, but did not show a decreased in the primary endpoint of heart failure hospitalizations or death from cardiovascular causes (PARAGON-HF, Solomon, 2019). Hopes were high since in animal labs, sacubitril regresses fibrosis and improves ventricular compliance. Similarly, angiotensin II receptor blockers (ARBs) have demonstrated  improvement in hypertrophic cardiomyopathy. Thus, the thought was that these treatments would be targeting biology, not just the symptoms.

Goals and Learning Objectives

Goal

Listeners will differentiate HFpEF from HFrEF, explain its pathophysiology, and list the current possible future evidence based therapies for HFpEF.

Learning objectives

After listening to this episode listeners will…

1. Differentiate between HFpEF and HFrEF.
2. Propose treatment modalities based upon cardiometabolic phenotype and additional symptoms.
3. Describe the current understanding of pathophysiology of HFpEF.
4. Manage diuresis in HFpEF vs. HFrEF.
5. Weigh options for evaluating Coronary Artery Disease in patients with newly diagnosed HFpEF.

Disclosures

Dr Yancy reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.

Links from the show

1. The City of Chicago
2. The Chicago Cubs

Sources and Additional Reading

Axelsson A, Iversen K, Vejlstrup N, Ho C, Norsk J, Langhoff L, Ahtarovski K, Corell P, Havndrup O, Jensen M, et al. Lancet Diabetes Endocrinol. 2015 Feb; 3(2):123-31. Epub 2014 Dec 19.

https://www.ncbi.nlm.nih.gov/pubmed/25533774

Kaye DM, Petrie MC, McKenzie S, et al. Impact of an interatrial shunt device on survival and heart failure hospitalization in patients with preserved ejection fraction. ESC Heart Fail. 2018;6(1):62–69. doi:10.1002/ehf2.12350

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351895/

Oktay AA, Rich JD, Shah SJ. The emerging epidemic of heart failure with preserved ejection fraction. Curr Heart Fail Rep. 2013;10(4):401–410. doi:10.1007/s11897-013-0155-7

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870014/

Chan MMY, Lam CSP. How do patients with heart failure with preserved ejection fraction die? European Journal of Heart Failure. 2013;15(6):604-613. doi:10.1093/eurjhf/hft062.

https://www.ncbi.nlm.nih.gov/pubmed/23610137

Carolyn S P et al.  Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study, European Heart Journal, Volume 39, Issue 20, 21 May 2018, Pages 1770–1780.

https://www.ncbi.nlm.nih.gov/pubmed/29390051

Sharma K, Kass DA. Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circ Res. 2014;115(1):79–96. doi:10.1161/CIRCRESAHA.115.302922

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146618/

Feldman T et al. Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure: Rationale and Design of the Randomized Trial to REDUCE Elevated Left Atrial Pressure in Heart Failure (REDUCE LAP-HF I). Circ Heart Fail. 2016 Jul;9(7).  pii: e003025. doi: 10.1161/CIRCHEARTFAILURE.116.003025.

https://www.ahajournals.org/doi/pdf/10.1161/CIRCHEARTFAILURE.116.003025

Shah SJ, Feldman T, Ricciardi MJ, et al. One-Year Safety and Clinical Outcomes of a Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction in the Reduce Elevated Left Atrial Pressure in Patients With Heart Failure (REDUCE LAP-HF I) Trial: A Randomized Clinical Trial. JAMA Cardiol. 2018;3(10):968–977. doi:10.1001/jamacardio.2018.2936

https://www.ncbi.nlm.nih.gov/pubmed/30167646

Felkner, GM et al.  Diuretic strategies in patients with acute decompensated heart failure.  NEJM. 2011; 364: 797-805.

https://www.nejm.org/doi/10.1056/NEJMoa1005419?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.nih.gov

Tromp J, Westenbrink BD, Ouwerkerk W, et al. Citation:Identifying Pathophysiological Mechanisms in Heart Failure With Reduced Versus Preserved Ejection Fraction. J Am Coll Cardiol 2018;72:1081-1090

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https://www.nejm.org/doi/full/10.1056/NEJMcp1511175

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488800/

Hayashi H, et al. S-Nitrosylation of β-Arrestins Biases Receptor Signaling and Confers Ligand Independence. J Molecular Cell 2018; 70. 3: 473-487.E6, MAY 03, 2018

DOI: https://doi.org/10.1016/j.molcel.2018.03.034

Yancy CW et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.  Circulation. 2013;128:e240-e327.

https://www.ahajournals.org/doi/pdf/10.1161/CIR.0b013e31829e8776

Yancy CW et al.  2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136:e137–e161

https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000509

Pitt B et al.  Spironolactone for heart failure with preserved ejection fraction.  N Engl J Med 2014; 370:1383-1392

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Park J et al. Global Longitudinal Strain to Predict Mortality in Patients With Acute Heart Failure. Journal of the American College of Cardiology, May 2018, 71 (18) 1947-1957; DOI: 10.1016/j.jacc.2018.02.064

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