Clinical Concept of Heart Failure Clinical Concept of Heart Failure

Mihai Gheorghiade MD, FACC

Professor of Medicine and SurgeryDirector of Experimental TherapeuticsCenter for Cardiovascular Innovation

Northwestern University Feinberg School of Medicine

FDAFDA’’s View s View --Treat the Disease instead Treat the Disease instead of the Conditionof the Condition

“Heart Failure is not a disease and we should no longer approve drugs for a heterogeneous broad population, but for a well defined sub-population where we can demonstrate a marked benefit”

Dr. Stephen GrantDeputy Director, Division of Cardiovascular

Renal Products, CDER

ACC/AHA 2009 Guideline: ACC/AHA 2009 Guideline: Classification of HFClassification of HF

• Marked symptoms at rest despite maximal medical therapy (eg, those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions)

Refractory end-stage HF(200000)D

• Known structural heart disease• Shortness of breath and fatigue• Reduced exercise tolerance

Symptomatic HF

5 mil.C

• Previous MI• LV systolic dysfunction• Asymptomatic valvular disease

Asymptomatic HF

10 mil.B

• HTN• CAD • Diabetes mellitus

High risk for(60mil.)

developing HFA

Patient DescriptionStage

Hunt SA et al. J Am Coll Cardiol. 2009.

Congestive Heart FailureCongestive Heart Failure

• Congestive heart failure (CHF) is a life-threatening condition in which the heart isn't able to pump enough blood to the rest of the body. The failing heart continues to work, but not as efficiently as it should. Many conditions that lead to congestive heart failure can't be reversed, but heart failure can often be treated with medications and lifestyle changes.

• 51 year-old Elecrophysiologist• Functional Class III for 6 months • BP 90/60 mmHg; PCWP 30 mmHg; LVEF 10%• Angiogram: no significant coronary disease; MRI: no

hyper-enhancement (no scar tissue)• Receiving: furosemide, digoxin, enalapril• Started on carvedilol 3.125 mg BID that was titrated to

25 mg BID in addition to micro and macronutrients• 6 months later:

– EF 60%– Functional Class I

Case Study Case Study

Bruce H AJC 2005Bruce H AJC 2005

Improve HFImprove HF

Viable but Dysfunctional Myocardium:Viable but Dysfunctional Myocardium:Possibility for RecoveryPossibility for Recovery

Gheorghiade M. JACC 2009

Etiologic Factors

Ischemia/HibernationNeurohormones (e.g. NE)

HemodynamicsMetabolic

Cytokines (e.g. TNF a)

Myocyte

The human heart weighs between 200-425 g

This relatively small mass uses more energy, in the form of adenosine triphosphate (ATP), than any other organ

It pumps 5 liters of blood per minute, 7200 liters per day, and over 2.6 million liters per year

Over 6 kilograms of ATP is hydrolyzed by the heart daily undergo constant turnover and rebuilding.

Every 30 days, an entire heart itself is reconstructed with brand new protein components

Soukoulis et al JACC 2010

Metabolism NeedsMetabolism Needs

Chronic Heart FailureChronic Heart Failure

• >3 million admissions in US

• Cardiac injury (+troponin)• Rapid changes in lab

values• Mortality and re

hospitalization as high as 15% and 30%, respectively, within 60-90 after d/c

• Event rate has not changed in the last decade

• Prevalence of 6 million (Stage C and D AHA/ACC)

• Very abnormal, but relatively stable lab values

• Mortality <5% annually in clinical trials

• Decreased morbidity and mortality in last two decades

• Death often sudden

HOSPITALIZED OUTPATIENTS

• Worsening chronic heart failure (HF):80% of all admissions*

• Acute de novo heart failure (diagnosed for the first time) :15%

• Advanced/end-stage/refractory HF:5%

Hospitalizations for HFHospitalizations for HF

Gheorghiade et al Circulation 2005

*The majority managed by non cardiologist

Heart Failure HospitalizationsHeart Failure HospitalizationsEVEREST - HHF TRILOGY - ACS

Both registries and clinical trials highlight the u nmet need in new therapies for patients hospitalized for heart failure.

Clinical Clinical Characteristics of HHF PatientsCharacteristics of HHF Patients

Median age (years) 75Hx of Atrial Fibrillation

30%

Women >50% Renal abnormalities 30%

Hx of CAD 60% SBP >140 mm Hg 50%

Hx of Hypertension 70% SBP 90-140 mm Hg 45%

Hx of Diabetes 40% SBP <90 mm Hg 5%

Gheorghiade et al JACC 2013;61:391-403.

Data on 200,000 US patients

Characteristic % (SD) Admission SBP mmHg≤≤≤≤119

(n=12,252)

120-139

(n=12,096)

140-161

(n=12,099)

≥≥≥≥161

(n=12,120)Mean Age, y 72.9 (14.0) 74.0 (13.5) 73.8 (13.6) 72.1 (14.6)

Mean EF (%) 33.3 (17.4) 37.8 (17.6) 40.9 (17.1) 44.4 (16.5)Ischemic Etiology 50.7 48.8 44.1 39.2HTN Etiology 13.4 18.1 25.4 34.8Serum Cr>2 (mg/dl) 20.7 18.0 18.1 21.5Mean Wt change (kg) -2.45 (5.00) -2.68 (4.82)-2.60 (4.64)-2.42 (4.62)Edema Admission 63.9 65.1 65.6 63.9Total mortality in-hospital 7.2 3.6 2.5 1.7Total mortality 60-90d 14.0 8.4 6.0 5.4Readmission 30.6 29.9 30.3 27.6Mean LOS, days 6.5 (6.6) 5.7 (5.3) 5.4 (5.0) 5.1 (4.8)

Admission Systolic BP and Outcomes in Hospitalized Admission Systolic BP and Outcomes in Hospitalized Patients With HF: An OPTIMIZEPatients With HF: An OPTIMIZE --HF AnalysisHF Analysis

Gheorghiade M et al. JAMA. 2008;299:2656-66

In an experimental study of short-term hibernation, dobutamine infusion resulted in myocardial infarction (right) when subendocardial blood flow was further reduced from 0.17 mL/min per gram (right). With and Without indicate with and without infarction. Reproduced with kind permission of Professor Gerd Heusch, Essen, Germany.

Hibernating MyocardiumHibernating Myocardium

Hospitalization for Heart Hospitalization for Heart Failure(HHF)Failure(HHF)

• Improving post-discharge mortality and prevention of readmissions are the most important goals for HHF patients.

Treat Beyond Clinical Congestion .

The main reason for admission and readmission among patients Although this goal is often accomplished, some patients may be discharged with high left ventricular filling pressures as illustrated by high circulating natriuretic peptide levels, orthopnea, and poor exercise capacity.A more aggressive strategy to treat “subclinical”

congestion may potentially improve outcomes.

Gheorghiade and Braunwald JAMA 2012

Adopt a Mechanistic Approach to Cardiac Abnormalities.

Heart failure is not a disease, but a manifestation of differentcardiac abnormalities.Accordingly, an in-depth systematic assessment should be

conducted of cardiac abnormalities (eg, valvular disease, cardiac dyssynchrony,ischemia).

Gheorghiade and Braunwald JAMA 2011

Pang,Komajda,Gheorghiade EHJ 2010

Treat Noncardiac Comorbidities.

The increasing rates of important non cardiac comorbidities, including hypertension and renal dysfunction, overthe last decade, highlight the importance of targeting these conditions in the overall management of HF.In addition, diabetes, chronic obstructive pulmonary disease, and sleep apnea may also contribute to this high event rate after hospitalization.

Gheorghiade and Braunwald JAMA 2011

Augment Use of Underused Agents Known to Decrease Hospitalizations.

The use of digoxin is on a steep decline andmineralocorticoid antagonists are underused in patients withHF in the United States. DIG trial showed that use of digoxin reduced overall hospitalization rate by almost 30%,EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization

and Survival Study in Heart Failure) trial revealedthat compared with placebo, use of eplerenone reducedall-cause hospitalization by almost 25%.

Gheorghiade and Braunwald JAMA 2011

Results by highResults by high --risk patients subgroups: HF risk patients subgroups: HF Hospitalization or HF mortality in DIG Trial Hospitalization or HF mortality in DIG Trial

% (events/total) Absolute risk

difference

Hazard ratio

(95% CI)

P valuePlacebo Digoxin

NYHA class III or IV 40% (445/1105)

29% (329/1118)

– 11% 0.65 (0.57–0.75)

<0.001

LVEF <25% 39% (444/1129)

27% (304/1127)

– 12% 0.61 (0.53–0.71)

<0.001

CTR >55% 40% (465/1170)

29% (336/1175)

– 11% 0.65 (0.57–0.75)

<0.001

High risk (either of the above)

36% (783/2167)

26% (566/2191)

– 10% 0.66 (0.59–0.73)

<0.001

Gheorghiade et al, LBCT ESC HF Belgrade 2012

Translating the Basic Knowledge of Mitochondrial Translating the Basic Knowledge of Mitochondrial

Functions to Metabolic TherapyFunctions to Metabolic Therapy

Mitochondrial dysfunction is at the basis of a constellation of metabolic

abnormalities that significantly contribute to Chronic conditions and diseases .

Summary Summary

� Myocardium as a main target for therapy� Hospitalized Heart Failure (HHF) � Practical consideration to improve HHF

outcomes