Journal of Cardiac Failure
Volume 9, Issue 1 , Pages 1-3, February 2003

“Systolic and diastolic dysfunction” in heart failure? Time for a new paradigm☆

Tufts-New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts

Article Outline

 

The importance of the ejection fraction (EF) and the terms systolic and diastolic dysfunction have become so broadly accepted and applied in the evaluation of patients with heart failure that it would be barely imaginable to challenge them. But challenge we must.

Low EF has been an entry criterion for most heart failure clinical trials. Heart failure clinical practice guidelines have mostly ignored patients with higher EF. The two quality measures formulated by the Centers for Medicare and Medicaid Services for patients with heart failure both involve EF: mandating its measurement and requiring treatment with angiotensin-converting enzyme (ACE) inhibitors only when EF is low. All of this attention to the EF is predicated on the assumption of differing pathophysiology—and therefore differing response to treatment—in those with “systolic” and “diastolic dysfunction.”

I am going to argue that it's time for a new set of terms, a new conceptual paradigm, and movement away from EF as the most cherished measurement in cardiology.

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EF does little to define the underlying pathologic or physiologic condition 

We learn little about the underlying disease state by measuring EF. Amyloid cardiomyopathy and hypertrophic, hypertensive heart disease, 2 disorders that may cause heart failure with preserved EF, vastly differ in terms of etiology, pathology, pathophysiology, and hemodynamics. Yet we lump them as “diastolic dysfunction” (and sometimes erroneously treat them the same). Among patients with heart failure and normal EF, the vast majority have concentric left ventricular (LV) hypertrophy (LVH), associated with long-standing hypertension. EF does little to define the clinical course or prognosis. Although heart failure with hypertensive, hypertrophic heart disease and normal EF is most prevalent in the elderly, its overall demographics and prognosis are not dissimilar from those of patients with heart failure who have reduced EF.1, 2

If we wish to divide patients, let's do so according to pathology and pathophysiology, beginning with the 3 conditions responsible for the vast majority of heart failure cases: ischemic cardiomyopathy, dilated cardiomyopathy, and hypertensive-hypertrophic disease (Fig 1).

  • View full-size image.
  • Fig. 1. 

    Gross pathology in the three most common conditions responsible for heart failure in the United States: (A) ischemic cardiomyopathy; (B) idiopathic, dilated cardiomyopathy; and (C) hypertensive-hypertrophic cardiomyopathy.

Other, less-common conditions may stand alone and are worthy of special therapeutic considerations.

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In patients with chronic heart failure, EF is largely driven by the degree of ventricular dilatation 

Although acute changes in EF reflect alteration in preload, afterload, and contractility, when we divide patients with chronic heart failure into those with low and normal EF, we are essentially segregating them according to the presence or absence of ventricular dilatation. Figure 2 displays the fixed relationship between EF and LV end-diastolic volume (EDV) at 3 levels of cardiac output (CO), and a constant heart rate.

It assumes absent valvular regurgitation, the presence of which increases EDV at any EF and renders EF an even poorer marked of contractility. For patients with chronic heart failure, a low EF relates little about contractility or LV load, but mostly identifies a patient whose LV has remodeled with dilatation. If recognizing such patients is important, then we would do so more accurately by focusing on LV volumes, rather than EF.

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The terms systolic and diastolic dysfunction are misnomers 

The myocardium and left ventricle of most patients with heart failure have many similarities and are abnormal during both systole and diastole, regardless of EF. Table 1 summarizes similarities in cardiac characteristics between patients with dilated or ischemic cardiomyopathy vs. those with hypertensive heart disease.

Table 1. Comparison of myocardial and left ventricular chamber characteristics in patients with dilated or ischemic cardiomyopathy with low EF and those with hypertensive heart disease with normal EF
Low EFNormal EF
Increased LV massIncreased LV mass
Myocyte hypertrophyMyocyte hypertrophy
Interstitial fibrosisInterstitial fibrosis
Abnormal calcium handlingAbnormal calcium handling
Reduced contractilityReduced contractility
Slowed relaxationSlowed relaxation
Depleted preload reserveDepleted preload reserve
Large volumesSmall volumes

EF, ejection fraction; LV, left ventricular.

The myocardium in patients with dilated or ischemic cardiomyopathy or hypertensive heart disease is similarly characterized by increased LV mass, myocyte hypertrophy and increased interstitial collagen.3, 4 Hypertrophic myocardium in these and other conditions have similar abnormalities of calcium handling and similar functional abnormalities of contraction and relaxation,5 regardless of EF. Myocardium from patients with dilated cardiomyopathy and from those with hypertrophic cardiomyopathy shows similar delay in diastolic cytosolic calcium reuptake, associated with delayed relaxation.5

EF provides no information regarding functional capacity.6 Rather, in patients with normal EF7 and in those with low EF,8 functional status is linked, in part, to the LV capacity for diastolic distension and preload recruitment during exertion. We have observed that among patients with low EF, diastolic distension during exercise, with associated stroke volume augmentation, distinguishes asymptomatic patients from those with symptoms of heart failure.8

Therefore, patients with heart failure and low EF and those with heart failure and more normal EF both have myocardium and a left ventricle that function abnormally during both systole and diastole. EF in patients with chronic heart failure, rather than signifying distinct pathophysiology, principally distinguishes the pattern of hypertrophic LV remodeling: between a left ventricle with hypertrophic cavity dilation and one with hypertrophic concentric thickening, without cavity dilatation.

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Most patients with low and normal EF are likely to respond favorably to the same treatments 

Because most patients enrolled in clinical trials of heart failure had low EF, clinicians are appropriately concerned that the findings of these trials do not apply to patients with more normal EF. Of course, a similar concern should be raised with regard to other patient groups, such as women, the elderly, and nonwhites. However, based on the arguments presented here, it is not likely that EF will accurately subdivide patients according to response to a given treatment, particularly because myocardial hypertrophy with remodeling represents an appropriate therapeutic target across the various common conditions responsible for heart failure.

Table 2 lists treatment goals in patients with hypertensive hypertrophic disease, based on our understanding of its pathology and pathophysiology, along with treatments likely to help achieve those goals.

Table 2. Goals in patients with hypertensive hypertrophic disease
1. Treat hypertension, prevent/regress hypertrophy
Use diuretics, ACE inhibitors, ARBs, beta-blockers
2. Meticulous volume management
Use diuretics, Establish Na restriction
3. Increase diastolic filling time
Use beta-blockers, calcium channel blockers
4. Improve dynamic relaxation
Use ACE inhibitors, ARBs, calcium channel blockers
5. Diminish/prevent ischemia
Use beta-blockers, ACE inhibitors, calcium channel blockers, nitrates, antiplatelet agents, revascularization

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.

ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, and diuretics—standard treatments in patients with heart failure and low EF—are well-represented in this table. In the absence of demonstrable difference in the response to digoxin, based on EF,9 we might add this drug to this list of therapeutic agents.

Numerous studies have now demonstrated the impact of ACE inhibitors or ARBs on important clinical endpoints, and in regressing LVH, in a variety of populations with preserved EF, including those with atherosclerotic disease,10 cardiovascular risk factors including diabetes,10 hypertension with LVH,11 and diabetes with proteinuria.12, 13 It is unfortunate that these studies did not include many patients with symptoms of heart failure at baseline. However, it is beyond reason to deny the likelihood of benefit from these agents in the majority of patients with heart failure with relatively normal EF. Ongoing investigations with ARBs will, hopefully, substantiate this likelihood.

Future heart failure trials should not perpetuate the misguiding error of excluding patients based on EF.

To put it mildly, the terms systolic and diastolic dysfunction, as applied to lower vs. higher EF in the presence of chronic heart failure, have exhausted their usefulness. In fact, these terms have deterred advances in pathophysiologic understanding and therapeutics. It's time for a new paradigm. Let's focus on LV volumes rather than EF to characterize the remodeled ventricle; let's switch to terms that more ably describe the underlying pathology and physiology; and let's seek a more broad-minded view in investigating and applying drug treatment to patients with heart failure.

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References 

  1. Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction. J Am Coll Cardiol. 1999;33:1948–1955
  2. Senni M, Tribouilloy CM, Rodeheffer RJ, Jacobsen SJ, Evans JM, Bailey KR, et al.  Congestive heart failure in the community: a study of all incident cases in Olmsted County, Minnesota, in 1991. Circulation. 1998;98:2282–2289
  3. Pearlman ES, Weber , Janicki JS, Pietra GG, Fishman AP. Muscle fiber orientation and connective tissue content in the hypertrophied human heart. Lab Invest. 1982;46:158–164
  4. Huysman JA, Vliegen HW, Van der Laarse A, Eulderink F. Changes in nonmyocyte tissue composition associated with pressure overload of hypertrophic human hearts. Pathol Res Practice. 1989;184:577–581
  5. Gwathmey JK, Copelas L, MacKinnon R, Schoen FJ, Feldman MD, Grossman W, et al.  Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ Res. 1987;61:70–76
  6. Baker BJ, Wilen MM, Boyd CM, Dinh H, Franciosa JA. Relation of right ventricular ejection fraction to exercise capacity in chronic left ventricular failure. Am J Cardiol. 1984;54:596–599
  7. Kitzman DW, Higginbotham MB, Cobb FR, Sheikh KH, Sullivan MJ. Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: failure of the Frank-Starling mechanism. J Am Coll Cardiol. 1991;17:1065–1072
  8. Konstam MA, Kronenberg MW, Udelson JE, Kinan D, Metherall J, Dolan N, et al  Effectiveness of preload reserve as a determinant of clinical status in patients with left ventricular systolic dysfunction. Am J Cardiol. 1992;69:1591–1595
  9. Digitalis Investigation Group . The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525–533
  10. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145–153
  11. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, et al.  Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995–1003
  12. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al.  Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–869
  13. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al.  Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–860

☆ Reprint requests to: Marvin A. Konstam, MD, Tufts-New England Medical Center, Box 108, 750 Washington St., Boston, MA 02111

PII: S1071-9164(02)25409-3

doi:10.1054/jcaf.2003.9

Journal of Cardiac Failure
Volume 9, Issue 1 , Pages 1-3, February 2003

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