As the population ages in the United States (US),

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1 AJH 2003; 16:18S 22S From Hypertension to Heart Failure: Update on the Management of Systolic and Diastolic Dysfunction John B. Kostis The aging of the population of the United States (US) will bring with it higher numbers of patients with coronary heart disease and heart failure (HF). Because HF already imposes severe economic and medical burdens on our health care system, it is imperative to optimize primary and secondary prevention of cardiovascular (CV) disease. In most cases, HF develops as a result of either longstanding hypertension or a myocardial infarction (MI). Other than cardiac death, HF represents the last stage in the progression of CV disease, which begins with CV risk factors such as hypertension, dyslipidemia, obesity, and smoking. These risk factors lead to the development of left ventricular (LV) hypertrophy or an MI (or both), which lead to LV dysfunction and, finally, to HF. The prognosis of HF As the population ages in the United States (US), the number of patients with coronary heart disease (CHD) and heart failure (HF) will continue to impose substantial medical and economic burdens on our health care system. A study that we conducted in the state of New Jersey, for example, showed that although CHD fatalities declined between 1986 and 1996, the rate of nonfatal events increased, particularly in individuals 75 years old. 1 Furthermore, although the median age at which subjects experienced a first myocardial infarction (MI) was 68 years in 1986, it increased to 70 years in These data suggest that a rising life expectancy could bring with it a higher number of patients with cardiovascular (CV) events. The consequences of an aging population are already apparent: hospital discharges for HF in the US more than quintupled in women and quadrupled in men between 1970 and The total economic expenditure for HF in the US is now estimated to be $22.2 billion annually. 2 The Continuum of Cardiovascular Disease Findings from the Systolic Hypertension in the Elderly Program (SHEP) study show that HF is the end result of is poor, the 5-year survival rate being approximately 25%. Heart failure may be due to either LV systolic or diastolic dysfunction, the latter having a normal ejection fraction. Because CV disease is progressive, interventions are possible at all stages along the CV continuum. -Blockers ( B) are recommended agents at several stages of CV disease. Large-scale trials have shown that B significantly reduce risks for morbidity and mortality in patients with HF. Ongoing studies should help to clarify further the optimal cardioprotective therapies in patients with HF. Am J Hypertens 2003;16:18S 22S 2003 American Journal of Hypertension, Ltd. Key Words: Hypertension, heart failure, -blockers, cardiovascular disease. earlier stages of CV disease. 3 Heart failure may develop from either long-standing hypertension or an acute MI. Cardiovascular disease is a continuous and progressive disease, usually starting with the classic risk factors such as hypertension, obesity, diabetes, smoking, and dyslipidemia 4 (Fig. 1). In this early stage, left ventricle (LV) structure and function will typically be normal. Over time, however, the pathologic effects of one or more CV risk factors may cause LV hypertrophy (LVH) to develop or an MI to occur. Through LV remodeling, systolic or diastolic dysfunction may develop, which can lead to symptomatic HF. Systolic HF and diastolic HF (better named HF with preserved ejection fraction [EF]) have many similar cardiac characteristics, including high LV mass, reduced contractility, interstitial fibrosis, and depleted preload reserve 5 (Table 1). The most important difference between them is that systolic HF is characterized by low EF with large ventricular volumes, whereas diastolic HF is associated with normal EF and small ventricular volumes. 5 Heart failure with preserved systolic function and normal EF is more likely to occur among elderly patients, women, and those with systolic hypertension (Table 2). The Cardiovascular Health Study in 5888 subjects 65 Received June 10, First decision June 10, Accepted June 10, From the Department of Medicine, Robert Wood Johnson Medical School, New Brunswick, New Jersey. Address correspondence and reprint requests to Dr. John B. Kostis, Professor of Medicine and Pharmacology, Chairman, Department of Medicine, Robert Wood Johnson Medical School, One Robert Wood Johnson Place, Room MEB-491, New Brunswick, NJ 08903; kostis@umdnj.edu /03/$ by the American Journal of Hypertension, Ltd. doi: /s (03)00966-x Published by Elsevier Inc.

2 AJH September 2003 VOL. 16, NO. 9, PART 2 MANAGEMENT OF SYSTOLIC AND DIASTOLIC DYSFUNCTION 19S FIG. 1. Progression from hypertension to heart failure. 4 CHF congestive heart failure; CV cardiovascular; HF heart failure; LV left ventricular; LVH left ventricular hypertrophy; MI myocardial infarction. (Reprinted with permission from Vasan RS et al: The role of hypertension in the pathogenesis of heart failure. A clinical mechanistic overview. Arch Intern Med 1996;156: ) years of age, for example, found that LV function was normal in 63% of the 269 participants with HF. 6 Although the mortality risk was lower among the HF patients with normal LV systolic function, there was a higher number of absolute deaths among them because of the higher prevalence, compared to subjects with HF and impaired LV systolic function. 6 Implications for Treatment Left ventricular remodeling is a key mechanism in the progression of systolic and diastolic dysfunction. 7 Reversal of LV remodeling, with a return to more normal ventricular dimensions, has been seen as a result of therapy with angiotensin-converting enzyme (ACE) inhibitors, -blockers ( B), and cardiac resynchronization. 7 The ability to reverse LVH in HF patients is an important surrogate Table 1. Characteristics of systolic and diastolic heart failure 5 Systolic Heart Failure Low EF High LV mass Myocyte hypertrophy Interstitial fibrosis Abnormal calcium handling Reduced contractility Slowed relaxation Depleted preload reserve Large volumes Diastolic Heart Failure Normal EF High LV mass Myocyte hypertrophy Interstitial fibrosis Abnormal calcium handling Reduced contractility Slowed relaxation Depleted preload reserve Small volumes EF ejection fraction; LV left ventricular. (Reprinted with permission from Konstam MA: Systolic and Diastolic Dysfunction in heart failure? Time for a new paradigm. J Card Fail 2003;9:1 3.) Table 2. Characteristics of patients with heart failure and normal ejection fraction Older age and female sex Systolic hypertension Exacerbated hypertensive response Cardiac artery disease Diabetes Abrupt pulmonary edema Ventricular stiffening Arterial stiffening Diastolic dysfunction Impedance mismatch endpoint, indicating the potential usefulness of antihypertensive or cardioprotective therapy. Primary and secondary prevention of CV disease cannot be achieved through antihypertensive therapy alone, however, but must also encompass treatment of other common CV risk factors. One study in 2489 men and 2856 women found, for example, that about 28% of CHD events in men and 29% in women were attributable to blood pressure levels of 130/85 mm Hg after adjustment for other factors. 8 This analysis also showed that 27% of CHD events in men and 34% in women were attributable after adjustment to an elevated total cholesterol level (ie, 200 mg/dl). Evaluating Heart Failure In clinical practice, the functional status of patients with HF is most commonly assessed using the New York Heart Association (NYHA) classification, 9 based on the degree of physical activity needed to elicit HF symptoms: Class I: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea. Class II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea. Class III: Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity results in fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort. Symptoms at rest. If any physical activity is undertaken, discomfort is increased. A new classification of HF was developed to emphasize the progression of the disease and the role of neurohormonal activation in the pathogenesis of LV remodeling 10 (Table 3). Diminished arterial or peripheral perfusion in HF triggers activation of the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS). 11 Chronic activation of these compensatory neurohormonal responses over time contribute to the progression of HF. -Blockers, which suppress SNS activation,

3 20S MANAGEMENT OF SYSTOLIC AND DIASTOLIC DYSFUNCTION AJH September 2003 VOL. 16, NO. 9, PART 2 Table 3. Stages of heart failure (American College of Cardiology/American Heart Association) 10 Stage A Stage B Stage C Stage D At high risk for developing heart failure No identified structural or functional abnormality; no signs/symptoms Developed structural heart disease that is strongly associated with the development of heart failure, but without signs/symptoms Symptomatic heart failure associated with underlying structural heart disease Advanced structural heart disease and marked symptoms of heart failure at rest despite maximal medical therapy and ACE inhibitors, which inhibit RAAS activity, are highly beneficial at each stage of HF 10 (Fig. 2). -Blockers in Heart Failure The primary aims of HF therapy are to improve symptoms and to prolong life by slowing disease progression. 12 Chronic use of B in patients with HF has been shown in several large-scale studies to improve signs and symptoms of HF and to reduce mortality. The first evidence of the beneficial effects of -blockade on survival in patients with HF came from a pooled analysis from four separate placebo-controlled trials involving a total of 1094 subjects with mild, moderate, or severe HF (EF 35%). In this pooled analysis, the B carvedilol demonstrated significant reductions in the risk of all-cause mortality and of CV hospitalizations as compared with placebo. 13 To investigate further the impact of B on survival in patients with HF, the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II) was conducted in 2647 patients with NYHA Class III or IV HF (LV EF 35%) who were receiving standard therapy with diuretics and ACE inhibitors. 14 Subjects were randomly assigned to the B bisoprolol 1.25 mg (n 1327) or placebo (n 1320) once daily, with drug treatment progressively increased to a FIG. 2. Recommendations for management of heart failure by stage include the use of -blockers at all stages. ACE angiotensinconverting enzyme. 10 FIG. 3. In the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study, treatment with carvedilol reduced the relative risk of death by 35% (P.0014), and the combined risk of death or hospitalization by 24% (P.001), compared with placebo, in 2289 patients with severe heart failure who were clinically euvolemic. RRR relative risk reduction. 15 (Reprinted with permission from Packer M, et al: Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344: Copyright Massachusetts Medical Society. All rights reserved.) maximum of 10 mg/day. Mean follow-up was 1.3 years, and the primary endpoint was all-cause mortality. Secondary endpoints included all-cause hospitalizations, CV mortality or CV hospitalizations, and premature withdrawals from treatment. After a mean follow-up of 1.3 years, the B bisoprolol was associated with a 34% risk reduction for all-cause mortality as compared with placebo (P.0001). The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study evaluated the effect of B on survival in 2287 patients with severe HF who were clinically euvolemic, had an EF of 25% and were receiving standard HF therapy with diuretics and ACE inhibitors. 15 In this double-blind trial, subjects were randomized either to carvedilol mg twice daily (titrated up to 25 mg twice daily, n 1156) or to placebo (n 1133), with mean follow-up of 10.4 weeks. The B carvedilol reduced the risk of death by 35% (P.0014) (Fig. 3), and the combined risk of death or hospitalization by 24% (P.001) as compared with placebo. The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) was conducted to investigate whether the B extended-release (ER) metoprolol succinate would improve survival in patients with HF. 16 The MERIT-HF enrolled 3991 patients with NYHA Class II to Class IV HF, who had an EF of 40% and were receiving standard therapy with diuretics and ACE inhibitors. In this double-blind study, subjects were randomized to either ER metoprolol succinate 12.5 mg (titrated up to 200 mg once daily, n 1990), or to placebo (n 2001). The co-primary endpoints were all-cause mortality, and death or hospitalization for any reason. The study was stopped early because of a significant reduction in mortality. Therapy with ER metoprolol succinate achieved a 34% reduction in all-cause mortality as compared with placebo (P.0006) (Fig. 4). A post hoc analysis investigating results by mode of

4 AJH September 2003 VOL. 16, NO. 9, PART 2 MANAGEMENT OF SYSTOLIC AND DIASTOLIC DYSFUNCTION 21S FIG. 4. The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) found that ER metoprolol succinate achieved an RRR of 34% for all-cause mortality, compared with placebo (P.0062), in 3991 patients with NYHA Class II to Class IV HF and an EF of 40%, who were receiving standard therapy with diuretics and angiotensin-converting enzyme inhibitors. EF ejection fraction; ER extended release; HF heart failure; NYHA New York Heart Association; RRR relative risk reduction. 16 (Reprinted with permission from MERIT-HF Study Group: Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353: ) death found that the leading cause of mortality was sudden death, and that treatment with ER metoprolol succinate reduced the risk of sudden death by 41% (P.0002). 16 Additional subgroup analyses of MERIT-HF found that ER metoprolol succinate therapy achieved similar risk reductions in all-cause mortality and all-cause hospitalization in diabetic and nondiabetic patients, 17,18 in the 65- year-old and 65-year-old age groups, 19 and in both men and women. 20 Furthermore, in the subgroup of patients FIG. 5. A substudy was conducted in patients enrolled in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) with severe HF (NYHA Class III/IV) and an EF of 25% (n 795). This trial found that treatment with ER metoprolol succinate achieved a significant relative risk reduction of 39% in total mortality (P.009). EF ejection fraction; ER extended release; HF heart failure; NYHA New York Heart Association; RRR relative risk reduction. 21 (Reprinted with permission from Goldstein S, et al: Metoprolol controlled release/extended release in patients with severe heart failure: analysis of the experience in the MERIT-HF Study. J Am Coll Cardiol 2001;38: Copyright The American College of Cardiology Foundation. All rights reserved.) with severe HF (NYHA Class III/IV) and EF of 25% (n 795), treatment with ER metoprolol succinate significantly reduced all mortality endpoints, including a 39% risk reduction in total mortality (P.009) 21 (Fig. 5). Heart Failure With Preserved Systolic Function Although the management of HF in patients with poor systolic function has been well studied, the optimal therapeutic strategies for diastolic HF are less well known. Theoretical treatments, based on our knowledge of the complex pathophysiology of this condition, include relieving volume overload with diuretics, reducing heart rate with B, and general control of hypertension. The ongoing Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program is being conducted to evaluate the effects of the angiotensin II receptor blocker candesartan as compared with placebo, in a broad spectrum of HF patients, including those with a normal EF. 22 Results are expected later this year. Conclusions Heart failure is a major public health problem. It may develop either as a result of long-standing hypertension or of cardiac damage resulting from an acute MI. Risk factors for developing HF should be identified and treated even before patients show any evidence of structural heart disease. Left ventricular function should be evaluated in all patients with HF to detect those with systolic dysfunction. Patients with evidence of fluid retention should receive diuretic therapy until euvolemia is achieved. Angiotensinconverting enzyme inhibitors and B are recommended at all stages of HF to reduce the risk of morbidity and mortality. Ongoing studies will further illuminate potential therapies in HF patients with preserved systolic function. References 1. Kostis JB, Wilson AC, Lacy CR, Cosgrove NM, Ranjan R, Lawrence-Nelson J, and the Myocardial Infarction Data Acquisition System (MIDAS #7) Study Group: Time trends in the occurrence and outcome of acute myocardial infarction and coronary heart disease death between 1986 and 1996 (a New Jersey statewide study). Am J Cardiol 2001;88: American Heart Association: Heart disease and stroke statistics 2003 update. Dallas: American Heart Association, Kostis JB, Davis BR, Cutler J, Grimm RH Jr, Berge KG, Cohen JD, Lacy CR, Perry HM Jr, Blaufox MD, Wassertheil-Smoller S, Black HR, Schron E, Berkson DM, Curb JD, Smith WM, McDonald R, Applegate WB, for the SHEP Cooperative Research Group: Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1997;278: Vasan RS, Levy D: The role of hypertension in the pathogenesis of heart failure. A clinical mechanistic overview. Arch Intern Med 1996;156: Konstam MA: Systolic and diastolic dysfunction in heart failure? Time for a new paradigm. J Card Fail 2003;9:1 3.

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