diagnosis and management of stage a heart failure

diagnosis and management of stage A HF may . june 2006146

www.lejacq.com ID:4621

Mohan Shenoy, MD;1 Carrie B. Chapman, MD;1 M. Zaim Nawaz, MD;2 Nancy K. Sweitzer, MD, PhD1

From the Departments of Medicine, University of Wisconsin, Madison, WI;1 and Texas A&M University, Temple, TX2

Address for correspondence: Nancy K. Sweitzer, MD, PhD, Cardiovascular Medicine, University of Wisconsin, E5/582 CSC MC5710, 600 Highland Avenue, Madison, WI 53792-3220E-mail: [email protected] received November 9, 2005; revised January 23, 2006; accepted February 14, 2006

Stage A heart failure (HF) is the ear-liest stage of a devastating disease

associated with significant morbidity and mortality. Stage A patients are at risk for HF development but have no detectable cardiac abnormalities. Once overt, the statistics are stun-ning: HF accounted for approximately $28 billion in costs in the United States in 2004. Medicare expenditures on beneficiaries with HF are 431% of the average Medicare expenditure per beneficiary.1 More than half of HF costs are associated with hospitaliza-tion. There was a 274% increase in hospitalization for HF between 1979 and 2003 and a 120% increase in death due to HF.2 Recent successes in treating heart disease, particularly coronary heart disease (CHD), as well as general population aging, have led to increasing numbers of people with or at risk for HF.

Once HF is established, despite advances in treatment (many with a

marked effect on mortality), the prog-nosis remains poor, with a 12% 30-day and 33% 1-year mortality following HF hospitalization.3 Emphasis has thus been placed on early HF stages in an attempt to shift focus from treat-ing established HF to prevention. In the American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for the Diagnosis and Management of Chronic Heart Failure in the Adult, HF is divided into four stages: A through D.4 The stage A patient has identified risk factors for HF without manifestations of cardio-vascular disease and no detectable structural abnormality. Most stage A HF patients have known CHD, hyper-tension, and/or diabetes mellitus.

HF RiskMany studies have explored risk fac-tors and future HF development (Table I). Fewer studies have dem-onstrated the impact of treating risk

factors to decrease the incidence of HF. Of the risk factors shown in Table I, CHD, diabetes, and hyperten-sion account for the majority of HF cases and carry the highest population attributable risks (PARs) (Figure 1).

Two large studies have provided invaluable data about HF risk: the Framingham Heart Study5–10 and the National Health and Nutrition Examination Survey (NHANES).11 In their cohort of more than 8000 subjects between 40 and 94 years of age,5 the Framingham group reports a lifetime risk of 20%, or 1 in 5, for the future development of HF.6 Lifetime risk was identical regardless of age and sex (Figure 2). Short-term HF risk rises steeply with age; the 5-year risk is 0.2% at age 40 and 8.3% at age 80. In the Framingham study, the most significant risk factor for women was hypertension while, in men, both hypertension and CHD contributed equally to future HF risk (Figure 1).

R E V I E W P A P E R • C M E

Diagnosis and Management of Stage A Heart Failure

Reduction of the monetary and societal costs of the heart failure epidemic can best be achieved by prevention of new heart failure cases. To effectively prevent heart failure, patients at risk must be identified and treated. The American College of Cardiology/American Heart Association Guidelines for Evaluation and Management of Chronic Heart Failure in the Adult define the stage A heart failure patient as one with identified risk factors for heart failure, particularly coronary heart disease, hypertension, and diabetes, but no evidence of cardiovascular damage. In this review, the authors discuss the commonly recognized, as well as some less commonly recognized, risk factors that define the stage A patient. The authors also discuss data demonstrating that risk factor modification can reduce heart failure incidence. Given the size of the population at risk, through increased awareness of heart failure risk and aggressive treatment, health care providers can critically impact this

public health concern. (CHF. 2006;12:146–152) ©2006 CHF, Inc.

Congestive Heart Failure® (ISSN 1527-5299) is published bimonthly (Feb., April, June, Aug., Oct., Dec.) by CHF, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2005 by CHF, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in Congestive Heart Failure® do not necessarily reflect those of the Editor and Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at [email protected] or 203.656.1711 x106.

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diagnosis and management of stage A HF may . june 2006 147

In the NHANES prospective cohort study, 13,643 persons without HF and a mean age of 50 were studied.11 CHD emerged as the most significant risk factor in NHANES, with the PAR being 61.6% (Figure 1).

Coronary Heart DiseaseIn the United States, most patients with systolic HF have underlying CHD. CHD is a more significant risk factor in men than women (Figure 1).5,6 In Framingham, the PAR for angina and myocardial infarction combined was 39% for men and 18% for women. In NHANES, the PAR for CHD was 62%.11 Given this association between HF and CHD, it follows that primary and secondary prevention of CHD will prevent progression to HF.

In fact, there is evidence that CHD prevention can reduce HF inci-dence. The Scandinavian Simvastatin Survival Study (4S)12 randomized patients with known CHD (stage A HF) to placebo or simvastatin. The incidence of HF decreased by 21% in the simvastatin group compared with placebo. There was a clear delay between the average time to a major coronary event (1 month) and average time to HF (5 months), demonstrating that CHD often preceded HF. The Treating to New Targets (TNT) trial13 randomized patients with CHD and a mean low-density lipoprotein level of <130 mg/dL to atorvastatin 10 mg or 80 mg daily. There was a lower inci-dence of hospitalizations for HF in the higher-dose atorvastatin group, sug-gesting that intensive lipid-lowering therapy prevents development of HF.

The Heart Outcomes Prevention Evaluation (HOPE) trial14 randomized patients with stage A HF to ramipril or placebo. Treatment with ramipril reduced new HF by 24%. In the Type 2 Diabetes, Hypertension, Cardiovascular Events and Ramipril (DIABHYCAR) study,15 there were no significant dif-ferences in HF incidence between patients with type 2 diabetes on low-dose ramipril and those on placebo. In the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events

(CURE) trial,16 patients with recent acute coronary syndromes were ran-domized to clopidogrel or placebo; all received aspirin. The clopidogrel group had significantly fewer patients with radiologic evidence of HF in-hospital.

Although the link between CHD and HF is clear, the true impact of aggres-sive primary and secondary prevention remains largely undefined. While half the benefit in preventing HF in these trials has been due to prevention of acute coronary syndromes and CHD progres-sion,12,16 these therapies may have other effects to prevent development of HF that remain undefined. Aggressive preventive therapies in the patient with CHD risk are warranted and will reduce the future burden of HF if applied universally.

HypertensionMultiple epidemiologic studies have shown hypertension to be an inde-pendent risk factor for HF.5,6,11,17 Hypertension is a more important risk factor in women than in men. Elevation of systolic blood pressure or pulse pres-sure confers higher risk than diastolic blood pressure elevation.7 Multiple randomized clinical trials have shown reduction in new-onset HF in patients treated for hypertension, with an aver-age risk reduction of 40%–50%.18

While treatment of hypertension prevents HF, not all antihypertensive medications reduce risk equally. The Antihypertensive and Lipid-Lowering

Treatment to Prevent Heart Attack Trial (ALLHAT)19,20 demonstrated increased HF risk in the doxazosin arm, while there was no increased benefit of amlodipine or lisinopril over chlorthalidone to prevent new HF. Similarly, in the Intervention as a Goal in Hypertension Treatment (INSIGHT) trial,21 there was increased risk of nonfatal HF with nifedipine compared with diuretic therapy.

HF is a complex end point in hyper-tension trials. Diuretic use may result in less edema and reduce HF diagnosis. Conversely, edema is a known side effect of calcium channel blockers; whether this leads to overdiagnosis of HF is unknown. Further, there has been no uniform defi-nition of HF in these studies.

Patients at risk for HF warrant aggressive antihypertensive treatment. Optimal hypertension treatment in patients at risk for HF has yet to be defined. Using the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines,22 a thiazide diuret-ic would be a reasonable initial choice. In clinical conditions such as the dia-betic hypertensive patient or patients with diabetic nephropathy, other agents may be preferable.

DiabetesDiabetes and HF have a complex association, with diabetes being both

Figure 1. Population attributable risk of heart failure from the Framingham Heart Study and the first National Health and Nutrition Examination Survey (NHANES I)

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a cause and a consequence of HF.23,24 Poor glycemic control may promote atherosclerosis and subsequent CHD and may contribute to the develop-ment of diabetic cardiomyopathy, pos-sibly related to microangiopathy.25

In a study of patients with type 2 diabetes, those who developed HF were 5.5 years younger and developed HF 2.5 times more than nondiabetic subjects.26 Diabetic patients who developed HF

had a longer duration of diabetes, more CHD, and more advanced renal disease and proteinuria.

Glycemic control is related to HF incidence (Figure 3).20 Each 1% increase in hemoglobin A1c has a hazard ratio of 1.18 for HF development.15 Similarly, in glucose-intolerant patients, HF risk increases as the level of fasting blood glucose increases from <90 mg/dL to 125 mg/dL.27 Insulin resistance is an independent predictor of future HF.28 These studies demonstrate a graded increase in HF risk from subclinical insulin resistance to impaired fasting glycemic control to diabetes.

The relationship between the meta-bolic syndrome and HF is less clear. In one case-control study, patients with the metabolic syndrome had increased incidence of severe inhospital HF.29 Of the five metabolic syndrome compo-nents, hyperglycemia was the major determinant of severe HF.

Clustering of risk factors is com-mon in diabetic patients, further increasing HF risk. The DIABHYCAR study defined the following risk fac-tors for HF among diabetic patients: age, CHD, urine protein, hemoglobin A1c, and smoking >15 cigarettes a day (Table II).15 The Organization to Assess Strategies for Ischemic Syndromes (OASIS) Registry30 examined cluster-ing of diabetes and CHD. HF rates

were highest for patients with both dia-betes and known CHD before an acute coronary event. The UK Prospective Diabetes Study Group 38 (UKPDS 38) trial31 explored clustering of diabe-tes and hypertension. Diabetic patients with tighter blood pressure control had significantly lower HF event rates.

Two treatment trials have demon-strated the efficacy of renin–angiotensin system blockade to prevent HF in diabet-ic patients. The Reduction of Endpoints in Non–Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial32 showed a 32% risk reduction of new HF in losartan-treated patients. In the Losartan Intervention For Endpoint Reduction in Hypertension study (LIFE)33 there was a 41% relative risk reduction in new HF incidence in the losartan group compared with atenolol. These data add to those suggesting that blocking the renin–angiotensin system is critical in diabetics and can prevent HF in this group of patients.

Tight glycemic control should be the goal in every diabetic and will prevent HF in addition to preventing other complications. Clustering of risk factors in diabetics warrants aggressive screening and risk factor management specifically targeted to this popula-tion. In patients with diabetes and hypertension, renin–angiotensin sys-tem blockade should be initial antihy-pertensive therapy. Although impaired fasting glucose has been associated with HF risk, it remains to be demon-strated that early treatment prevents progression to HF.

Renal DiseaseRenal disease, especially microalbu-minuria, is strongly associated with an increased incidence of first hospi-talization for HF.34 The mechanism is unknown. Microalbuminuria may be a marker of poor glycemic con-trol, hypertension, inflammation, and/or endothelial dysfunction. In the DIABHYCAR study, a 10-fold increase in urinary albumin con-centration more than doubled the risk of HF.15 In a substudy of HOPE,

Table I. Identified Heart Failure Risk FactorsCoronary heart disease5,6,11–16

Hypertension5–7,11,17,19–21,54–57

Diabetes15,25–28,30–33

Renal disease15,32,34

Obesity9

Metabolic syndrome29

Physical inactivity36

Microalbuminuria34

Smoking11,15,17

Depression40,41

Male genderAlcohol8,38,39

Atrial fibrillation48,49

Elevated C-reactive protein/erythrocyte sedimentation rate28,42,43

Left ventricular hypertrophy6

Sleep apneaExposure to cardiac toxinsValvular heart disease5,11

Right ventricular pacing45–47

Figure 2. Lifetime risk of heart failure. Reprinted with permission from Circulation. 2002;106:3068–3072.5


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microalbuminuria increased the risk of hospitalization in both diabetics and nondiabetics.34 Risk was present even with levels of microalbuminuria below that typically used to screen for diabetic nephropathy. Interestingly, treatment with ramipril did not reduce the risk of HF in the microalbumin-uric group. Whether treatment to reduce microalbuminuria will result in reduced HF risk is unknown.

Obesity and Physical ActivityObesity and physical inactivity are associated with increased HF risk. Obesity is linked to diabetes, hyper-tension, and dyslipidemia, all known risk factors for CHD. A substudy of the Framingham study demonstrated that a 1-unit increase in body mass index was associated with an increase in the risk of HF in both men and women (Figure 4).9 Increased body mass index preceded the development of HF. Paradoxically, higher body mass index, even into ranges of frank obesity, is associated with improved HF survival in those with established disease.35

In women undergoing coronary angiography for suspected ischemia, higher self-reported physical fitness scores were associated with lower rates of incident HF, independent of body mass index.36 Although no stud-ies have demonstrated that weight loss or regular exercise prevents HF, clearly it is wise to instruct overweight patients to restrict calories and sed-entary patients to increase physical activity to improve overall health and well-being.

SmokingEpidemiologic studies have defined a strong association between smoking and risk of developing HF. Smoking at age 50 was associated with a 60% higher risk of HF after adjusting for hypertension, body weight, and other HF risk factors.17 In NHANES, smok-ers carried a 45% higher risk of HF in men and an 88% higher risk of HF in women.11 The PAR for smoking as a cause of HF was 17% (Figure 1). In diabetic patients, smoking >15

cigarettes a day is associated with increased incidence of HF.15 Smoking cessation reduces mortality in patients with established HF.37 Although smok-ing cessation has not been shown to reduce risk of future HF, abstinence from tobacco products should be uni-versally advised as an intervention that prevents death and morbidity and may reduce the risk of HF.

Alcohol and Other CardiotoxinsThe relationship between alcohol intake and HF is complex and not well-defined. Alcohol is a myocardial depres-sant leading to subclinical impairment of left ventricular function, which, in early stages, can only be demonstrated by sensitive testing such as echocardiog-

raphy or radionuclide angiography.38 Heavy alcohol consumption carries increased risk of HF. Mild-to-moder-ate alcohol consumption, however, has been associated with reduced risk. In a Swedish cohort of men, history of alcohol abuse was associated with an increased risk of HF.39 On the other hand, mild-to-moderate alcohol con-sumption was inversely associated with the risk of HF.8 This effect of moderate alcohol consumption to reduce HF is possibly mediated by decreasing the risk of CHD and subsequent myocardial infarction. Recommendations regarding alcohol consumption are best tailored to the individual stage A patient.

Other drugs, such as amphet-amines, cocaine, and anthracycline chemotherapeutic agents, are known

Table II. Predictors of Heart Failure in Diabetes MellitusHAZARD RATIO 95% CONFIDENCE INTERVAL P VALUE

Age (for every 10-year increase) 1.72 1.68–1.76 <0.0001History of cardiovascular disease 2.55 1.80–3.62 <0.0001Urine albumin/creatinine ratio

(per 10-fold increase)2.30 1.71–3.09 <0.0001

Hemoglobin A1c (for every 1% increase)

1.18 1.08–1.29 0.0003

Smoking >15 cigarettes a day 1.98 1.15–3.40 0.013Reprinted with permission from Diabetes Care. 2003;26:855–860.15

Figure 3. Glycemic control, measured as hemoglobin (HbA1c) (%), and incidence of heart failure hospitalization and/or death per 1% increase in HbA1c. Reprinted with permission from Diabetes Care. 2003;26:855–860.15 Data derived from Circulation. 2001;103:2668–2673.

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to have the potential for cardiotoxicity in patients who are exposed to such compounds.4 A careful medical history should be taken, and all patients should be strongly advised against recreational drug use. Anthracyclines should be used with particular caution in patients with other risk factors for HF.

DepressionHigh prevalence rates of major depres-sion, ranging from 36% to 59%, have been reported in patients with HF.40 In the Systolic Hypertension in the Elderly (SHEP) trial,41 depression was associated with an increase in the risk of future HF. It has been suggested that depression may be a marker of subclinical HF or an independent risk factor for HF. Further studies are required to confirm and define the nature of this association. Whether treatment of depression will prevent HF is unknown.

OtherElevated levels of inflammatory mark-ers have been associated with new HF. Possible mechanisms include depressed myocardial contractility from proinflammatory cytokines and cyto-kine-mediated endothelial dysfunc-tion. In the Health Aging and Body Composition42 and the Framingham43 studies, interleukin-6, tumor necrosis factor-α and C-reactive protein were

associated with increased incidence of HF. There was a graded increase in the risk of HF with each standard devia-tion increase in inflammatory markers. In the Uppsala longitudinal Study of Adult Men (ULSAM),44 erythrocyte sedimentation rate >6 mm was an independent predictor of HF. No stud-ies have explored the impact of anti-inflammatory therapies on HF risk.

The Mode Selection Trial (MOST)45 compared dual-chamber pacemakers with ventricular pacemakers to investi-gate relative contributions of atrioven-tricular synchrony and ventricular dys-synchrony on outcomes, including risk of HF hospitalization. Duration of ven-tricular pacing >40% for dual-chamber pacing and >80% for ventricular pacing more than doubled HF hospitalizations. Other clinical trials analyzing patients with stages B and CHF showed an increasing incidence of HF hospitaliza-tions in patients who required frequent right ventricular pacing.46,47

Atrial fibrillation with uncontrolled ventricular rate can cause cardiomyop-athy and HF, which may resolve after cardioversion.48 Tachycardia-induced cardiomyopathy also improves with rate control, with improvement in ejection fraction and reduction in HF hospitalizations.49

Finally, while hereditary forms of cardiomyopathy have been recognized for some time,50 newer data suggest

that more subtle genetic predisposi-tion to HF is also important. Among identified β1-adrenergic receptor poly-morphisms, the Ser-49 variant is more common in patients with HF than in healthy controls, while the Arg-389 variant carries increased HF risk in animal models.51,52 It has been sug-gested that abnormalities in the dys-trophin gene, even when clinically silent, may predispose to viral cardio-myopathy.53 Much will undoubtedly be learned about the genetics of HF risk in the coming decades.

Currently, no simple mechanism exists to help the primary care phy-sician screen patients for HF risk. Framingham Heart Study investigators have applied multivariate risk formu-lation to develop a scoring system to identify patients at high risk for HF.10 Unfortunately, in its current iteration, the system is cumbersome and difficult to implement in routine practice.

ConclusionsStage A HF is present when risk factors for developing HF exist with normal cardiovascular function. CHD, diabe-tes, and hypertension account for a majority of future HF cases and are modifiable. Obesity, smoking, the meta-bolic syndrome, and physical inactivity are modifiable as well; whether reduc-ing these risks produces a decreased HF incidence is unknown.

Figure 4. Heart failure incidence stratified by body mass index. Reprinted with permission from N Engl J Med. 2002;347:305–313.9

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To reduce the societal bur-den of this incurable chronic dis-ease, prevention of HF is essen-tial. Effective treatment of stage A patients requires: 1) increased rec-ognition of the significance of HF risk; 2) aggressive treatment of iden-tified risk factors; and 3) continual reassessment throughout adult life, since risk never diminishes, even in advanced age.

We recommend screening for HF risk as a routine part of primary care practice, particularly in individuals older than 50. Risk factors for CHD overlap with HF risk factors and should be treat-ed aggressively when present. Tight gly-cemic control with goal hemoglobin A1c <7% and aggressive blood pressure con-trol according to current guidelines22 will reduce the incidence of HF. Every adult should be counseled on the health

importance of smoking cessation and increased physical activity. Obese indi-viduals should be counseled to restrict portion size and caloric intake. Further study will determine whether treatment of depression, renal disease, or micro-albuminuria will reduce the incidence of HF. When identified, HF risk factors warrant aggressive treatment with avail-able interventions to maximally reduce society’s future HF burden.

REFERENCES 1 Zhang JX, Rathouz PJ, Chin MH. Comorbidity

and the concentration of healthcare expendi-tures in older patients with heart failure. J Am Geriatr Soc. 2003;51:476–482.

2 Thom T, Haase N, Rosamond W, et al. Heart Disease and Stroke Statistics—2006 Update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113:e85–e151.

3 Jong P, Vowinckel E, Liu PP, et al. Prognosis and determinants of survival in patients newly hospital-ized for heart failure: a population-based study. Arch Intern Med. 2002;162:1689–1694.

4 Hunt SA, Abraham MH, American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to update the 2001 Guidelines for the Evaluation and Management of Heart Failure). ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the J Am Coll Cardiol. 2005;46:e1–e82

5 Lloyd-Jones DM, Larson MG, Leip EP, et al. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation. 2002;106:3068–3072.

6 Levy D, Larson MG, Vasan RS, et al. The progression from hypertension to congestive heart failure. JAMA. 1996;275:1557–1562.

7 Haider AW, Larson MG, Franklin SS, et al. Systolic blood pressure, diastolic blood pres-sure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study. Ann Intern Med. 2003;138:10–16.

8 Walsh CR, Larson MG, Evans JC, et al. Alcohol consumption and risk for congestive heart failure in the Framingham Heart Study. Ann Intern Med. 2002;136:181–191.

9 Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of heart failure. N Engl J Med. 2002;347:305–313.

10 Kannel WB, D’Agostino RB, Silbershatz H, et al. Profile for estimating risk of heart failure. Arch Intern Med. 1999;159:1197–1204.

11 He J, Ogden LG, Bazzano LA, et al. Risk fac-tors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med. 2001;161:996–1002.

12 Kjekshus J, Pedersen TR, Olsson AG, et al. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail. 1997;3:249–254.

13 LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–1435.

14 Arnold JM, Yusuf S, Young J, et al. Prevention of heart failure in patients in the Heart Outcomes Prevention Evaluation (HOPE) study. Circulation. 2003;107:1284–1290.

15 Vaur L, Gueret P, Lievre M, et al. Development of congestive heart failure in

type 2 diabetic patients with microalbumin-uria or proteinuria: observations from the DIABHYCAR (type 2 DIABetes, Hypertension, CArdiovascular Events and Ramipril) study. Diabetes Care. 2003;26:855–860.

16 Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes with-out ST-segment elevation. N Engl J Med. 2001;345:494–502.

17 Eriksson H, Svardsudd K, Larsson B, et al. Risk factors for heart failure in the general population: the study of men born in 1913. Eur Heart J. 1989;10:647–656.

18 Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA. 2003;289:2534–2544.

19 Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlortha-lidone: the Antihypertensive and Lipid-lower-ing Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT Collaborative Research Group. JAMA. 2000;283:1967–1975.

20 Whelton PK, Barzilay J, Cushman WC, et al. Clinical outcomes in antihypertensive treat-ment of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2005;165:1401–1409.

21 Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet. 2000;356:366–372.

22 Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206–1252.

23 Kostis JB, Sanders M. The association of heart failure with insulin resistance and the develop-ment of type 2 diabetes. Am J Hypertens. 2005;18:731–737.

24 Vermes E, Ducharme A, Bourassa MG, et al. Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the Studies of Left Ventricular Dysfunction (SOLVD). Circulation. 2003;107:1291–1296.

25 Iribarren C, Karter AJ, Go AS, et al. Glycemic control and heart failure among adult patients with diabetes. Circulation. 2001;103:2668–2673.

26 Nichols GA, Gullion CM, Koro CE, et al. The incidence of congestive heart failure in type 2 diabetes: an update. Diabetes Care. 2004;27:1879–1884.

27 Nielson C, Lange T. Blood glucose and heart failure in nondiabetic patients. Diabetes Care. 2005;28:607–611.

28 Ingelsson E, Sundstrom J, Arnlov J, et al.

Insulin resistance and risk of congestive heart failure. JAMA. 2005;294:334–341.

29 Zeller M, Steg PG, Ravisy J, et al. Prevalence and impact of metabolic syndrome on hospital outcomes in acute myocardial infarction. Arch Intern Med. 2005;165:1192–1198.

30 Malmberg K, Yusuf S, Gerstein HC, et al. Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry. Circulation. 2000;102:1014–1019.

31 Tight blood pressure control and risk of macro-vascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317:703–713.

32 Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and car-diovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–869.

33 Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortal-ity in patients with diabetes in the Losartan Intervention For Endpoint reduction in hyper-tension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:1004–1010.

34 Gerstein HC, Mann JF, Yi Q, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic indi-viduals. JAMA. 2001;286:421–426.

35 Curtis JP, Selter JG, Wang Y, et al. The obesity paradox: body mass index and outcomes in patients with heart failure. Arch Intern Med. 2005;165:55–61.

36 Wessel TR, Arant CB, Olson MB, et al. Relationship of physical fitness vs body mass index with coronary artery disease and cardiovascular events in women. JAMA. 2004;292:1179–1187.

37 Suskin N, Sheth T, Negassa A, et al. Relationship of current and past smoking to mortality and morbidity in patients with left ventricular dysfunction. J Am Coll Cardiol. 2001;37:1677–1682.

38 Urbano-Marquez A, Fernandez-Sola J. Alcohol consumption and heart failure. J Card Fail. 2005;11:329–332.

39 Wilhelmsen L, Rosengren A, Eriksson H, et al. Heart failure in the general population of men—morbidity, risk factors and prognosis. J Intern Med. 2001;249:253–261.

40 Koenig HG. Depression in hospitalized older patients with congestive heart failure. Gen Hosp Psychiatry. 1998;20:29–43.

41 Abramson J, Berger A, Krumholz HM, et al. Depression and risk of heart failure among older persons with isolated systolic hypertension. Arch Intern Med. 2001;161:1725–1730.

42 Cesari M, Penninx BW, Newman AB, et al. Inflammatory markers and onset of cardio-vascular events: results from the Health ABC


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study. Circulation. 2003;108:2317–2322. 43 Vasan RS, Sullivan LM, Roubenoff R, et al.

Inflammatory markers and risk of heart failure in elderly subjects without prior myocar-dial infarction: the Framingham Heart Study. Circulation. 2003;107:1486–1491.

44 Ingelsson E, Arnlov J, Sundstrom J, et al. Inflammation, as measured by the erythrocyte sedimentation rate, is an independent predic-tor for the development of heart failure. J Am Coll Cardiol. 2005;45:1802–1806.

45 Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS dura-tion in a clinical trial of pacemaker thera-py for sinus node dysfunction. Circulation. 2003;107:2932–2937.

46 Steinberg JS, Fischer A, Wang P, et al. The clinical implications of cumulative right ventricular pacing in the Multicenter Automatic Defibrillator Trial II. J Cardiovasc Electrophysiol. 2005;16:359–365.

47 Wilkoff BL, Cook JR, Epstein AE, et al.

Dual-chamber pacing or ventricular back-up pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA. 2002;288:3115–3123.

48 Raymond RJ, Lee AJ, Messineo FC, et al. Cardiac performance early after cardiover-sion from atrial fibrillation. Am Heart J. 1998;136:435–442.

49 Nerheim P, Birger-Botkin S, Piracha L, et al. Heart failure and sudden death in patients with tachycardia-induced cardiomyopa-thy and recurrent tachycardia. Circulation. 2004;110:247–252.

50 Franz WM, Muller OJ, Katus HA. Cardiomyopathies: from genetics to the prospect of treatment. Lancet. 2001;358:1627–1637.

51 Pasotti M, Repetto A, Tavazzi L, et al. Genetic predisposition to heart failure. Med Clin North Am. 2004;88:1173–1192.

52 Mialet Perez J, Rathz DA, Petrashevskaya NN, et al. Beta 1-adrenergic receptor poly-morphisms confer differential function and predisposition to heart failure. Nat Med.

2003;9:1300–1305. 53 Xiong D, Lee GH, Badorff C, et al. Dystrophin

deficiency markedly increases enterovirus-induced cardiomyopathy: a genetic predis-position to viral heart disease. Nat Med. 2002;8:872–877.

54 Kostis JB, Davis BR, Cutler J, et al. Prevention of heart failure by antihypertensive drug treat-ment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group. JAMA. 1997;278:212–216.

55 Amery A, Birkenhager W, Brixko P, et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet. 1985;1:1349–1354.

56 Coope J, Warrender TS. Randomised trial of treatment of hypertension in elderly patients in primary care. Br Med J (Clin Res Ed). 1986;293:1145–1151.

57 Dahlof B, Lindholm LH, Hansson L, et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet. 1991;338:1281–1285.


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diagnosis and management of stage a heart failure

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