Congestive Heart Failure and Genomic Medicine: A Look into the 21st Century

Congestive heart failure (CHF) has emerged as one of the leadingcardiovascular disorders in developed countries, as indicated by theprevalence of the disease; the incidence of hospitalization, morbidity, andmortality; and its global economic burden. Furthermore, it is expected thatheart failure and other cardiovascular disorders will become the majordisease burdens in developing countries by the year 2020. It is wellestablished that pharmacological therapy of CHF, although still notoptimum, improves patient quality of life and reduces morbidity andmortality. However, CHF remains a relentlessly progressive disease. In thisbrief review an attempt is made to explore the contemporary,state-of-the-art pharmacological approach to the treatment of heartfailure, the unmet medical need that still remains, and the potentialimpact of genomic medicine on the treatment of heart failure in the 21stcentury.     

2型糖尿病中降糖药与心力衰竭风险

长期以来2型糖尿病作为心血管事件高危因素,显著增加各类心血管并发症风险,而心力衰竭(心衰)已成为2型糖尿病患者最常见死因,降糖治疗可显著降低心血管死亡风险和心衰住院率,但目前临床上对于各类降糖药尤其是传统降糖药的心衰风险研究资料有限,自从2008年美国FDA和欧洲医学会临床研究指南求新型降糖药须评估心血管结局风险,使得...     

Therapeutic management of dilated cardiomyopathy

Summary The therapeutic approach to dilated cardiomyopathy (DCM) still remains nonspecific and symptomatic, since no specific etiology is identified. Nevertheless, the recent introduction of angiotensin converting enzyme (ACE) inhibitors and beta-blockers greatly improved the treatment of DCM. The poor prognosis of patients with DCM encourages maximal aggressive attempts to prevent progression of ventricular dysfunction rather than to wait for treatable symptoms. To achieve this goal, vasodilators, particularly ACE inhibitors, now appear to be essential for the treatment of DCM. Digitalis is added unless contraindicated by adverse effects. Diuretics should be used only to relieve congestive symptoms. In the presence of sinus tachycardia or ventricular arrhythmias, beta-blockers are the next choice in our practice. When congestive symptoms or low output state are not controlled with vasodilators, diuretics, and digitalis, inotropic agents are indicated, with or without mechanical assist devices. For severely ill patients unresponsive to maximal medical management, heart transplantation is needed.     

Heart failure – from pathophysiology to therapy

Swedberg K et al. (Department of Medicine, Östra University Hospital, Göteborg, Sweden). Heart failure – from pathophysiology to therapy (Minisymposium). J Intern Med 1996; 239 : 305–43. Population studies, together with data from clinical records, reveal a range of estimated heart failure prevalence of 1–10%. Estimated incidence rates vary around 1% per annum. In community studies, the five-year mortality is between 50–60%, while in patients requiring hospital admission, the annual mortality is 10–20% in those with mild–moderate symptoms and as high as 40–60% in severe heart failure. Many definitions of heart failure have been formulated. Making a diagnosis is a complex process. Heart failure is not a diagnosis or even one syndrome, but is a cluster of syndromes. The diagnosis is therefore only part of the assessment process. Essential parts for the diagnosis include symptomatology, objective evidence of important cardiac dysfunction and evaluation of the response to therapy. The cardinal symptom is exertional breathlessness. At present, echocardiography remains the most useful tool for confirming cardiac dysfunction, but determination of atrial natriuretic peptide or magnetic resonance imaging may supersede it. Heart failure has been viewed primarily as an oedematous disorder, in which fluid retention occurs because the heart cannot pump adequate quantities of blood to the kidneys. This model led to the utilization of diuretics for heart failure, but it failed to recognize that heart failure is a chronic progressive disorder that impairs both the quality and quantity of life, even when oedema is adequately controlled. A new model has been developed in which the development and progression of heart failure is viewed as resulting from the interplay of haemodynamic and neurohormonal mechanisms. Both mechanisms support the inotropic state of the heart following an injury to the myocardium, but when sustained for long periods, these mechanisms act to enhance ventricular wall stress, and, thereby, impair ventricular performance. As the heart failure evolves, endogenous mechanisms that are normally activated to control wall stress become exhausted, and peripheral vasoconstriction and sodium retention develop. Unopposed activation of haemodynamic stresses and neurohormonal systems leads to further destruction of myocardium and progression of the underlying disease. The acceptance of this haemodynamic–neurohormonal model has led to the development of vasodilators and neurohormonal antagonists which have been shown to be useful alone  – or added to diuretics – in the treatment of heart failure. Non-pharmacological therapy includes counselling of life style and, for patients with moderate heart failure, light exercise. Within the last decade, pharmacological therapy was improved considerably. Asymptomatic patients with left ventricular dysfunction benefit from acetylsalicylic acid (ASA) and beta-blockers. In patients with progressive dilatation of the left ventricle and with an established left ventricular dysfunction treatment with angiotensin-converting enzyme (ACE) inhibitors has beneficial effects on mortality and morbidity. In symptomatic patients and those with clear systolic left ventricular dysfunction in addition to digitalis and diuretics, ACE inhibitors are clearly indicated in addition to ASA. Beta-blockers may be added but the true benefit is not established. The initiation of both ACE inhibitors and beta-blockers should be careful and the dose titrated slowly. Antiarrhythmic class I agents should be avoided unless clear indications are present, e.g. life-threatening arrhythmias. Amiodarone might be considered as an alternative. The prognosis for patients with heart failure remains serious and the search for even better therapies should continue.     

应用大剂量西拉普利治疗慢性心力衰竭的安全性及疗效观察

目的　评价大剂量西拉普利在慢性心力衰竭 (CHF)患者中应用的安全性及疗效。方法　 10 3例CHF患者 (男 83例 ,女 2 0例 ) ,平均年龄 5 9岁 ,心功能Ⅱ Ⅳ级 ,左室射血分数 (LVEF) 35 %。从小剂量开始使用 ,只要能耐受 ,尽可能递增到 5～ 7 5mg d ,治疗中严密监测各项相关指标。结果　平均随访时间近 2 0周 ,随访期间死亡 5例 ,其中心性死亡 4例 ,非心性死亡 1例 ,2例因心力衰竭加重而再次住院。治疗后心功能和 6min步行距离较治疗前明显改善 [( 2 0 4± 0 6 6 )比 ( 3 0 5± 0 6 5 )和( 310 2 9± 180 14)m比 ( 2 0 0 87± 175 97)m ,P <0 0 0 1],超声心动图检查示左室舒张末径 (LVEDD)和收缩末径 (LVESD)减小 [( 6 1 17± 9 90 )mm比 ( 6 3 86± 10 2 0 )mm和 ( 47 2 4± 11 0 2 )mm比 ( 5 1 4 9±11 0 7)mm ,P <0 0 0 1],LVEF明显增加 [( 34 82± 8 14) %比 ( 43 78± 10 37) % ,P <0 0 0 1]。本组患者治疗后血压略有下降 ,血钾略升高 ,但均在正常范围内 ,血肌酐无明显变化。非缺血性心脏病组与缺血性心脏病组比较 ,LVESD变化率和LVEF变化率差异有显著性 [( 9 13± 12 72 ) %比 ( 4 38±10 39) % ,( 39 6 9± 42 11) %比 ( 2 0 97± 2 2 84) % ,P <0 0 5和 0 0 1]。结论　大剂量应     

Heart failure: a growing public health problem

Abstract. At a time when deaths from coronary heart disease and stroke are markedly declining, mortality from heart failure is increasing. Heart failure is a costly and devastating disease, and throughout much of the industrialized world, escalating health-care costs constitute a serious burden on both public and private systems of financing health care, and about one-third of all heart failure patients are admitted to hospital each year. Both prevalence and incidence of heart failure increase steeply with increasing age. The prevalence rate is about 1% at the age of 50, whilst at the age of 80 and above, almost one out of 10 persons will suffer from heart failure. Until recently, the goals for heart failure treatment were to relieve symptoms and enhance functional capacity. Recently, some large scale studies have shown that ACE inhibitors can reduce mortality, prevent development of heart failure, avoid the need for hospitalization and improve prognosis. ACE inhibitors may therefore have promising effects both on patients and on society. A challenge for the future must be early recognition and timely and adequate treatment of heart failure. Such a strategy might have great economic benefits as far as public health is concerned. However, the most rewarding efforts for the population will be to prevent the underlying causes of coronary heart failure as well as risk factors for heart failure. This review will study the magnitude of heart failure as a growing public health problem, the underlying causes, risk factors and treatment.     

Heart failure: Lessons learned over the past 25 years

Over the past 25 years, a great deal has been learned about the pathophysiology and management of heart failure—a major health problem whose prevalence and incidence have not declined, unlike other cardiovascular disorders. Several of these lessons are reviewed herein. However, despite these advances, important issues remain to challenge both the practicing physician and the research scientist.     

Correlates of cognitive impairment among patients with heart failure: results of a multicenter survey

PURPOSE: Cognitive impairment is an exceedingly prevalent condition among patients with heart failure, independently associated with disability and mortality. However, the determinants of cognitive dysfunction associated with heart failure are still unclear. We assessed the correlates of cognitive impairment among patients with heart failure enrolled in a multicenter pharmacoepidemiology survey. METHODS: The association with cognition of demographic characteristics, objective tests and measures, medications, and comorbid conditions was assessed in 1511 patients with heart failure who had been admitted to 81 hospitals throughout Italy. Cognitive impairment was defined by a Hodkinson Abbreviated Mental Test score < 7. RESULTS: According to multivariate logistic regression modeling, age (per each decade: OR = 2.01; 95% confidence interval [CI] 1.72-2.35), the comorbidity score (OR 1.11; 95% CI 1.03-1.20), education (OR 0.88; 95% CI 0.84-0.2), low serum albumin (OR 1.78; 95% CI 1.35-2.34), sodium (OR 1.56; 95% CI 1.06-2.29), and potassium levels (OR 1.58; 95% CI 1.09-2.29), hyperglycemia (OR 1.33; 95% CI 1.02-1.73), anemia (OR 1.38; 95% CI 1.09-1.75), and systolic blood pressure levels > or = 130 mm Hg (OR 0.60; 95% CI 0.37-0.97) were independently associated with cognitive impairment, after adjusting for potential confounders. Among participants with abnormal laboratory findings on admission, restoration of normal glucose, potassium, and hemoglobin levels during hospital stay was associated with improved cognitive performance at discharge. CONCLUSIONS: Cognitive impairment among patients with heart failure is associated with several comorbid conditions, some of which are potentially treatable. This highlights the key role of comprehensive approach to the assessment and treatment of patients with heart failure.     

The incidence of congestive heart failure associated with antidiabetic therapies

BACKGROUND: Increased risk for CHF in persons with type 2 diabetes is well established. Our objectives were to estimate the CHF risk associated with specific therapies for diabetes and to determine the differences in incidence rates of CHF associated with adding various antidiabetic agents. METHODS: Subjects were members of the Kaiser Permanente Northwest (KPNW) diabetes registry as of 1 January 1998, with no prior history of CHF (n = 8063). We identified their therapy as of that date and then defined the start of the subject study period as the date when their drug regimen changed, either by switching to or by adding another antidiabetic drug. We defined the new therapy as the index therapy and the date of initiating the new therapy as the index date. Follow-up on the patients was done until the index therapy was discontinued or changed, or until 31 December 2002, whichever came earlier. We calculated the incidence rate of CHF in patients on various therapeutic regimens adjusting for age, gender, diabetes duration, existing ischemic heart disease, hypertension, renal insufficiency and glycemic control (HbA(1c)). RESULTS: CHF incidence rates were highest in index therapy categories that included insulin and lowest in regimens that included metformin. When insulin was added to an initial therapy, CHF incidence was increased 2.33 times (p < 0.0001) and 2.66 times (p < 0.0001) compared to the addition of sulphonylurea or metformin respectively. CONCLUSIONS: Our findings support the theory that elevated serum insulin levels promote the development of cardiac disease. Consistent with the UKPDS, metformin may offer some protection from incident CHF relative to sulphonylurea or insulin.     

白细胞介素-6与慢性心衰的相关性及血管紧张素转换酶抑制剂的影响

目的：探讨慢性心力衰竭（CHF）患者血清白细胞介素-6（IL-6）水平的变化及血管紧张素转换酶抑制剂（ACEI）的影响。方法：采用双抗体夹心酶联免疫吸附法（ELISA）检测38例CHF患者及23例健康自愿者（健康对照组）血清IL-6水平,CHF患者被随机分为常规治疗组（17例）和ACEI治疗组（21例,常规治疗＋ACEI治疗）共观察4周。结果：①CHF患者血清IL-6水平显著高于健康对照组[（9．82±4．67）ng／L比（4．2±2.65）ng／L,P〈0.01],且与左室射血分数（LVEF）呈负相关（r=-0．55,P〈0．01）;②经4周治疗后与治疗前比较,ACEI组患者IL-6水平明显降低[（9．86±4．57）ng／L比（7．43±4．39）ng／L,P〈0．05],且伴有心率明显下降[（84±9）次／min比（76±8）次／min,P〈0．057,LVEF明显升高[（32±3．2）％比（37±4．7）％,P〈0．05],常规治疗组治疗前后无显著差异（P〉0．05）。结论：慢性心力衰竭患者自细胞介素-6水平明显升高,并与左室收缩功能呈负相关,血管紧张素转换酶抑制剂可降低血清自细胞介素-6水平,有助于慢性心力衰竭患者心功能的改善。     

Left ventricular diastolic dysfunction in patients with chronic renal failure: impact of diabetes mellitus.

AIMS: Left ventricular (LV) hypertrophy and LV diastolic dysfunction are cardiac changes commonly observed in patients with chronic renal failure (CRF) as well as hypertension. Although the impairment of LV diastolic function in patients with diabetes mellitus has been shown, little is known about the specific effect of diabetes on LV diastolic function in patients with CRF. The present study was designed to investigate the impact of diabetic nephropathy on LV diastolic dysfunction, independent of LV hypertrophy, in CRF patients. METHODS: In 67 patients with non-dialysis CRF as a result of chronic glomerulonephritis (n = 33) or diabetic nephropathy (n = 34), and 134 hypertensive patients with normal renal function, two-dimensional and Doppler echocardiographic examinations were performed, and LV dimension, mass, systolic function, and diastolic function were evaluated. RESULTS: LV mass was increased and LV diastolic dysfunction was advanced in subjects with CRF compared with hypertensive controls. In the comparison of echocardiographic parameters between the two groups of CRF patients, i.e. chronic glomerulonephritis and diabetic nephropathy groups, all indices of LV diastolic function were more deteriorated in the diabetic nephropathy group than in the chronic glomerulonephritis group, although LV structure including hypertrophy and systolic function did not differ between the groups. In a multiple regression analysis, the presence of diabetes (i.e. diabetic nephropathy group) was a significant predictor of LV diastolic dysfunction in CRF subjects, independent of other influencing factors such as age, blood pressure, renal function, anaemia and LV hypertrophy. CONCLUSION: The present findings suggest that LV diastolic dysfunction, independent of LV hypertrophy, is specifically and markedly progressed in patients with CRF as a result of diabetic nephropathy.     

Use of angiotensin-converting enzyme inhibitors and variations in cognitive performance among patients with heart failure.

AIMS: Cognitive dysfunction is a prevalent condition among patients with heart failure, and is independently associated with disability and mortality. Angiotensin-converting enzyme (ACE)-inhibitors might increase cerebral blood flow in subjects with heart failure. Our aim was to assess whether starting treatment with ACE-inhibitors might improve cognition in patients with heart failure. METHODS AND RESULTS: Analyses involved 12 081 subjects, 1220 of whom had a verified diagnosis of heart failure, enrolled in a multi-centre pharmaco-epidemiology survey. None of these participants received ACE-inhibitors before hospitalization. Among participants with heart failure, cognitive performance improved in 30% of 446 participants who started ACE-inhibitors, but only in 22% of remaining patients (P=0.001). Among participants without heart failure, cognition improved in 19% of those receiving ACE-inhibitors, and in 18% of untreated patients (P=0.765). Use of ACE-inhibitors among patients with heart failure was associated with improving cognition (odds ratio=1.57; 95% CI 1.18-2.08) also in the multivariable regression modelling, independently of baseline or discharge blood pressure levels. The probability of improving cognitive performance was higher for dosages above the median values, as compared with lower doses (odds ratios=1.90 and 1.42; P for trend=0.001), and increased with duration of treatment (odds ratios for the lower, middle, and upper tertiles=1.25, 1.34, and 1.59; P for trend=0.007). CONCLUSION: Treatment with ACE-inhibitors might selectively improve cognitive performance in patients with heart failure. However, up-titration of these agents might be required to yield the greatest benefit.     

Heart failure in diabetes and related conditions

BackgroundDespite advances in therapy for congestive heart failure (CHF), mortality remains 40% to 80% higher for diabetics with CHF than nondiabetics. Diabetes prevalence is increasing worldwide with prevalence of diabetes among patients with CHF increasing at an even faster pace.Methods and ResultsAlthough multiple mechanisms are responsible for development of CHF in diabetes, ischemic heart disease plays a major role. In the foreseeable future, physicians will have to deal with increasing numbers of subjects with diabetes, coronary disease, and heart failure. Several recent developments in the field of heart failure have revolutionized the way patients are treated for CHF with improvements in quality of life and mortality. Although long-term prospective studies specifically addressing heart failure in diabetes are lacking, extrapolation of data from recent large trials has shed light on management of CHF in diabetes.ConclusionsThis review summarizes new developments in the field of CHF among subjects with diabetes, metabolic syndrome, and obesity.     

Efficacy and tolerability of the long-term administration of carvedilol in patients with chronic heart failure with and without concomitant diabetes mellitus

BACKGROUND: Diabetes is frequently associated with heart failure and is an independent risk factor for an increased mortality and morbidity. Beta-blockers are traditionally regarded as relatively contraindicated in patients with diabetes mellitus. AIM OF THE STUDY: To assess the efficacy and tolerability of carvedilol administration in patients with heart failure and concomitant diabetes. METHODS AND RESULTS: One hundred ninety-three patients (68 diabetics, 125 non-diabetics) with chronic heart failure were assessed by radionuclide ventriculography, cardiopulmonary exercise testing and right heart catheterization before and after 12 months of maintenance carvedilol treatment (mean dose, 40+/-19 mg daily). Diabetic patients were older and with a lower peak VO2, compared with non-diabetics. Long-term carvedilol administration was associated with an improvement in left ventricular function, clinical symptoms, resting and exercise hemodynamic parameters compared to baseline, with no significant difference between the diabetic and the non-diabetic patients. The incidence of adverse effects was also similar between the two groups. Diabetics had higher all-cause mortality with a similar mortality and hospitalization rate, compared to non-diabetics during 33+/-20 months of follow-up. CONCLUSION: Concomitant diabetes does not influence the efficacy and tolerability of carvedilol administration in patients with chronic heart failure.     

Epidemiology of gestational diabetes mellitus and its association with Type 2 diabetes.

Gestational diabetes (GDM) is defined as carbohydrate intolerance that begins or is first recognized during pregnancy. Although it is a well-known cause of pregnancy complications, its epidemiology has not been studied systematically. Our aim was to review the recent data on the epidemiology of GDM, and to describe the close relationship of GDM to prediabetic states, in addition to the risk of future deterioration in insulin resistance and development of overt Type 2 diabetes. We found that differences in screening programmes and diagnostic criteria make it difficult to compare frequencies of GDM among various populations. Nevertheless, ethnicity has been proven to be an independent risk factor for GDM, which varies in prevalence in direct proportion to the prevalence of Type 2 diabetes in a given population or ethnic group. There are several identifiable predisposing factors for GDM, and in the absence of risk factors, the incidence of GDM is low. Therefore, some authors suggest that selective screening may be cost-effective. Importantly, women with an early diagnosis of GDM, in the first half of pregnancy, represent a high-risk subgroup, with an increased incidence of obstetric complications, recurrent GDM in subsequent pregnancies, and future development of Type 2 diabetes. Other factors that place women with GDM at increased risk of Type 2 diabetes are obesity and need for insulin for glycaemic control. Furthermore, hypertensive disorders in pregnancy and afterwards may be more prevalent in women with GDM. We conclude that the epidemiological data suggest an association between several high-risk prediabetic states, GDM, and Type 2 diabetes. Insulin resistance is suggested as a pathogenic linkage. It is possible that improving insulin sensitivity with diet, exercise and drugs such as metformin may reduce the risk of diabetes in individuals at high risk, such as women with polycystic ovary syndrome, impaired glucose tolerance, and a history of GDM. Large controlled studies are needed to clarify this issue and to develop appropriate diabetic prevention strategies that address the potentially modifiable risk factors.     

Angiotensin-converting enzyme inhibitors in heart failure: Physicians' prescribing behavior

Background: Several studies document an underuse of angiotensin-converting enzyme inhibitors (ACEIs) in heart failure (HF) patients, despite their proven efficacy and good tolerability. Also, there is some evidence that the doses used in clinical practice are far lower than those used in clinical trials.Methods and Results: To identify patterns of ACEI use in HF patients this study examined data collected on admission day regarding demographic, clinical, and medical care characteristics of 355 patients hospitalized because of decompensated HF who were treated with and without ACEIs. Additionally, measures of in-hospital outcome were compared among the two groups. Fifty-eight point six percent of patients were receiving ACEIs at admission and 80.6% were treated with ACEIs during hospitalization. The average ACEI does was low. No differences were observed in age and measures of severity of HF between ACEI-prescribed and nonprescribed patients. Patterns that could explain ACEI underuse included female sex, lower systolic blood pressure, worse renal function, left ventricular diastolic dysfunction, use of alternate drugs (eg, spironolactone), and overall less intense medical management. Patterns associated with the use of lower doses of ACEIs included older age, higher New York Heart Association functional class, and lower systolic blood pressure. In-hospital death rates were significantly higher for patients not treated with ACEIs.Conclusions: This study suggests that many patients eligible for ACEI treatment were deprived of the advantages of these drugs because of erroneous clinical strategies. Nevertheless, the patterns of ACEI use were similar to those reported by other studies. Clinical trials conducted to determine the risk/benefit ratio of ACEI use in patients with renal dysfunction and the utility of ACEIs in diastolic HF, as well as programs to educate care providers on proper use of ACEIs in HF patients, are strongly recommended.     

The effects of frusemide and angiotensin-converting enzyme inhibitors and their combination on cardiac and renal haemodynamics in heart failure

Few studies exist on the interaction of diuretics and angiotensin-convertingenzyme inhibitors in patients with chronic heart failure. Twelvesubjects with heart failure were studied before and after theirusual oral dose of frusemide in random order on consecutivedays during fixed sodium, potassium and water intake. Patientsthen received 10 mg day ^–1 of enalapril for 5 days andsubsequently restudied before and after their usual dose offrusemide. Frusemide was not observed to have an effect on systemic orrenal haemodynamics prior to enalapril, but urine volume andsodium content rose as expected. Treatment with enalapril, inthe absence of frusemide, was associated with a fall in meanblood pressure from 89 ±5 mmHg to 85 ±4 mmHg (P< 0.02) and a rise in renal blood flow from 424 ±202ml min^–1 to 494±225ml min^–1 (P<0.02),but cardiac output and glomerular filtration rate were againunchanged. Addition of frusemide to enalapril therapy resultedin a greater fall in mean blood pressure (87±5mmHg to79±4 mmHg; P<001) and an increase in cardiac output(3.1 ± 11 lmin-1 to 3.6± 1.01 min^–1; P<0.02).Renal blood flow increased further than after enalapril aloneto 579 ±211 ml min^–1 but the glomerular filtrationrate fell to 63±26 ml min^–1 (P<0.01) and thefiltration fraction fell to 19±5% (P<0.001). Weightgain occurred and the diuretic response to frusemide was reducedduring this early phase of enalapril therapy.