Recent advances and limitations of medical treatment on heart failure

Main part of the management of chronic heart failure is pharmaceutical therapy. In patients with chronic heart failure due to left ventricular systolic dysfunction, enhanced activation of neurohormonal systems including sympathetic nerve and renin-angiotensin-aldosterone system plays the most important role in its progression and poor prognosis. Therefore, principle of treatment of chronic heart failure is inhibition of the elevated neurohormonal activity. Angiotensin converting enzyme inhibitors and beta blockers are class I drugs of choice. In patients who can not tolerate angiotensin converting enzyme inhibitors, angiotensin II receptor blockers are used as replacement. In patients with severe heart failure [New York Heart Association (NYHA) class > III], aldosterone antagonists are added. Diuretics are also class I drug necessary for an improvement of symptoms of heart failure. Recently, implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT) are implanted more frequently, because volume of evidence indicates benefits of these non-pharmacological treatments. In this paper, recent advance in medical therapy for patients with heart failure and its limitation is discussed.     

Management of heart failure

Heart failure is an increasingly common syndrome, which is associated with a high 1-year mortality and significant morbidity. Currently ischaemic heart disease is the most common cause in western societies but the majority of causes produce a similar clinical picture of reduced cardiac output, salt and water retention and peripheral vasoconstriction. Advances in the understanding of the pathophysiology of heart failure have lead to an alteration in the way in which it is managed and the development of different models of heart failure. Salt and water retention is managed with the use of fluid restriction and diuretics. Inotropic therapy remains useful in the short-term management of heart failure when acute decompensation leads to critical hypoperfusion of vital organs. Finally the maladaptive neurohumoral activation found in heart failure can be antagonised by the use of beta-blockers, angiotensin converting enzyme inhibitors and spironolactone, all of which reduce mortality and improve symptoms.     

Cytokines and heart failure

Chronic heart failure is a major cause for mortality and morbidity in western civilizations. Previous hypothesises regarding the pathogenesis of chronic heart failure did not sufficiently explain the aetiology and the progression of the disease. However, it has been shown that a group of peptides called cytokines are expressed during chronic heart failure and that cytokines might play an important role for the pathogenesis. The expression of cytokines can be modulated from specific ACE-inhibitors as well as from different beta-blockers and angiotensin type 1 antagonists. Numerous investigations have shown that cytokines depress left ventricular function and can be responsible for different characteristics of chronic heart failure. The present article resumes experimental and clinical investigations and recent pharmacologic attempts for the treatment of chronic heart failure. The previous results demonstrate the importance to further investigate anti-inflammatory approaches to treat chronic heart failure.     

Which drug should be used to treat patients with uncomplicated essential hypertension?

PURPOSE OF REVIEW: To review recent data and guidelines on selecting the initial antihypertensive drug. RECENT FINDINGS: The main driver of benefit from blood pressure-lowering therapy is blood pressure reduction, and there is little evidence supporting additional drug class-specific benefits in primary prevention of major cardiovascular outcomes. The results also confirm that in the patient with uncomplicated hypertension as well as in those patients with diabetes without nephropathy, initial therapy with 'newer therapies' (i.e. angiotensin-converting enzyme inhibitors, calcium channel blockers, and angiotensin receptor blockers) are effective, but not more effective than thiazide diuretics, at reducing stroke, coronary heart disease, morbidity or mortality, or all-cause mortality. SUMMARY: While compelling indications may exist for specific drug classes in those with specific target organ damage (i.e. heart failure, renal insufficiency, and coronary artery disease), thiazide diuretics remain unsurpassed in lowering blood pressure and in preventing hypertension-related clinical outcomes. Despite a more favorable metabolic profile, alpha-blockers are less effective in preventing cardiovascular disease, especially heart failure and stroke. Calcium channel blockers produce a similar reduction in blood pressure and cardiovascular disease outcomes compared with thiazide-type diuretics, although they are consistently less effective in preventing heart failure. In the absence of heart failure or renal disease, angiotensin-converting enzyme inhibitors have shown little advantage in clinical trials over diuretics in preventing cardiovascular disease and are not indicated as an initial therapy in Blacks.     

高输出量性心力衰竭的诊断与治疗

有心衰的症状和体征、并伴有心输出量升高的心衰被称作“高输出量性心力衰竭”。伴有心衰的心输出量升高与多种疾病有关．包括：慢性贫血．全身性动-静脉瘘．脓毒症、高碳酸血症和甲状腺功能亢进症。发生这种病变的生理学基础是动-静脉分流或外周血管扩张所导致的全身血管阻力降低。这两方面原因都可以引起全身动脉压的下降和神经内分泌活动增强．进而导致心衰的临床表现。与低输出量性心力衰竭不同。关于高输出量性心力衰竭的临床试验比较缺乏。治疗心衰的常规疗法。如血管紧张素转化酶抑制剂、血管紧张素受体阻滞剂和一些能扩张血管的β受体阻断剂的应用．对于高输出量性心衰非但没效,反而会进一步降低全身血管阻力,使病情恶化。高输出量性心衰尽管少见,但常伴有一些可纠正的潜在病因。治疗方案比较局限：可以限制饮食中盐和水,并辅以利尿剂的适当应用。不建议使用血管扩张剂和β肾上腺素受体正性肌力药。     

Angiotensin-converting enzyme inhibitors. Current indications

Angiotensin-converting enzyme (ACE) inhibitors are a relatively homogenous drug class widely used today. They have been shown to reduce morbidity or mortality in congestive heart failure, myocardial infarction, chronic renal insufficiency, diabetes mellitus, and atherosclerotic cardiovascular disease. Pathologies underlying these conditions are partially attributable to the renin-angiotensin-aldosterone system. Angiotensin II contributes to endothelial dysfunction, altered renal hemodynamics, and vascular and cardiac hypertrophy. ACE inhibitors attenuate these effects. Clinical outcomes of ACE inhibition include lower incidence of fatal and nonfatal myocardial infarction, reinfarction, angina, stroke, end-stage renal disease, and morbidity and mortality associated with heart failure. ACE inhibitors are generally well tolerated and have few contraindications.     

Cardio-renal syndrome type 4: epidemiology, pathophysiology and treatment

Cardiovascular diseases such as coronary artery disease, congestive heart failure, arrhythmia, and sudden cardiac death represent the leading causes of morbidity and mortality in patients with CKD, increasing sharply as patients approach end-stage renal disease. The pathogenesis includes a complex, bidirectional interaction between the heart and kidneys that encompasses traditional and nontraditional risk factors, and has been termed cardio-renal syndrome type 4. In this review, an overview of the epidemiology and scope of this problem is provided, some suggested mechanisms for the pathophysiology of this disorder are discussed, and some of the key treatment strategies are described, with particular focus on recent clinical trials, both negative and positive.     

Extracorporeal ultrafiltration for heart failure: Focus on organ cross talk and clinical trials

Despite major advances in pharmacological therapy and cardiac devices, heart failure patients continue to be frequently (re-)hospitalized with signs and symptoms of fluid overload. Diuretics improve the symptoms of fluid overload, but their effectiveness is reduced by a number of factors including excess salt intake, underlying chronic kidney disease, renal adaptation to their actions and neurohormonal activation. Ultrafiltration (UF) is a mechanical method of fluid removal with several potential advantages over diuretic-based conventional therapies: several recent studies have demonstrated favorable clinical response to UF therapy. Such studies have shown that removal of large amounts of isotonic fluid, in addition to relieving symptoms of congestion, can improve exercise capacity, reduce cardiac filling pressures, restore diuretic responsiveness, and portend a favorable effect on cardio-pulmonary, cardiorenal interactions, and neurohormonal hyperactivation. However, despite these proposed benefits, so far, no clinical study has yet been carried out to explore the impact of UF therapy on hard clinical endpoints such as long-term mortality. In this article, we review a number of mechanistic aspects of UF therapy, with particular emphasis on cardio-pulmonary and cardiorenal interactions, and revisit the results of more recent clinical trials in order to highlight the characteristics that can help identify patients who are more likely to benefit from this therapeutic modality.     

The muscle hypothesis: a model of chronic heart failure appropriate for osteopathic medicine.

Chronic heart failure is one of the most serious medical problems in the United States, affecting some 4 million persons. In spite of its common occurrence, and comprehensive literature regarding this condition, no unifying hypothesis has been accepted to explain the signs and symptoms of chronic heart failure. The cardiocirculatory and neurohormonal models place an emphasis on left ventricular ejection fraction and cardiac output and do not provide appropriate explanations for the symptoms of breathlessness and fatigue. The muscle hypothesis supplements these conventional models. It proposes that abnormal skeletal muscle in heart failure results in activation of muscle ergoreceptors, leading to an increase in ventilation and sensation of breathlessness, the perception of fatigue, and sympathetic activation. At least one fourth of patients with chronic heart failure are limited by skeletal muscle abnormalities rather than cardiac output. Cardiac rehabilitation exercise can lead to an increase in exercise capacity that is superior to that gained from digitalis or angiotensin-converting enzyme inhibitors. Exercise tends to reverse the skeletal muscle myopathy of chronic heart failure and reduces the abnormal ergoreflex. Other interventions that have been shown to have a favorable outcome include localized muscle group training, respiratory muscle training, and dietary approaches. The possibility that osteopathic manipulative treatment might be of benefit is an attractive, but untested, possibility.     

Use of diuretics in heart failure and cirrhosis

Sodium and water retention in cardiac failure and cirrhosis is pivotal in the morbidity and mortality of patients with these disorders. Moreover, the pathophysiology of these edematous disorders is quite similar. Both disorders have activation of the renin-angiotensin-aldosterone system, increased sympathetic activity, and nonosmotic stimulation of arginine vasopressin, which is initiated by unloading of the arterial baroreceptors; this occurs secondary to diminished cardiac output with heart failure and primary systemic arterial vasodilation with cirrhosis. With this common pathophysiology causing pulmonary congestion, ascites, and peripheral edema, diuretics are pivotal in the therapy of patients with heart failure and cirrhosis. Advanced cardiac failure and cirrhosis both show secondary hyperaldosteronism and impaired renal escape from the sodium-retaining effect of aldosterone. However, currently there are contradictory uses of mineralocorticoid-receptor antagonists in cardiac failure (non-natriuretic doses) versus cirrhosis (natriuretic doses). This disparity relates to the greater potential of hyperkalemia in cardiac failure patients receiving inhibitors of the renin-angiotensin-aldosterone system. This review discusses the beneficial and potentially deleterious effects of diuretic use in patients with cardiac failure and cirrhosis.     

Adaptation of Renal Function in Heart Failure

Congestive heart failure is the only major cardiovascular disease with an increasing incidence and prevalence in industrialized countries. Despite considerable progress in the clinical management of heart failure during the last 20 years, the prognosis is still worse than in many common types of cancer. The kidney is the main organ affected when cardiac function is compromised. In addition, the kidney significantly contributes to the development of the clinical syndrome of heart failure. Specific hemodynamic and neurohormonal abnormalities define the pathophysiology, clinical presentation, and prognosis of this disorder. In this setting, the kidney plays a dual role: the activation of the renin-angiotensin-aldosterone system and the regulation of sodium and water excretion. The kidney is generally intact in heart failure, but extrarenal stimuli alter its function to a point where mechanisms that are initially homeostatic become maladaptive. In this review article, the mechanisms involved in renal adaptation to heart failure are presented.     

The hypothalamic paraventricular nucleus and cardiovascular homeostasis: a role in chronic heart failure

A pathophysiological characteristic of chronic heart failure is sympatho-excitation and sympathetic activity is a major factor contributing to the morbidity and mortality of heart failure. Current research suggests a central mechanism to be a major contributor to the abnormal sympathetic activation in heart failure. The paraventricular nucleus of the hypothalamus (PVN) is an important site that integrates sympathetic nerve activity and recent evidence suggests this nucleus plays a role in the exaggerated sympathetic outflow observed in heart failure. Experimental studies using animal models have identified nitric oxide (NO) and γ-aminobutyric acid (GABA) within the PVN as providing inhibitory mechanisms to regulate sympathetic outflow and that these inhibitory mechanisms are attenuated in heart failure. Furthermore, the degree of sympathetic activation is a balance of interactions between excitatory (angiotensin II and glutamate) and inhibitory (NO and GABA) neurotransmitters within the PVN. The attenuated actions of NO and GABA within the PVN may allow for an increase in the actions of angiotensin and glutamate and this may be a source of the sympatho-excitation observed in heart failure.     

心力衰竭患者的非药物治疗进展

心力衰竭是由各种疾病引起心肌收缩或／和舒张能力减弱，从而使心排血量减少产生的一系列症状和体征；是各种心脏病的终末期表现，也是心脏病患者死亡的主要原因之一。随着人群年龄的增长，心力衰竭的发病率在上升。尽管药物治疗在不断地改进，但其发病率和死亡率仍然很高。近年来，心力衰竭的非药物治疗越来越受到临床医师的重视，外科手术方式日益创新，内科介入也不断推出新的辅助装置，基因学和干细胞技术为其治疗带来了新的希望。现对心力衰竭的外科手术、介入治疗及其相关基因和细胞治疗的研究现状和进展进行综述。     

Adaptation of renal function in heart failure

Congestive heart failure is the only major cardiovascular disease with an increasing incidence and prevalence in industrialized countries. Despite considerable progress in the clinical management of heart failure during the last 20 years, the prognosis is still worse than in many common types of cancer. The kidney is the main organ affected when cardiac function is compromised. In addition, the kidney significantly contributes to the development of the clinical syndrome of heart failure. Specific hemodynamic and neurohormonal abnormalities define the pathophysiology, clinical presentation, and prognosis of this disorder. In this setting, the kidney plays a dual role: the activation of the renin-angiotensin-aldosterone system and the regulation of sodium and water excretion. The kidney is generally intact in heart failure, but extrarenal stimuli alter its function to a point where mechanisms that are initially homeostatic become maladaptive. In this review article, the mechanisms involved in renal adaptation to heart failure are presented.     

Aktuelle konservative Therapie der chronischen Herzinsuffizienz

Systolic heart failure and heart failure with preserved systolic function occur with similar prevalence rates in primary care. Nowadays we are equipped with drugs which effectively counteract the pathophysiological dysregulations in systolic heart failure and have resulted in significant reductions of morbidity and mortality. In recent years device therapy with implantable defibrillators and cardiac resynchronization devices has further supplemented and improved therapy. Due to the lack of dedicated randomized, controlled studies therapy of heart failure with preserved systolic function is mainly based on pathophysiological assumptions and targeted to symptom relief. Based on recent heart failure guidelines and latest studies this report gives an overview of the current recommendations for conservative treatment of both types of chronic heart failure.     

Diabetic cardiomyopathy: Pathophysiology,theories and evidence to date

The prevalence of type 2 diabetes(T2D) has increased worldwide and doubled over the last two decades. It features among the top 10 causes of mortality and morbidity in the world. Cardiovascular disease is the leading cause of complications in diabetes and within this, heart failure has been shown to be the leading cause of emergency admissions in the United Kingdom. There are many hypotheses and well-evidenced mechanisms by which diabetic cardiomyopathy as an entity develops. This review aims to give an overview of these mechanisms,with particular emphasis on metabolic inflexibility. T2D is associated with inefficient substrate utilisation, an inability to increase glucose metabolism and dependence on fatty acid oxidation within the diabetic heart resulting in mitochondrial uncoupling, glucotoxicity, lipotoxicity and initially subclinical cardiac dysfunction and finally in overt heart failure. The review also gives a concise update on developments within clinical imaging, specifically cardiac magnetic resonance studies to characterise and phenotype early cardiac dysfunction in T2D. A better understanding of the pathophysiology involved provides a platform for targeted therapy in diabetes to prevent the development of early heart failure with preserved ejection fraction.     

Cardio-renal syndrome type 1: epidemiology, pathophysiology, and treatment

One third of heart failure admissions may be complicated by acute kidney injury, resulting in a three-fold increase in length of stay and a greater likelihood of rehospitalization. Cardio-Renal syndrome type 1 refers to acute decompensation of cardiac function leading to acute renal failure. It often complicates acute coronary syndrome and acute decompensated heart failure. Both components of the syndrome contribute to morbidity and mortality. The pathophysiology of renal dysfunction is complex. Reduced cardiac output, passive congestion of the kidneys, and increased intra-abdominal pressure may contribute to the disorder. The heart, kidneys, renin-angiotensin system, sympathetic nervous system, immune system, and vasculature interact through intricate feedback loops. An imbalance in this complex system often will cause deterioration in both cardiac and renal function. Appreciation of these interactions is crucial to understanding the overall burden of disease, as well as its natural history, risk factors, associated morbidity and mortality, and therapeutic implications.     

Antihypertensive, cardiovascular, and pleiotropic effects of angiotensin-receptor blockers

PURPOSE OF REVIEW: To review the antihypertensive, cardiovascular and pleiotropic effects of angiotensin-receptor blockers (ARBs). RECENT FINDINGS: ARBs are the most recently approved class of antihypertensive agents. They selectively block the angiotensin II type 1 receptor, thus inhibiting most of the deleterious effects of angiotensin II. In addition to blood-pressure control, other benefits may be gained using ARBs. This is because the renin-angiotensin system plays a crucial role in circulatory homoeostasis, and in patients with atherosclerosis, diabetes or hypertension, angiotensin II contributes to the pathophysiology of disease. Evidence-based medicine includes well-controlled studies with mortality and morbidity endpoints in patients with a variety of conditions including hypertension, type 2 diabetes, stroke, renal disease, heart failure, left-ventricular hypertrophy and coronary heart diseases. In addition to these hard endpoints, it has been shown that treatment with ARBs prevents the development of type 2 diabetes, ameliorates coronary and peripheral vascular endothelial dysfunction and decreases plasma levels of several markers of vascular inflammation. SUMMARY: ARBs are first-line agents for the treatment of hypertension and cardiovascular diseases. Blocking the renin-angiotensin system with these agents has special advantages due to specific vascular and antiatherosclerotic effects, which contribute to a better cardiovascular and renal protection in patients at risk from or with cardiovascular disease.     

Cardiovascular disease in chronic renal failure: pathophysiologic aspects

Cardiovascular complications are the leading cause of mortality in patients with end-stage renal disease (ESRD). The excess cardiovascular risk and mortality is already demonstrable in early renal disease and in patients with chronic renal failure (CRF), with the highest relative risk of mortality in the youngest patients. The high risk for cardiovascular disease (CVD) results from the additive effect of multiple factors, including hemodynamic overload and several metabolic and endocrine abnormalities more or less specific to uremia. CVD includes disorders of the heart (left ventricular hypertrophy [LVH], cardiomyopathy) and disorders of the vascular system (atherosclerosis, arteriosclerosis), these two disorders being usually associated and interrelated. LVH is the most frequent cardiac alteration in ESRD, resulting from a combined pressure and volume overload. LVH in general is an ominous prognostic sign and an independent risk factor for arrhythmias, sudden death, heart failure, and myocardial ischemia. Regression of LVH needs a combined intervention to reduce hemodynamic overload and is associated with improved prognosis and survival. Clinical studies have shown that damage of large conduit arteries is a major contributing factor for the high incidence of congestive heart failure (CHF), LVH, ischemic heart disease (IHD), sudden death, cerebrovascular accidents, and peripheral artery diseases. Damage to large conduit arteries is principally related to highly calcified occlusive atherosclerotic lesions and to stiffening of large capacitive arteries. These two complications are independent risk factors for survival, and improvement of arterial stiffness is associated with better prognosis and survival. The present review summarizes the most recent works dealing with the pathophysiology of CVD and some aspects of the therapeutic approach.     

Angiotensin II in the failing heart. Short communication

In the failing heart, the local angiotensin II concentration is increased, and the extent of cardiac angiotensin II release is related to the clinical signs of heart failure. The enzymes involved in myocardial generation of angiotensin II are the angiotensin-converting enzyme (ACE) and chymases. While myocardial angiotensin II is mainly generated by chymases in the human heart, ACE inhibitors nevertheless improve left ventricular (LV) function, attenuate LV remodelling and reduce mortality in heart failure patients. These beneficial actions of ACE inhibitors, however, relate to their beneficial effect on kinin metabolism. Angiotensin II type 1 receptor (AT1) antagonists also mediate part of their beneficial effects through increased bradykinin formation. However, in contrast to ACE inhibitors, AT1 receptor antagonists attenuate downstream signalling of angiotensin II-induced AT1 receptor activation, which increases the activity of existing proteins (e.g. NADPH oxidase) and the de novo synthesis of proteins (e.g. inducible nitric oxide synthase, tumor necrosis factor-alpha ) in cardiomyocytes. Given the multiple actions of AT1 receptor activation on cardiomyocyte and non-cardiomyocyte function in the presence of an increased myocardial AngII concentration, the reduction of cardiovascular mortality and rate of hospitalization following AT1 receptor blockade in heart failure patients not receiving ACE inhibitors is not surprising. Most importantly, the beneficial effects of AT1 receptor blockade are not only achieved when used as an alternative to ACE inhibition, but also when used on top of ACE inhibitors.