The last frontier: transcatheter devices for percutaneous or minimally invasive treatment of chronic heart failure

Heart failure has a high prevalence in the general population. Morbidity and mortality of heart failure patients remain high, despite improvements in drug therapy, implantable cardioverter-defibrillators and cardiac resynchronisation therapy. New transcatheter implantable devices have been developed to improve the treatment of heart failure. There has been a rapid development of minimally invasive or transcatheter devices used in the treatment of heart failure associated with aortic and mitral valve disease and these devices are being incorporated into routine clinical practice at a fast rate. Several other new transcatheter structural heart interventions for chronic heart failure aimed at a variety of pathophysiologic approaches are currently being developed. In this review, we focus on devices used in the treatment of chronic heart failure by means of left ventricular remodelling, left atrial pressure reduction, tricuspid regurgitation reduction and neuromodulation. The clinical evaluations of these devices are early-stage evaluations of initial feasibility and safety studies and additional clinical evidence needs to be gathered in appropriately designed clinical trials.     

Debate: at what level of coronary heart disease risk should a statin be prescribed?

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are effective treatments for the primary and secondary prevention of coronary heart disease, but an outstanding issue is determining who should have such treatment. The benefit from treatment with statins appears to be proportional to the underlying risk of coronary heart disease and independent of the factors increasing risk. Most benefit will therefore be achieved by treating people at increased risk of coronary heart disease. Statins reduce coronary morbidity even when the risk of coronary heart disease is relatively low (6% over 10 years), but reduction in all-cause mortality, the true measure of safety has been shown only when the risk of a major coronary heart disease event is 15% over 10 years or greater. At this level of risk patients appear willing to take treatment to gain the benefit expected from statin treatment, and the cost effectiveness of statin treatment is within the range accepted for other treatments. The major impediments to the systematic introduction of statin treatment at this level of risk are the very high overall cost and the large workload in countries like Britain, where the population risk of coronary heart disease is high. For this reason, recent British guidelines correctly advise statin treatment for secondary prevention and primary prevention when the 10 year coronary heart disease risk is 30% or greater as the first priority, moving to a lower coronary heart disease threshold for primary prevention only when resources permit.     

Cardiac toxicity of lung cancer radiotherapy

Radical radiotherapy of lung cancer with dose escalation has been associated with increased tumor control. However, these attempts to continually improve local control through dose escalation, have met mixed results culminating in the findings of the RTOG trial 0617, where the heart dose was associated with a worse overall survival, indicating a significant contribution to radiation-induced cardiac morbidity. It is, therefore, very likely that poorly understood cardiac toxicity may have offset any potential improvement in overall survival derived from dose escalation and may be an obstacle that limits disease control and survival of patients. The manifestations of cardiac toxicity are relatively common after high dose radiotherapy of advanced lung cancers and are independently associated with both heart dose and baseline cardiac risk. Toxicity following the treatment may occur earlier than previously thought and, therefore, heart doses should be minimized. In patients with lung cancer, who not only receive substantial heart dose, but are also older with more comorbidities, all cardiac events have the potential to be clinically significant and life-threatening.Sophisticated radiation treatment planning techniques, charged particle therapy, and modern imaging methods in radiotherapy planning, may lead to reduction of the heart dose, which could potentially improve the clinical outcomes in patients with lung cancer. Efforts should be made to minimize heart radiation exposure whenever possible even at doses lower than those generally recommended. Heart doses should be limited as much as possible.A heart dosimetry as a whole is important for patient outcomes, rather than emphasizing just one parameter.     

Angiotensin receptor blockers in heart failure after the ELITE II trial

Specific blockers of the angiotensin type1 receptor, angiotensin receptor blockers (ARBs), have been introduced as an alternative to angiotensin-converting enzyme inhibitors (ACEi) for the treatment of heart failure. In comparison with ACEi, ARBs are better tolerated and have similar effects on haemodynamics, neurohormones and exercise capacity. Early studies have suggested that ARBs might have a superior effect on mortality. However, the first outcome trial, ELITE II (Losartan Heart Failure Survival Study), did not show any significant difference between losartan and captopril in terms of mortality or morbidity. This commentary outlines the role of ARBs in the treatment of heart failure.     

Targeting inflammation in heart failure with histone deacetylase inhibitors

Cardiovascular insults such as myocardial infarction and chronic hypertension can trigger the heart to undergo a remodeling process characterized by myocyte hypertrophy, myocyte death and fibrosis, often resulting in impaired cardiac function and heart failure. Pathological cardiac remodeling is associated with inflammation, and therapeutic approaches targeting inflammatory cascades have shown promise in patients with heart failure. Small molecule histone deacetylase (HDAC) inhibitors block adverse cardiac remodeling in animal models, suggesting unforeseen potential for this class of compounds for the treatment of heart failure. In addition to their beneficial effects on myocardial cells, HDAC inhibitors have potent antiinflammatory actions. This review highlights the roles of HDACs in the heart and the potential for using HDAC inhibitors as broad-based immunomodulators for the treatment of human heart failure.     

Congestive heart failure. New frontiers.

Congestive heart failure is a common syndrome with high mortality in its advanced stages. Current therapy includes the use of vasodilator drugs, which have been shown to prolong life. Despite current therapy, mortality remains high in patients with severe heart failure. Potent new inotropic vasodilators have improved ventricular performance but have not prolonged life in patients with end-stage heart failure. Serious arrhythmias are implicated in the sudden deaths of 30% to 40% of patients with severe heart failure, but the benefits of antiarrhythmic therapy have not been established. Upcoming trials will address this question. Ventricular remodeling and progressive dilatation after myocardial infarction commonly lead to congestive heart failure; early unloading of the ventricle with an angiotensin-converting enzyme inhibitor may attenuate these events. These findings support the concept that angiotensin-converting enzyme inhibitors may be useful in managing heart failure of all degrees of severity, including left ventricular dysfunction and end-stage heart failure. Part of the damage that may occur with acute myocardial infarction, particularly in this era of thrombolysis therapy, is reperfusion injury, which may be mediated by oxygen-derived free radicals. Better knowledge of the mechanisms and treatment of myocardial infarction, the leading cause of congestive heart failure, may help prevent or attenuate the development of this syndrome.     

Potential of resveratrol in the treatment of heart failure

The concept of food has expanded beyond its traditional role of survival and hunger satisfaction, to include a role in the prevention and treatment of disease. Polyphenols are classes of compounds that are synthesized by plants to serve a wide variety of functions including growth pollination and defense. These compounds have recently received increased attention in medical research. In this group, one of the most studied has been resveratrol (3,5,4,-trihydroxystilbene), a polyphenol, which is found predominantly in grapes and berries. Over the past two decades, researchers have studied the ability of resveratrol to prevent or reverse the development of abnormalities in heart structure and function in animal models of heart disease and heart failure. The results from animal studies have been promising, and very recently, this knowledge has been translated into examining the efficacy of resveratrol in humans with heart disease/failure. In this review we will discuss the current status of resveratrol research on cardioprotection.     

G protein-coupled receptors in cardiac biology: old and new receptors

G protein-coupled receptors (GPCRs) are seven-transmembrane-spanning proteins that mediate cellular and physiological responses. They are critical for cardiovascular function and are targeted for the treatment of hypertension and heart failure. Nevertheless, current therapies only target a small fraction of the cardiac GPCR repertoire, indicating that there are many opportunities to investigate unappreciated aspects of heart biology. Here, we offer an update on the contemporary view of GPCRs and the complexities of their signalling, and review the roles of the ‘classical’ GPCRs in cardiovascular physiology and disease. We then provide insights into other GPCRs that have been less extensively studied in the heart, including orphan, odorant and taste receptors. We contend that these novel cardiac GPCRs contribute to heart function in health and disease and thereby offer exciting opportunities to therapeutically modulate heart function.     

Aldosterone and the heart: from basic research to clinical evidence

Recent views suggest that long-term exposure to elevated aldosterone concentrations might result in cardiac, vascular, renal, and metabolic sequelae that occur independent of the blood pressure level. Indirect evidence of the untoward effects of aldosterone on the heart has been clearly established in clinical studies that have tested the effects of mineralocorticoid receptor antagonists in the treatment of systolic heart failure. As it has become clear in recent years, the interaction between aldosterone and the heart has to deal with additional actions of the hormone on specific cell types, cellular mechanisms, and molecules that are involved in regulation of tissue responses, leading to hypertrophy, remodeling, and fibrosis. The majority of these effects are mediated by activation of the mineralocorticoid receptors that are expressed in cardiomyocytes and cardiac fibroblasts, and mediate the genomic effects of the hormone. Evidence of interactions between aldosterone and the heart that occur independent of the renal effects of aldosterone, however, is not limited to the context of systolic heart failure and observations obtained in other disease states have led, together with findings of animal studies, to a better understanding of the potential benefits of aldosterone antagonists. In this narrative overview, we highlight the most recent findings that have been obtained in experimental animal models and in clinical conditions that include, in addition to systolic heart failure, primary aldosteronism, essential hypertension, diastolic heart failure, and arrhythmia.     

Beneficial cardiovascular effects of endothelin ET(A) receptor blockade in established long-term heart failure after myocardial infarction

Although experimental prevention studies have suggested therapeutic potential of endothelin (ET) antagonists for the treatment of heart failure, the results of clinical trials using ET antagonists on top of standard heart failure medications have been largely disappointing. This experimental study investigated the effects of chronic ET(A) receptor blockade in long-term survivors of myocardial infarction who had developed stable chronic heart failure in the absence of other treatments. Systolic blood pressure, heart rate, organ weights of the right atrium and ventricle, and the lungs were determined, and tissue ET-1 peptide levels were measured in cardiac tissue, lung, and aorta. The results show that chronic blockade of ET(A) receptors stabilizes systolic blood pressure and reverses the heart failure-induced weight increases of right heart chambers and lung. The changes observed occurred independently of tissue ET-1 concentrations and heart rate, suggesting mechanisms independent of local cardiac or pulmonary ET-1 synthesis, which are yet to be identified.     

Diabetes mellitus and raised serum triglyceride concentration in treated hypertension--are they of prognostic importance? Observational study.

OBJECTIVE: To analyse whether metabolic changes during long term treatment with antihypertensive drugs are associated with an increased risk of coronary heart disease. DESIGN: Observational study. SETTING: Gothenburg, Sweden. SUBJECTS: 686 middle aged hypertensive men, recruited after screening of a random population sample, and followed for 15 years during treatment with predominantly beta adrenoceptor blockers or thiazide diuretics, or both. Coronary heart disease and diabetes mellitus were registered at yearly patient examinations. Entry characteristics, as well as within study serum concentrations of cholesterol and triglycerides and the development of diabetes mellitus, were related to the incidence of coronary heart disease in a time dependent Cox''s regression analysis. MAIN OUTCOME VARIABLE: Coronary heart disease morbidity. RESULTS: Diabetes mellitus, raised serum cholesterol and triglyceride concentrations present at the beginning of the study were all significantly predictive of coronary heart disease in univariate analysis. The relative risk of diabetes mellitus and of a 1 mmol/l increase in the cholesterol and triglyceride concentrations was 2.12 (95% confidence interval 1.11 to 4.07), 1.21 (1.05 to 1.39), and 1.21 (1.03 to 1.43) respectively. However, when the within study metabolic variables were analysed, only the serum cholesterol concentration was significantly and independently associated with coronary heart disease (relative risk 1.07 (1.02 to 1.13)). Although the triglyceride concentrations increased slightly during the follow up, the within study serum triglyceride concentrations were not associated with the incidence of coronary heart disease (1.04 (0.96 to 1.10)). New diabetes mellitus-that is, onset during follow up-was not significantly associated with an increased risk for coronary heart disease (1.48 (0.37 to 6.00)). CONCLUSIONS: Metabolic disturbances such as diabetes mellitus and hyperlipidaemia presenting before the start of antihypertensive treatment have a prognostic impact in middle aged, treated hypertensive men. Moreover, while within study cholesterol concentration was an independent predictor of coronary heart disease, drug related diabetes mellitus and raised serum triglyceride concentrations that are associated with treatment do not seem to have any major impact on the coronary heart disease prognosis in this category of patients.     

Treatment options in end-stage heart failure: where to go from here?

Chronic heart failure is a major healthcare problem associated with high morbidity and mortality. Despite significant progress in treatment strategies, the prognosis of heart failure patients remains poor. The golden standard treatment for heart failure is heart transplantation after failure of medical therapy, surgery and/or cardiac resynchronisation therapy. In order to improve patients' outcome and quality of life, new emerging treatment modalities are currently being investigated, including mechanical cardiac support devices, of which the left ventricular assist device is the most promising treatment option. Structured care for heart failure patients according to the most recent international heart failure guidelines may further contribute to optimal decision-making. This article will review the conventional and novel treatment modalities of heart failure.     

Tailored therapy for heart failure: neurohormones

Plasma B type cardiac natriuretic peptides reflect cardiac structure and function and have proven roles in assisting in the diagnosis of acute heart failure. They are also powerful independent prognostic indicators across the full spectrum of cardiovascular disease. The efficacy of serial measurements of plasma B type peptides in guiding titration of therapy for chronic heart failure has been the subject of a number of randomized controlled trials. These are summarized in the following brief review. In the decade 2000-2010, 8 trials have been completed. Study design, the characteristics of the heart failure population studied, duration of follow-up, the exact end points recorded, and target peptide levels pursued all differ somewhat between trials. However, an overall consistency is emerging, supported by 2 metaanalyses. In aggregate, the existing trial data suggest that adjustment of treatment in chronic heart failure according to serial B type peptide measurements used in conjunction with established clinical methods is likely to reduce cardiac mortality and admissions with heart failure, at least in those patients aged under 75?years with impaired left ventricular systolic function.     

Natriuretic peptides - physiology, pathophysiology and clinical use in heart failure

The natriuretic peptides - atrial, brain and C-type - were discovered during the last twenty years. Their effects on cardiovascular, renal, cerebral and other tissues through guanylyl cyclase were uncovered. Over the past decade natriuretic peptides (NPs) became a very useful tool in the management of heart failure patients. Results of many clinical trials have shown that BNP and NT-proBNP are helpful for diagnosis of heart failure. They are also independent markers of prognosis not only in heart failure patients but also in patients with other cardiovascular diseases. Recently published data document the utility of NPs in guiding treatment of heart failure patients. In this article, we focus on basic biochemical and physiological characteristics of NPs as well as on their significance in management of heart failure patients. Some limitations and pitfalls of NPs levels interpretation in diagnosing heart failure are also discussed.     

Estrogen effects in the heart

Gender specific differences in cardiovascular disease are largely mediated by sex hormones. The use of estrogens significantly reduces the overall incidence of heart disease in postmenopausal women. Beneficial effects of estrogens on plasma lipoprotein levels are clearly established. However, these do not explain the magnitude of risk reduction seen in clinical studies. Thus, additional and currently unknown functions of estrogens must be operative. Elucidation of the exact estrogen action in the heart will have important implications in the treatment of cardiovascular disease. It will probably enhance the therapeutic repertoire in treating heart disease, the most common cause of death in industrialized countries. We will review the current understanding of the function of estrogens in the heart and discuss potential strategies on how to apply these data to clinical practice.     

重组人脑利钠肽的临床应用进展

近年来,随着心力衰竭、肺动脉高压的病理生理及分子机制的深入研究,使上述疾病在临床药物治疗方面有了很大的进步,其中人脑利钠肽(BNP)作为体内唯一天然的肾素-血管紧张素-醛固酮拮抗剂在诊断及治疗心力衰竭等方面均引起了广泛关注,但由于其在心衰状态下降解快且生物活性明显减弱而限制了临床应用。因此,在心力衰竭治疗上补充外源性BNP成为了又一研究热点。重组人脑利钠肽(rhBNP)是一种人工合成的内源性激素,具有扩张血管、排钠利尿、降低心脏前后负荷、抑制肾素-血管紧张素-醛固酮系统和交感神经系统等作用,能够有效的改善充血性心力衰竭患者的血流动力学障碍。新近研究表明,rhBNP在治疗心血管疾病方面疗效显著,本文将就其在临床中的应用予以综述。     

Development of the linkage of beta-adrenergic receptors to cardiac hypertrophy and heart rate control: neonatal sympathectomy with 6-hydroxydopamine

Presynaptic neural projections are thought to participate in the maturation of postsynaptic sensitivity to neurotransmitters. In the current study, we have examined the effects of sympathectomy with 6-hydroxydopamine on the ontogeny of the linkage of beta-adrenergic receptors to cardiac growth and heart rate control in the rat. Destruction of sympathetic projections at birth compromised the ability of beta-receptor stimulation to evoke cardiac hypertrophy, a defect which persisted into young adulthood. The chronotropic response to beta-receptor activation, assessed by acute challenge with a submaximally-effective dose of isoproterenol, also exhibited a slowed development, but did eventually achieve normal sensitivity. In contrast, neonatal sympathectomy had only minor effects on resting heart rate, basal heart rate (the intrinsic rate in the absence of autonomic input) or maximal heart rate; these animals also showed beta-receptor desensitization of chronotropic action in response to chronic isoproterenol treatment. Chronic isoproterenol treatment itself lowered the basal heart rate, regardless of whether animals were normal or sympathectomized. Thus, during critical developmental periods, sympathetic input to beta-receptors selectively programmes the linkage between postsynaptic receptors, tissue growth and heart rate.     

Heart valve macro- and microstructure

Each heart valve is composed of different structures of which each one has its own histological profile. Although the aortic and the pulmonary valves as well as the mitral and the tricuspid valves show similarities in their architecture, they are individually designed to ensure optimal function with regard to their role in the cardiac cycle.In this article, we systematically describe the structural elements of the four heart valves by different anatomical, light- and electron-microscopic techniques that have been presented. Without the demand of completeness, we describe main structural features that are in our opinion of importance in understanding heart valve performance. These features will also have important implications in the treatment of heart valve disease. They will increase the knowledge in the design of valve substitutes or partial substitutes and may participate to improve reconstructive techniques. In addition, understanding heart valve macro- and microstructure may also be of benefit in heart valve engineering techniques.     

Idiopathic dilated cardiomyopathy: possible triggers and treatment strategies

Despite recent advances in the management of patients with heart failure, morbidity and mortality rates remain high. Common causes of heart failure are ischaemic heart disease, uncontrolled hypertension and valvular disease. However, in up to 50?% of the cases its exact cause remains initially unknown; this condition is called idiopathic dilated cardiomyopathy (DCM). Improved diagnostic methods, most notably the advancements in molecular and immunohistological biopsy techniques and genetic research, have endorsed a new era in the diagnosis and classification of patients with idiopathic DCM. These insights have led to novel aetiology-based treatment strategies and improved outcome. The present article will briefly discuss all causes of DCM with a special focus on inflammatory- and virus-mediated forms of DCM.