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Novel Strategies for the Management of Acute Decompensated Heart Failure Pp.1-5
W.H. Wilson Tang and Robert E. Hobbs
[Abstract] [Full text article]

Heart Failure Modulates the Muscle Reflex Pp.7-16
Jianhua Li and Lawrence I. Sinoway
[Abstract] [Full text article]

Myocardial Energy Transport and Heart Failure Pp.17-27
Michael A. Portman and Jianyi Zhang
[Abstract] [Full text article]

Assessment of Cardiac Sympathetic Innervation in Heart Failure and Lethal Arrhythmias: Therapeutic and Prognostic Implications Pp.29-36
Tomoaki Nakata, Takeru Wakabayashi and Daigo Nagahara
[Abstract] [Full text article]

Mitochondrial Oxidative Stress and Heart Failure ~Novel Pathophysiological Insight and Treatment Strategies Pp.37-44
Hiroyuki Tsutsui
[Abstract] [Full text article]

A Palliative Care Approach to the Advanced Heart Failure Patient Pp.45-52
Susan Quaglietti, Michael Pham and Victor Froelicher
[Abstract] [Full text article]

Clinical and Molecular Genetic Aspects of Hypertrophic Cardiomyopathy Pp.53-63
Ali J. Marian
[Abstract] [Full text article]

Peripheral Chemoreceptors and Sudden Infant Death Syndrome: A Wide Open Problem Pp.65-70
Luigi Matturri, Giulia Ottaviani, Anna M. Lavezzi and Simone G. Ramos
[Abstract] [Full text article]

Noncardiac Surgery: Evaluating and Minimizing Cardiac Risk Pp.71-79
Rajendra H. Mehta, Michael H. Sketch Jr., Eduardo Bossone and Christopher B. Granger
[Abstract] [Full text article]

Apolipoprotein A-I Mimetic Peptides for the Treatment of Coronary Artery Disease Pp.81-84
Nicole K. Yamada
[Abstract] [Full text article]

Role of Magnetic Resonance Imaging in Myocardial Iron Assessment Pp.85-88
Sophie I. Mavrogeni
[Abstract] [Full text article]

Abstracts

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Novel Strategies for the Management of Acute Decompensated Heart Failure
W.H. Wilson Tang and Robert E. Hobbs
[Full text article]

Acute decompensated heart failure (ADHF) is the primary diagnosis for approximately one million hospital admissions in the United States, with an estimated $13.6 billion dollars of direct hospital cost in 2003. Until recently, diagnosis and management of ADHF has largely been “tradition-based” rather than evidence-based. Diuretic therapy has been the mainstay of symptom relief for pulmonary congestion and fluid retention. The introduction of nesiritide has revived the emphasis on vasodilator therapy for preload and afterload reduction in ADHF. Newer intravenous vasodilator drugs such as tezosentan, an endothelin antagonist, and carperitide, a natriuretic peptide, currently are being tested in multicenter clinical trials. New inotropic agents, such as levosimendan, appear to have an improved safety and efficacy profile. Vasopressin receptor antagonists and adenosine receptor antagonists may offer improved renal preservation during aggressive diuresis. Mechanical unloading with ultrafiltration devices and extracorporeal circulatory support devices have been developed to supplement pharmacological therapies and are undergoing clinical trials.

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Heart Failure Modulates the Muscle Reflex
Jianhua Li and Lawrence I. Sinoway
[Full text article]

Sympathetic nervous activity (SNA) increases with exercise in normal subjects and this response is accentuated in heart failure (HF). The muscle metaboreceptor contribution to regulation of muscle SNA is blunted in HF whereas the mechanoreceptor contribution is augmented. The underlying causes of these changes in the muscle afferent function are poorly understood. This review is based on recently published data from our laboratory demonstrating that: 1) muscle interstitial ATP rises with twitch contraction and stimulates P2X receptors on thin fibers muscle afferents; 2) ATP accentuates muscle mechanoreceptor responses; 3) activation of VR1 receptor induces an increase in arterial blood pressure; and 4) cardiovascular responses to VR1 receptor stimulation are blunted and P2X mediated responses are augmented in rats with HF as compared with a control group of animals. These results suggest that alternations in VR1 and P2X receptors on muscle afferent nerves influence the processing of sensory information in HF and in turn may alter the magnitude and distribution of SNA during exercise in HF.

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Myocardial Energy Transport and Heart Failure
Michael A. Portman and Jianyi Zhang
[Full text article]

Abnormalities in myocardial energy metabolism occur in association with progression to congestive heart failure. Conceivably, alterations in cardiac energy metabolism may initiate trophic responses or remodeling noted in myocardium during various disease processes. This review will explore the relationship between myocardial remodeling, contractile dysfunction, and myocardial bioenergetics. Attention will be given to data obtained from studies performed using intact animal models, which emulate congestive heart failure in humans. These data will be considered in relation to studies performed in vitro or in transgenic models. Focus will also be directed towards mechanisms of mitochondrial oxidative phosphorylation regulation (OXPHOS) and high energy phosphate transport.

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Assessment of Cardiac Sympathetic Innervation in Heart Failure and Lethal Arrhythmias: Therapeutic and Prognostic Implications
Tomoaki Nakata, Takeru Wakabayashi and Daigo Nagahara
[Full text article]

Sympathetic nerve activities have pivotal roles in pathophysiology and prognosis in patients with heart failure. Among the various available techniques for the analysis of sympathetic nerve function, cardiac neuroimaging with a norepinephrine analogue is a noninvasive, specific and powerful modality that enables in vivo assessment of cardiac sympathetic innervation and activity and has demonstrated pathophysiological alterations at pre-synaptic nerve terminals and their clinical implications. Impaired cardiac metaiodobenzylguanidine (MIBG) activity and, conversely, increased systemic sympathetic function drive closely correlate with clinical outcomes. Cardiac MIBG activities have independent but incremental prognostic values in combination with known clinical determinants in patients with heart failure. Systemic inhibition of sympathetic drive and the rennin-angiotension-aldosterone system can improve cardiac MIBG activity and kinetics together with functional improvement in heart failure patients. Prognostic efficacy of contemporary drug treatment is, however, likely to depend on the severity of the impairment of cardiac MIBG activity. Patients who have impaired cardiac MIBG activity with blunted heart rate variability, an elevated brain natriuretic peptide level or LV dysfunction are likely to have appropriate discharges of an implantable cardioverter defibrillator. Thus, cardiac neuroimaging could enable appropriate selection of patients at greater risk for lethal outcomes, who can probably benefit most from pharmacological and invasive strategies.

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Mitochondrial Oxidative Stress and Heart Failure ~Novel Pathophysiological Insight and Treatment Strategies~
Hiroyuki Tsutsui
[Full text article]

Previous basic, clinical, and population sciences have advanced the modern treatment of heart failure. An approach to solve this crucial issue is the further development of novel therapeutic strategies based on a novel insight into the pathophysiology of myocardial remodeling and failure. Recent experimental and clinical studies have suggested that oxidative stress is enhanced in heart failure. The production of oxygen radicals is increased in the failing heart whereas antioxidant enzyme activities are preserved in the normal heart. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and also a target against oxidant-induced damage. Chronic increases in oxygen radical production in the mitochondria can lead to a catastrophic cycle of mitochondrial DNA damage as well as functional decline, further oxygen radical generation, and cellular injury. These cellular events might play an important role in the development and progression of myocardial remodeling and failure. Therefore, mitochondrial oxidative stress and DNA damage are good therapeutic targets. This approach may lead to establish the novel and most effective treatment strategies for patients with heart failure.

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A Palliative Care Approach to the Advanced Heart Failure Patient
Susan Quaglietti, Michael Pham and Victor Froelicher
[Full text article]

Congestive heart failure can become a debilitating, terminal illness in many patients despite maximal medical therapy. Patients with advanced heart failure have persistence of severe clinical symptoms limiting their daily life, marked left ventricular systolic dysfunction, and poor exercise capacity. Although individual disease trajectory in these patients can be difficult to predict, overall mortality remains high despite recent advances in medical and surgical therapy. Palliative care should be considered for patients with high mortality estimates, especially those patients with a one-year survival estimate of less than 25% who are not candidates for cardiac transplantation or destination mechanical support. Palliative models for heart failure management shift the focus of care from curing this debilitating disease to managing symptoms and incorporating treatment based on patient quality of life and survival goals. This article discusses strategies for identifying and treating reversible causes of heart failure, for treating rhythm disturbances, and for maintaining hemodynamic stability. Confounding medical and psychological problems affecting overall patient energy levels and well-being are reviewed. Finally, various venues and sites of care are discussed.

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Clinical and Molecular Genetic Aspects of Hypertrophic Cardiomyopathy
Ali J. Marian
[Full text article]

Hypertrophic cardiomyopathy (HCM) is a fascinating disease with diverse phenotypic expression that spans from minimal hypertrophy to severe heart failure and sudden cardiac death (SCD). HCM is the most common cause of sudden cardiac death (SCD) in the young competitive athletes and a major cause of morbidity and mortality in elderly. Molecular genetic basis of HCM is all but elucidated by identification of several hundred different mutations in 11 different genes, all encoding sarcomeric proteins. The emphasis of current research is to develop genetic screening techniques in order to identify the mutation carriers prior to and independent of the clinical manifestations of HCM; to identify genetic and non-genetic determinants of clinical outcome in HCM; and to identify novel drug targets in order to prevent, attenuate or reverse the evolving phenotype. Recent studies have led to partial understanding of the molecular pathogenesis of HCM phenotypes and consequently, identification of new therapeutic targets, which have been tested in animal models of human HCM with promising results. Studies in transgenic animal models have shown the treatment with statins or blockade of renin-angiotensin-aldosterone system could attenuate and mitigate evolving cardiac phenotypes in HCM. Studies in human patients with HCM are needed to determine whether the observed beneficial effects of new pharmacological interventions also extend to humans with HCM.

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Peripheral Chemoreceptors and Sudden Infant Death Syndrome: A Wide Open Problem
Luigi Matturri, Giulia Ottaviani, Anna M. Lavezzi and Simone G. Ramos
[Full text article]

This review will focus on the basic mechanisms of the peripheral chemoreceptors elicited by studies on mature chemoreceptors and on the alterations observed in these structures related to sudden infant death. The integrated response of the peripheral chemoreceptors consists of the transduction of alterations in the chemical milieu, regulating the temperature of their environment to alterations in cardiovascular and respiratory performance. Over the years, much has been written about the relative importance of the carotid and aortic bodies in the peripheral chemoreceptor response, and it is therefore worthwhile to consider the current state-of-the-art on that issue. Several lines of evidence have suggested that abnormalities in chemoreception may play a role in central hypoventilation syndromes. The sudden infant death syndrome (SIDS) involves a failure of respiration and affects infants in their early postnatal months. Unstable respiratory activity during sleep, prolonged sleep apnea, and oropharyngeal/laryngeal dysfunction induced by liquid stimulation of the upper airways have been postulated to be implicated in its genesis. It has also been found that in comparison with normal infants, infants suffering from the “aborted syndrome” (near-miss infants) are hypoventilated during quiet sleep, and have an impaired ventilatory response to carbon dioxide breathing.

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Noncardiac Surgery: Evaluating and Minimizing Cardiac Risk
Rajendra H. Mehta, Michael H. Sketch Jr., Eduardo Bossone and Christopher B. Granger
[Full text article]

Perioperative cardiac complications remain a great concern during noncardiac surgeries since a large majority of patients undergoing such procedures are elderly, who have a greater prevalence of coronary artery disease. Thus, it is imperative to assess risk of perioperative cardiac complications in all patients scheduled for noncardiac surgery. The current review attempts to outline a systematic approach to assess cardiac risk for noncardiac surgery and suggest strategies to minimize these risks. This approach uses a combination of the urgency of noncardiac surgery, interval since prior revascularization to noncardiac surgery, the interval between prior evaluation of coronary artery disease, patients clinical risks for cardiac complications, and patients functional status to decide their perioperative cardiac risks. If surgery is urgent or the estimated risk for perioperative event is low, then irrespective of the risk, patients should proceed with noncardiac surgery under the influence of appropriate medical strategy to minimize risk. If patients risk of perioperative events is high, then postponing or canceling surgery and referral for invasive approach to identify and when appropriate revascularize coronary artery disease may help reduce the perioperative cardiac risk. In contrast, patients at intermediate risk for perioperative events may benefit from noninvasive assessment for coronary artery disease and referral for appropriate patients for coronary revascularization based on the results of such noninvasive testing. Medical perioperative strategy that should be part of all patients undergoing noncardiac surgery who have or are at risk for coronary artery disease, should include betablockers, adequate analgesia, monitoring fluid status, and maintaining hematocrit >30 gm/dl. Finally, the physician-patient interaction during the hospitalization during noncardiac surgery should be recognized as an important opportunity to institute secondary prevention strategies for coronary artery disease in patients at risk for coronary atherosclerosis.

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Apolipoprotein A-I Mimetic Peptides for the Treatment of Coronary Artery Disease
Nicole K. Yamada
[Full text article]

High density lipoprotein (HDL) plays a critical physiological role in protecting the body against atherosclerosis by facilitating reverse cholesterol transport and the removal of oxidized phosphoplipids from artery walls. Apolipoprotein A-I (apoA-I) is the principal protein component of HDL that is responsible for these atheroprotective effects. We have developed an apoA-I peptide analog called D-4F, which mimics the properties of apoA-I. D-4F is synthesized from Damino acids and thus can be administered orally. In murine models of atherosclerosis, D-4F markedly reduced atherosclerotic lesions in the absence of significant changes in total plasma cholesterol or HDL cholesterol levels. These results suggested that raw values of lipoprotein quantity are not the only indicators of atherosclerotic risk; the quality of the circulating lipoproteins is also important. As atherogenesis has been shown to be strongly linked to the presence of pro-inflammatory HDL, D-4F suggests therapeutic potential for treating atherosclerosis by improving the quality of patients’ HDL (i.e. converting pro-inflammatory HDL to anti-inflammatory HDL in vitro). ApoA-I mimetic peptides may also prove helpful in treating other symptoms of atherosclerosis, such as endothelial dysfunction and abnormal vasorelaxation. ApoA-I mimetic peptides like D-4F indicate much promise for becoming yet another part of achieving greater cardiovascular health.

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Role of Magnetic Resonance Imaging in Myocardial Iron Assessment
Sophie I. Mavrogeni
[Full text article]

Myocardial iron overload is a common finding in iron storage diseases like β-thalassemia. It is due to frequent transfusions and occurs despite chelation therapy. Cardiac complications (heart failure and arrythmias) lead to early death. MRI can offer a noninvasive index for heart iron deposition, before overt clinical and echocardiographic picture of heart failure takes place. Tissue iron is detected indirectly by the effects on relaxation times of ferritin and hemosiderin iron, interacting with hydrogen nuclei. Paramagnetic ferritin and hemosiderin iron shorten proton relaxation times, particularly T2 and T2*. Conventional MRI measurements are affected by iron excess, the instrumentation used, the applied field strength, the repetition time used in the imaging sequence, and other technical aspects. Myocardial T2* seems to be the most sensitive and easily reproducible index of myocardial iron deposition. However multicenter trials are needed for further evaluation of this technique.