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- Volume 21, Issue 4, 2015
Current Pharmaceutical Design - Volume 21, Issue 4, 2015
Volume 21, Issue 4, 2015
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Genetics of Cardiomyopathies: Novel Perspectives with Next Generation Sequencing
Cardiomyopathies are a heterogeneous group of primary diseases of the myocardium usually of genetic origin and with familial presentation. The identification of multiple genetic causes for these diseases has opened a new window for early diagnosis, understanding of their natural history and improvement in risk stratification and management. However, in the past years, the clinical application of genetics has been limited by the prohibiting cost and restricted yield of the available genotyping technologies. The emergence of Next Generation Sequencing (NGS) has completely changed this scenario. This group of sequencing technologies allow the evaluation of hundreds or even thousands of genes in parallel at an affordable cost. Now the challenge is not genotyping per se but the interpretation of the complex results that NGS generates. In this paper we review the main aspects related to the application and impact of Next Generation Sequencing in the study of cardiomyopathies: technology, analysis procedures, bioinformatics, clinical validation and interpretation of results.
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Targeting Cardiomyocyte Ca2 Homeostasis in Heart Failure
Authors: Asmund T. Roe, Michael Frisk and William E. LouchImproved treatments for heart failure patients will require the development of novel therapeutic strategies that target basal disease mechanisms. Disrupted cardiomyocyte Ca2+ homeostasis is recognized as a major contributor to the heart failure phenotype, as it plays a key role in systolic and diastolic dysfunction, arrhythmogenesis, and hypertrophy and apoptosis signaling. In this review, we outline existing knowledge of the involvement of Ca2+ homeostasis in these deficits, and identify four promising targets for therapeutic intervention: the sarcoplasmic reticulum Ca2+ ATPase, the Na+-Ca2+ exchanger, the ryanodine receptor, and t-tubule structure. We discuss experimental data indicating the applicability of these targets that has led to recent and ongoing clinical trials, and suggest future therapeutic approaches.
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Pharmacotherapy of Dilated Cardiomyopathy
Authors: Lenka Spinarova and Jindrich SpinarThe pharmacological treatment of dilated cardiomyopathy overlaps with the treatment of heart failure. The primary objective of this treatment is to slow the progression of disease and improve quality and length of life. All patients, including those with asymptomatic dysfunction of the left ventricle, ought to receive angiotensin converting enzyme inhibitors, (in the case of intolerance, angiotensin receptor blockers), and beta blockers. The results of studies involving aliskiren have been, so far, disappointing. In symptomatic heart failure NYHA II-IV diuretics and mineralcorticoid receptor antagonists should be added to treatment. Digoxin is recommended in the event of atrial fibrillation, and otherwise only in the event of NYHA III and IV. Ivabradine is recommended for patients with sinus rhythm and pulse rate of > 70/min. In decompensation of heart failure, dobutamine, phosphodiesterase inhibitors or levosimendan are administered over the short-term. Of the recent treatment options, the vasopressin blocker and adenosine A1 receptor antagonist (rolofylline) were disappointing. One treatment with potential for the future is omecamtiv mecarbil, a heart myosin activator.
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New Therapeutic Aspects of Inflammatory Cardiomyopathy
Authors: Petr Kuchynka, Tomas Palecek, Eduard Nemecek, Michal Fikrle and Ales LinhartInflammatory cardiomyopathy is a term used for left ventricular systolic dysfunction associated with myocarditis. In order to establish definitely the diagnosis, an endomyocardial biopsy (EMB) must be performed. Based on the results of EMB analysis, specific treatment may be added to conventional heart failure therapy. Immunosuppressive therapy in patients with non-viral inflammatory cardiomyopathy has been shown to be effective, and there is also some evidence that antiviral or antimicrobial therapy may be beneficial.
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Mechanisms and Medical Management of Exercise Intolerance in Hypertrophic Cardiomyopathy
Authors: V. Patel, C.H. Critoph and P.M. ElliottHypertrophic cardiomyopathy (HCM) is an inherited disorder of cardiac sarcomeric proteins characterised by the presence of myocardial hypertrophy in the absence of abnormal loading conditions. Individuals with HCM can remain asymptomatic throughout their lives but many experience chest pain, symptoms of heart failure, syncope and sudden ventricular arrhythmias. Cardiopulmonary exercise testing is an important part of the assessment of patients with HCM who often have reduced peak oxygen consumption and a lower anaerobic threshold compared with healthy age-matched controls. This review will focus on mechanisms of exercise limitation, which are complex and multifactorial, and the options for medical management.
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The Fabry Cardiomyopathy - Diagnostic Approach and Current Treatment
Authors: Frank Weidemann, Georg Ertl, Christoph Wanner and Johannes KramerAnderson-Fabry disease is an X-linked lysosomal storage disorder caused by alpha-galactosidase A deficiency. The intracellular storage of globotriaosylceramides in different tissues and organs leads to a multisystemic disease affecting kidneys, nervous system and the heart. Fabry cardiomyopathy is frequent and leads to concentric left-ventricular hypertrophy. Typical pattern in advanced stages is myocardial replacement fibrosis, first localized to mid myocardial layers of postero-lateral basal myocardium and then spreading to transmural fibrosis.Long term prognosis is dependent on timely initiation of specific and concomitant therapies, while therapy in advanced stages is only able to stabilize the organ affection. This review describes the characteristics of Fabry cardiomyopathy, shows the clinical assessment of cardiac involvement and highlights therapeutic issues aiming at the best outcome for patients with Fabry disease.
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Monitoring Cardiac Function During Idebenone Therapy in Friedreich's Ataxia
Authors: Di Salvo Giovanni, Pergola Valeria, Fadel Bahaa and Al Fayyadh MajidFriedreich’s ataxia (FA) is associated with progressive cardiac hypertrophy resulting from a genetic abnormality in the frataxin gene. Cardiac involvement is the most common cause of death (59%) in FA patients. Cardiac related death occurs at a significantly younger age than non-cardiac related death. Idebenone is a short-chain quinone analogue with a potent free-radical scavenger action. This drug has the potential to preserve and even improve mitochondrial function.Studies on Idebenone treatment showed rather conflicting results on FA cardiomyopathy. The present article reviews the clinical features of FA cardiomyopathy, imaging techniques used to diagnose, follow and monitor therapy which aimed to revert FA cardiomyopathy.
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Left Ventricular Non-compaction: From Recognition to Treatment
More LessWe have gained considerable insight and understanding about the etiology, embryogenesis of the myocardium, genetic background, diagnosis and outcome of left ventricular non-compaction (LVNC) over the last 2 decades. LVNC has a distinct morphological appearance with a thickened, two-layered myocardium consisting of an epicardial compacted and a thicker endocardial non-compacted layer. These features make the recognition with non-invasive imaging modalities highly feasible. We now recognize LVNC is a distinct phenotype of the myocardium with genetic heterogeneity. In several cases, LVNC shares a common genetic background with other forms of cardiomyopathy. Therefore, most likely it is not a distinct form of cardiomyopathy but rather a morphological expression of different diseases. LVNC can present as an isolated condition or associated with congenital heart disease, neuromuscular disease or genetic syndromes. It may be sporadic or a familial disease, with an autosomal dominant or X-linked mode of transmission. The clinical features associated with LVNC vary from asymptomatic individuals diagnosed during screening to symptomatic patients, with the potential for heart failure, arrhythmias, thromboembolic events, and sudden cardiac death. A comprehensive diagnostic approach includes clinical history, electrocardiogram, imaging (in many instances with more than one technique), genetic assessment, and screening of first-degree relatives. This increases the chances of instituting the most appropriate therapy. Therapy for the most part is very similar to the general heart failure population with the exception that anticoagulation is started at a lower threshold.
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Contemporary Treatment of Amyloid Heart Disease
The amyloidoses represent a group of diseases characterized by extracellular deposition of abnormal protein, amyloid, which is formed by insoluble extracellular fibrils in β-pleated sheets. Although cardiac involvement may occur in all types of amyloidoses, clinically relevant amyloid cardiomyopathy is a typical feature of AL amyloidosis and transthyretin-related amyloidoses. Congestive heart failure represents the commonest manifestation of amyloid heart disease. Noninvasive imaging techniques, especially echocardiography and cardiac magnetic resonance, play a major role in the diagnosis of amyloid cardiomyopathy; however, histological confirmation and exact typing of amyloid deposits is necessary whether in extracardiac location or directly in the myocardium. Early diagnosis of amyloid heart disease is of utmost importance as the presence and especially the severity of cardiac involvement generally drives the prognosis of affected subjects and plays a major role in determining the intensity of specific treatment, namely in AL amyloidosis. The management of patients with amyloid heart disease is complex. Loop diuretics together with aldosterone antagonists represent the basis for influencing signs of congestion. In AL amyloidosis, high-dose chemotherapy followed by autologous stem cell transplantation is generally considered to be a front-line treatment option, if the disease is diagnosed at its early stage. The combination of mephalan with dexamethasone has been the standard therapy for severely affected individuals; however, the combinations with several novel agents including immunomodulatory drugs and bortezomibe have been tested in clinical trials with promising results. New therapeutic substances with the potential to slow or even stop the progression of transthyretin-related amyloidosis are also extensively studied.
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Current Therapeutic Concepts in Peripartum Cardiomyopathy
Authors: Jan Krejci, Hana Poloczkova and Petr NemecPeripartum cardiomyopathy (PPCM) is a relatively rare disease characterized by systolic heart failure occuring towards the end of pregnancy or during the months following birth. It is most often seen in women of African descent, and its incidence seems to be slightly increasing in recent years. Other etiologies of heart failure should be excluded to determine the diagnosis of PPCM. The clinical picture corresponds to systolic heart failure. The rapid onset of the symptoms in relation to pregnancy is striking. The essential diagnostic procedures such as echocardiography, cardiac magnetic resonance imaging and endomyocardial biopsy may be beneficial in certain situations. The etiology of the disease remains unclear. Speculated causes include myocarditis, autoimmune disorders, cardiotropic virus infection, and abnormal responses to hemodynamic and hormonal changes during pregnancy. Particular attention is currently given to the concept of increased oxidative stress inducing production of proapoptotic, angiostatic and proinflammatory mediators. Recovery of left ventricular systolic function occurs in about half of the cases. Mortality has been decreasing in recent years, especially in the United States, but is still between 10-15% in less developed countries where therapeutic possibilities are limited. In addition to standard heart failure therapy, specific treatments (pentoxyfilline, bromocriptine, immunomodulatory therapy) have been tested. Mechanical circulatory support is sometimes needed. Heart transplantation is the therapeutic option for the most severe heart failure and is used in about 10% of the cases. Recurrence in subsequent pregnancy is common and therefore, another pregnancy is not recommended in many cases.
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Application of Current Diagnostic Criteria for Arrhythmogenic Right Ventricular Cardiomyopathy in Every Day Clinical Practice
Authors: Eleanor C. Wicks and Perry M. ElliottArrhythmogenic right ventricular cardiomyopathy is an inherited cardiac muscle disease associated with sudden cardiac death, ventricular arrhythmias and cardiac failure. It is primarily a disease of the desmosome, with mutations in desmosomal protein genes identified in approximately 50% of affected individuals. Mutations result in fibrofatty replacement of cardiomyocytes, aneurysm formation and dilatation of the right and often the left ventricle. The clinical diagnosis of ARVC is based upon complex criteria that consider pathology, genetics and clinical presentation. This review describes the application of the revised criteria for ARVC in everyday practice and illustrates the requirement for continued modification to improve their sensitivity and specificity.
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Pharmacological Therapy of Pericardial Diseases
Authors: Massimo Imazio and Yehuda Adler(117 words) Acute and recurrent pericarditis, isolated pericardial effusion, and constrictive pericarditis represent the main pericardial syndromes and therapy of these conditions should be targeted as much as possible at the specific aetiology, but unfortunately many cases still remain idiopathic with current diagnostic methods and should be empirically treated according to best available evidence. Unfortunately, treatment is often empirical since there are few clinical trials available. Nevertheless as for hypertension, even if we do not know the precise cause of the syndrome in all cases, we may provide excellent management for most cases. The aim of the present paper is to review current medical therapy for the main pericardial syndromes.
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Volumes & issues
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Volume 30 (2024)
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Volume 29 (2023)
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Volume 28 (2022)
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Volume 27 (2021)
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Volume 26 (2020)
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Volume 25 (2019)
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Volume 24 (2018)
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Volume 23 (2017)
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Volume 22 (2016)
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Volume 21 (2015)
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Volume 20 (2014)
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Volume 19 (2013)
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Volume 18 (2012)
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Volume 17 (2011)
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Volume 16 (2010)
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Volume 15 (2009)
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Volume 14 (2008)
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Volume 13 (2007)
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Volume 12 (2006)
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Volume 11 (2005)
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Volume 10 (2004)
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Volume 9 (2003)
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Volume 8 (2002)
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Volume 7 (2001)
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Volume 6 (2000)