Global Cardiology Science and Practice - Volume 2013, Issue 3

Lower vertebrates, such as newt and zebrafish, retain a robust cardiac regenerative capacity following injury. Recently, our group demonstrated that neonatal mammalian hearts have a remarkable regenerative potential in the first few days after birth. Although adult mammals lack this regenerative potential, it is now clear that there is measurable cardiomyocyte turnover that occurs in the adult mammalian heart. In both neonatal and adult mammals, proliferation of pre-existing cardiomyocytes appears to be the underlying mechanism of myocyte turnover. This review will highlight the advances and landmark studies that opened new frontiers in cardiac regeneration.

Transmembrane sodium (Na⁺) fluxes and intracellular sodium homeostasis are central players in the physiology of the cardiac myocyte, since they are crucial for both cell excitability and for the regulation of the intracellular calcium concentration. Furthermore, Na⁺ fluxes across the membrane of mitochondria affect the concentration of protons and calcium in the matrix, regulating mitochondrial function. In this review we first analyze the main molecular determinants of sodium fluxes across the sarcolemma and the mitochondrial membrane and describe their role in the physiology of the healthy myocyte. In particular we focus on the interplay between intracellular Ca²⁺ and Na⁺. A large part of the review is dedicated to discuss the changes of Na⁺ fluxes and intracellular Na⁺ concentration([Na⁺]i) occurring in cardiac disease; we specifically focus on heart failure and hypertrophic cardiomyopathy, where increased intracellular [Na⁺]i is an established determinant of myocardial dysfunction. We review experimental evidence attributing the increase of [Na⁺]i to either decreased Na⁺ efflux (e.g. via the Na⁺/K⁺ pump) or increased Na⁺ influx into the myocyte (e.g. via Na⁺ channels). In particular, we focus on the role of the “late sodium current” (INaL), a sustained component of the fast Na⁺ current of cardiac myocytes, which is abnormally enhanced in cardiac diseases and contributes to both electrical and contractile dysfunction. We analyze the pathophysiological role of INaL enhancement in heart failure and hypertrophic cardiomyopathy and the consequences of its pharmacological modulation, highlighting the clinical implications.

The central role of Na⁺ fluxes and intracellular Na⁺ physiology and pathophysiology of cardiac myocytes has been highlighted by a large number of recent works. The possibility of modulating Na⁺ inward fluxes and [Na⁺]i with specific INaL inhibitors, such as ranolazine, has made Na⁺a novel suitable target for cardiac therapy, potentially capable of addressing arrhythmogenesis and diastolic dysfunction in severe conditions such as heart failure and hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a complex cardiac condition characterized by variable degrees of asymmetric left ventricular (LV) hypertrophy, generally associated with mutations in sarcomere protein genes. While generally perceived as rare, HCM is the most common genetic heart disease with over one million affected individuals in Europe alone and represents a prevalent cause of sudden cardiac death in the young. To date, HCM remains an orphan disease, as recommended treatment strategies are based on the empirical use of old drugs with little evidence supporting their clinical benefit in this context. In the six decades since the original description of the disease, less than fifty pharmacological studies have been performed in HCM patients, enrolling little over 2,000 HCM patients, mostly comprising small non-randomized cohorts. No specific agent has been convincingly shown to affect outcome, and critical issues such as prevention of myocardial energy depletion, microvascular ischemia, progressive myocardial fibrosis and the peculiar mechanisms of arrhythmogenesis in HCM still need to be addressed in a systematic fashion. However, there is increasing evidence that a variety of drugs may counter the effects of sarcomere protein mutations and the resulting pathophysiological abnormalities at the molecular, cellular and organ level. Following major advances in our understanding of HCM and increasing opportunities for networking among large international referral centres, the opportunity now exists to identify potentially effective treatments and implement adequately designed pharmacological trials, with the ultimate aim to impact the natural course of the disease, alleviate symptoms and improve quality of life in our patients.

Ventricular arrhythmias in young people most commonly occur due to the presence of hypertrophic cardiomyopathy, long QT syndrome or Wolff-Parkinson-White syndrome. We present a case in which the patient had exercise induced syncopal spells and was found to have ventricular tachycardia (VT) during both exercise stress testing and an electrophysiology study. Further genetic studies showed a previously unseen desmosomal gene mutation confirming the presence of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC).

The renin-angiotensin-aldosterone system (RAAS) regulates the body's hemodynamic equilibrium, circulating volume, and electrolyte balance, and is a key therapeutic target in hypertension, the world's leading cause of premature mortality. Hypertensive disorders are strongly linked with an overactive RAAS, and RAAS inhibitors, like angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), are routinely used to treat high blood pressure (BP). BP reduction is one of the main goals of current European hypertension guidelines. Oral ACE inhibitors, the oldest category of RAAS inhibitor, were commercially released over 30 years ago in the early 1980s, over a decade before the first ARBs became available. The introduction of ACE inhibitors heralded major changes in the way hypertension and cardiovascular disease were treated. Although the decision of the medical community to replace older ACE inhibitors with more modern ARBs in the 1990s was debatable, it did nevertheless allow scientists to learn more about the angiotensin receptors involved in RAAS stimulation. This and much else of value have been discovered since RAAS inhibitors first became available, but some surprising gaps in our knowledge exist. Until recently, the effect of RAAS inhibition on mortality in hypertension was unknown. This question was recently addressed by a meta-analysis of randomized controlled trials in populations who received contemporary antihypertensive medication. The results of this meta-analysis have helped elucidate the long-term consequences of treatment with RAAS inhibitors on mortality in hypertension. This article will consider the differences between RAAS inhibitors in terms of pharmacological and clinical effects and analyze the impact of the main types of RAAS inhibitor, ACE inhibitors and ARBs, on mortality reduction in hypertensive patients with reference to this latest meta-analysis.

High resolution information about the three-dimensional (3D) structure of myosin filaments has always been hard to obtain. Solving the 3D structure of myosin filaments is very important because mutations in human cardiac muscle myosin and its associated proteins (e.g. titin and myosin binding protein C) are known to be associated with a number of familial human cardiomyopathies (e.g. hypertrophic cardiomyopathy and dilated cardiomyopathy). In order to understand how normal heart muscle works and how it fails, as well as the effects of the known mutations on muscle contractility, it is essential to properly understand myosin filament 3D structure and properties in both healthy and diseased hearts.

The aim of this review is firstly to provide a general overview of the 3D structure of myosin thick filaments, as studied so far in both vertebrates and invertebrate striated muscles. Knowledge of this 3D structure is the starting point from which myosin filaments isolated from human cardiomyopathic samples, with known mutations in either myosin or its associated proteins (titin or C-protein), can be studied in detail. This should, in turn, enable us to relate the structure of myosin thick filament to its function and to understanding the disease process. A long term objective of this research would be to assist the design of possible therapeutic solutions to genetic myosin-related human cardiomyopathies.

In recent years, several landmark studies have provided compelling evidence that cardiomyogenesis occurs in the adult mammalian heart. However, the rate of new cardiomyocyte formation is inadequate for complete restoration of the normal mass of myocardial tissue, should a significant myocardial injury occur, such as myocardial infarction. The cellular origin of postnatal cardiomyogenesis in mammals remains a controversial issue and two mechanisms seem to be participating, proliferation of pre-existing cardiomyocytes and myogenic differentiation of progenitor cells. We will discuss the relative importance of these two processes in different settings, such as normal ageing and post-myocardial injury, as well as the strengths and limitations of the existing experimental methodologies used in the relevant studies. Further clarification of the mechanisms underlying cardiomyogenesis in mammals will open the way for their therapeutic exploitation in the clinical field, with the scope of myocardial regeneration.

Designing of biologically active scaffolds with optimal characteristics is one of the key factors for successful tissue engineering. Recently, hydrogels have received a considerable interest as leading candidates for engineered tissue scaffolds due to their unique compositional and structural similarities to the natural extracellular matrix, in addition to their desirable framework for cellular proliferation and survival. More recently, the ability to control the shape, porosity, surface morphology, and size of hydrogel scaffolds has created new opportunities to overcome various challenges in tissue engineering such as vascularization, tissue architecture and simultaneous seeding of multiple cells. This review provides an overview of the different types of hydrogels, the approaches that can be used to fabricate hydrogel matrices with specific features and the recent applications of hydrogels in tissue engineering. Special attention was given to the various design considerations for an efficient hydrogel scaffold in tissue engineering. Also, the challenges associated with the use of hydrogel scaffolds were described.