The Incidence and Clinical Relevance of Graft Hypertrophy After Matrix-Based Autologous Chondrocyte Implantation

Background: Graft hypertrophy is the most common complication of periosteal autologous chondrocyte implantation (p-ACI). Purpose: The aim of this prospective study was to analyze the development, the incidence rate, and the persistence of graft hypertrophy after matrix-based autologous chondrocyte implantation (mb-ACI) in the knee joint within a 2-year postoperative course. Study Design: Case series; Level of evidence, 4. Methods: Between 2004 and 2007, a total of 41 patients with 44 isolated cartilage defects of the knee were treated with the mb-ACI technique. The mean age of the patients was 35.8 years (standard deviation [SD], 11.3 years), and the mean body mass index was 25.9 (SD, 4.2; range, 19-35.3). The cartilage defects were arthroscopically classified as Outerbridge grades III and IV. The mean area of the cartilage defect measured 6.14 cm2 (SD, 2.3 cm2). Postoperative clinical and magnetic resonance imaging (MRI) examinations were conducted at 3, 6, 12, and 24 months to analyze the incidence and course of the graft. Results: Graft hypertrophy developed in 25% of the patients treated with mb-ACI within a postoperative course of 1 year; 16% of the patients developed hypertrophy grade 2, and 9% developed hypertrophy grade 1. Graft hypertrophy occurred primarily in the first 12 months and regressed in most cases within 2 years. The International Knee Documentation Committee (IKDC) and visual analog scale (VAS) scores improved during the postoperative follow-up time of 2 years. There was no difference between the clinical results regarding the IKDC and VAS pain scores and the presence of graft hypertrophy. Conclusion: The mb-ACI technique does not lead to graft hypertrophy requiring treatment as opposed to classic p-ACI. The frequency of occurrence of graft hypertrophy after p-ACI and mb-ACI is comparable. Graft hypertrophy can be considered as a temporary excessive growth of regenerative cartilage tissue rather than a true graft hypertrophy. It is therefore usually not a persistent or systematic complication in the treatment of circumscribed cartilage defects with mb-ACI

Inhibition of histone deacetylase as a treatment for cardiac hypertrophy

The present invention provides for methods of treating and preventing cardiac hypertrophy. Class II HDACs, which are known to participate in regulation of chromatin structure and gene expression, have been shown to have beneficial effects on cardiac hypertrophy. Surprisingly, the present invention demonstrates that HDAC inhibitors inhibit cardiac hypertrophy by inhibiting fetal cardiac gene expression and interfering with sarcomeric organization.Board of Regents, University of Texas Syste

Cardiac hypertrophy and heart failure: from the case to review of literature

In response to an increased workload due to physiological or pathological stimuli, the heart may undergo a process of growth with increased muscle mass called cardiac hypertrophy. It is a particular mechanism of long term compensation used by the heart to adapt permanently to a greater workload. Although, through its peculiar structural, molecular and metabolic characteristics, in early stage the hypertrophy allows to maintain an adequate cardiac function, after a variable period of time, the same characteristics promote the evolution to contractile dysfunction and heart failure. The latter represents an important cause of death and so the cardiac hypertrophy increases the cardiovascular morbidity and mortality. In this paper we report a rare case of extremely high degree of concentric cardiac hypertrophy, with a heart weight of 1050 g and longitudinal diameter of 16.5 cm, transverse diameter of 16 cm and antero-posterior diameter of 9 cm. The thickness of the left ventricle free wall was 4.2 cm, of the septum 4.3 cm and at the apex level 3.5 cm. These data, compared with those described in scientific literature, indicate the exceptional nature of our necropsy finding of a huge cardiac hypertrophy. The analysis of the pathogenetic mechanisms, which may determinate the fatal event in case of cardiac hypertrophy, shows that in the described case the death cause can be the onset of heart failure in presence of cardiomegaly

Electrocardiographic (ECG) criteria for determining left ventricular mass in young healthy men; data from the LARGE Heart study

Background: Doubts remain over the use of the ECG in identifying those with increased left ventricular (LV) mass. This is especially so in young individuals, despite their high prevalence of ECG criteria for LV hypertrophy. We performed a study using cardiovascular magnetic resonance (CMR), which provides an in vivo non-invasive gold standard method of measuring LV mass, allowing accurate assessment of electrocardiography as a tool for defining LV hypertrophy in the young.Methods and results: Standard 12-lead ECGs were obtained from 101 Caucasian male army recruits aged (mean +/- SEM) 19.7 +/- 0.2 years. LV mass was measured using CMR. LV mass indexed to body surface area demonstrated no significant correlation with the Cornell Amplitude criteria or Cornell Product for LV hypertrophy. Moderate correlations were seen with the Sokolow-Lyon Amplitude (0.28) and Sokolow-Lyon Product (0.284). Defining LV hypertrophy as a body surface area indexed left ventricular mass of 93 g/m(2), calculated sensitivities [and specificities] were as follows; 38.7% [74.3%] for the Sokolow-Lyon criteria, 43.4% [61.4%] for the Sokolow-Lyon Product, 19.4% [91.4%] for Cornell Amplitude, and 22.6% [85.7%] for Cornell Product. These values are substantially less than those reported for older age groups.Conclusion: ECG criteria for LV hypertrophy may have little value in determining LV mass or the presence of LV hypertrophy in young fit males

Nuclear CaMKII enhances histone H3 phosphorylation and remodels chromatin during cardiac hypertrophy.

Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a central role in pathological cardiac hypertrophy, but the mechanisms by which it modulates gene activity in the nucleus to mediate hypertrophic signaling remain unclear. Here, we report that nuclear CaMKII activates cardiac transcription by directly binding to chromatin and regulating the phosphorylation of histone H3 at serine-10. These specific activities are demonstrated both in vitro and in primary neonatal rat cardiomyocytes. Activation of CaMKII signaling by hypertrophic agonists increases H3 phosphorylation in primary cardiac cells and is accompanied by concomitant cellular hypertrophy. Conversely, specific silencing of nuclear CaMKII using RNA interference reduces both H3 phosphorylation and cellular hypertrophy. The hyper-phosphorylation of H3 associated with increased chromatin binding of CaMKII occurs at specific gene loci reactivated during cardiac hypertrophy. Importantly, H3 Ser-10 phosphorylation and CaMKII recruitment are associated with increased chromatin accessibility and are required for chromatin-mediated transcription of the Mef2 transcription factor. Unlike phosphorylation of H3 by other kinases, which regulates cellular proliferation and immediate early gene activation, CaMKII-mediated signaling to H3 is associated with hypertrophic growth. These observations reveal a previously unrecognized function of CaMKII as a kinase signaling to histone H3 and remodeling chromatin. They suggest a new epigenetic mechanism controlling cardiac hypertrophy

Heat shock transcription factor 1 preserves cardiac angiogenesis and adaptation during pressure overload

To examine how heat shock transcription factor 1 (HSF1) protects against maladaptive hypertrophy during pressure overload, we subjected HSF1 transgenic (TG), knockout (KO) and wild type (WT) mice to a constriction of transverse aorta (TAC), and found that cardiac hypertrophy, functions and angiogenesis were well preserved in TG mice but were decreased in KO mice compared to WT ones at 4 weeks, which was related to HIF-1 and p53 expression. Inhibition of angiogenesis suppressed cardiac adaptation in TG mice while overexpression of angiogenesis factors improved maladaptive hypertrophy in KO mice. In vitro formation of vasculatures by microvascular endothelial cells was higher in TG mice but lower in KO mice than in WT ones. A siRNA of p53 but not a HIF-1 gene significantly reversed maladaptive hypertrophy in KO mice whereas a siRNA of HIF-1 but not a p53 gene induced maladaptive hypertrophy in TG mice. Heart microRNA analysis showed that miR-378 and miR-379 were differently changed among the three mice after TAC, and miR-378 or siRNA of miR-379 could maintain cardiac adaptation in WT mice. These results indicate that HSF1 preserves cardiac adaptation during pressure overload through p53-HIF-1-associated angiogenesis, which is controlled by miR-378 and miR-379

The Role of Natriuretic peptides in Renovascular Hypertension and its correlation with the Evolution of Myocardial Hypertrophy

The interactions between pressure and volume overload that occur in hypertension lead to different patterns of cardiac hypertrophy and to increase in natriuretic peptides (NPs). The profiles of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) synthesis and secretion have been investigated in models of hypertension. However, the different evolution of these profiles during the acute and chronic periods of pressure overload-induced cardiac hypertrophy is still unknown. For this reason, we studied one-kidney, one clip model using Sprague-Dawley rats at weeks 2, 4, 6 and 12 and correlated the evolution of these profiles with cardiac hypertrophy and hypertension. We observed a positive correlation between blood pressure elevation and the degree of cardiac hypertrophy, with a time-dependent increase in both parameters from week 2. Levels of BNP expression showed an early increase after 2 weeks of treatment while ANP increased significantly after 6 weeks. Yet, the increase in ANP expression was gradual, allowing its correlation with hypertrophy and hypertension. The NP expression has a differential response in the early stages of the development of hypertrophy induced by the renovascular model, with an early increase in BNP expression. Once hypertrophy develops, BNP expression is no longer specific and the increase of both NPs depends on and correlates with the degree of cardiac hypertrophy.Fil: Cerrudo, Carolina Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Cavallero, Carmen Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Rodríguez Fermepin, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Hertig, Cecilia Margarita. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Fernandez, Belisario Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentin

Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy

It is generally believed that increase in adult contractile cardiac mass can be accomplished only by hypertrophy of existing myocytes. Documentation of myocardial regeneration in acute stress has challenged this dogma and led to the proposition that myocyte renewal is fundamental to cardiac homeostasis. Here we report that in human aortic stenosis, increased cardiac mass results from a combination of myocyte hypertrophy and hyperplasia. Intense new myocyte formation results from the differentiation of stem-like cells committed to the myocyte lineage. These cells express stem cell markers and telomerase. Their number increased >13-fold in aortic stenosis. The finding of cell clusters with stem cells making the transition to cardiogenic and myocyte precursors, as well as very primitive myocytes that turn into terminally differentiated myocytes, provides a link between cardiac stem cells and myocyte differentiation. Growth and differentiation of these primitive cells was markedly enhanced in hypertrophy, consistent with activation of a restricted number of stem cells that, through symmetrical cell division, generate asynchronously differentiating progeny. These clusters strongly support the existence of cardiac stem cells that amplify and commit to the myocyte lineage in response to increased workload. Their presence is consistent with the notion that myocyte hyperplasia significantly contributes to cardiac hypertrophy and accounts for the subpopulation of cycling myocytes

EVIDENCE-BASED RESISTANCE TRAINING RECOMMENDATIONS FOR MUSCULAR HYPERTROPHY

Objective: There is considerable interest in attaining muscular hypertrophy in recreational gym-goers, bodybuilders, older adults, and persons suffering from immunodeficiency conditions. Multiple review articles have suggested guidelines for the most efficacious training methods to obtain muscular hypertrophy. Unfortunately these included articles that inferred hypertrophy markers such as hormonal measurements, used older techniques that might not be valid (e.g. circumference) and failed to appropriately consider the complexity of training variables. Methods: The present commentary provides a narrative review of literature, summarising main areas of interest and providing evidence-based guidelines towards training for muscular hypertrophy. Conclusions: Evidence supports that persons should train to the highest intensity of effort, thus recruiting as many motor units and muscle fibres as possible, self-selecting a load and repetition range, and performing single sets for each exercise. No specific resistance type appears more advantageous than another, and persons should consider the inclusion of concentric, eccentric and isometric actions within their training regime, at a repetition duration that maintains muscular tension. Between set/exercise rest intervals appear not to affect hypertrophy, and in addition the evidence suggests that training through a limited range of motion might stimulate similar results to full range of motion exercise. The performance of concurrent endurance training appears not to negatively affect hypertrophy, and persons should be advised not to expect uniform muscle growth both along the belly of a muscle or for individual muscles within a group. Finally evidence suggests that short (~3 weeks) periods of detraining in trained persons does not incur significant muscular atrophy and might stimulate greater hypertrophy upon return to training