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

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

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

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

Adaptations to iron deficiency: cardiac functional responsiveness to norepinephrine, arterial remodeling, and the effect of beta-blockade on cardiac hypertrophy.

BackgroundIron deficiency (ID) results in ventricular hypertrophy, believed to involve sympathetic stimulation. We hypothesized that with ID 1) intravenous norepinephrine would alter heart rate (HR) and contractility, 2) abdominal aorta would be larger and more distensible, and 3) the beta-blocker propanolol would reduce hypertrophy.Methods1) 30 CD rats were fed an ID or replete diet for 1 week or 1 month. Norepinephrine was infused via jugular vein; pressure was monitored at carotid artery. Saline infusions were used as a control. The pressure trace was analyzed for HR, contractility, systolic and diastolic pressures. 2) Abdominal aorta catheters inflated the aorta, while digital microscopic images were recorded at stepwise pressures to measure arterial diameter and distensibility. 3) An additional 10 rats (5 ID, 5 control) were given a daily injection of propanolol or saline. After 1 month, the hearts were excised and weighed.ResultsEnhanced contractility, but not HR, was associated with ID hypertrophic hearts. Systolic and diastolic blood pressures were consistent with an increase in arterial diameter associated with ID. Aortic diameter at 100 mmHg and distensibility were increased with ID. Propanolol was associated with an increase in heart to body mass ratio.ConclusionsID cardiac hypertrophy results in an increased inotropic, but not chronotropic response to the sympathetic neurotransmitter, norepinephrine. Increased aortic diameter is consistent with a flow-dependent vascular remodeling; increased distensibility may reflect decreased vascular collagen content. The failure of propanolol to prevent hypertrophy suggests that ID hypertrophy is not mediated via beta-adrenergic neurotransmission

Protein kinase A (PKA) phosphorylation of Shp2 inhibits its phosphatase activity and modulates ligand specificity.

Pathological cardiac hypertrophy (an increase in cardiac mass resulting from stress-induced cardiac myocyte growth) is a major factor underlying heart failure. Src homology 2 domain-containing phosphatase (Shp2) is critical for cardiac function as mutations resulting in loss of Shp2 catalytic activity are associated with congenital cardiac defects and hypertrophy. We have identified a novel mechanism of Shp2 inhibition that may promote cardiac hypertrophy. We demonstrate that Shp2 is a component of the A-kinase anchoring protein (AKAP)-Lbc complex. AKAP-Lbc facilitates protein kinase A (PKA) phosphorylation of Shp2, which inhibits Shp2 phosphatase activity. We have identified two key amino acids in Shp2 that are phosphorylated by PKA: Thr73 contributes a helix-cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phospho-deficient (T73A/S189A) and phospho-mimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein tyrosine phosphatase activity. Overall, our data indicate that AKAP-Lbc integrates PKA and Shp2 signaling in the heart and that AKAP-Lbc-associated Shp2 activity is reduced in hypertrophic hearts in response to chronic β-adrenergic stimulation and PKA activation. Thus, while induction of cardiac hypertrophy is a multifaceted process, inhibition of Shp2 activity through AKAP-Lbc-anchored PKA is a previously unrecognized mechanism that may promote this compensatory response

Mechanisms of exercise-induced improvements in the contractile apparatus of the mammalian myocardium

One of the main outcomes of aerobic endurance exercise training is the improved maximal oxygen uptake, and this is pivotal to the improved work capacity that follows the exercise training. Improved maximal oxygen uptake in turn is at least partly achieved because exercise training increases the ability of the myocardium to produce a greater cardiac output. In healthy subjects, this has been demonstrated repeatedly over many decades. It has recently emerged that this scenario may also be true under conditions of an initial myocardial dysfunction. For instance, myocardial improvements may still be observed after exercise training in post-myocardial infarction heart failure. In both health and disease, it is the changes that occur in the individual cardiomyocytes with respect to their ability to contract that by and large drive the exercise training-induced adaptation to the heart. Here, we review the evidence and the mechanisms by which exercise training induces beneficial changes in the mammalian myocardium, as obtained by means of experimental and clinical studies, and argue that these changes ultimately alter the function of the whole heart and contribute to the changes in whole-body function

The role of reactive astrocitose in the chronological evolution of traumatic brain injury

Introduction and objectives. This study aims to investigate whether the cerebral modifications of posttraumatic reactive astrocitose can be considered an objective criterion for determining the age of traumatic cranio-cerebral lesions. Materials and methods. The present study consists of a series of 23 medico-legal cases that underwent autopsy inTeleormanCounty(Romania) Department of Forensic Medicine during 2007–2016, with full immune-histochemical microscopic examination using GFAP staining. The study consists of two groups, a series of 13 cases with cranio-cerebral trauma with different posttraumatic survival periods and 9 cases as a control group. Results and discussions. We discovered GFAP+ reactive astrocytes even when death occurred immediately after the trauma event and up to 4 months after the traumatic incident. We also discovered an intense positive correlation between the density of the GFAP+ cell from the perilesional area and the posttraumatic survival period. The highest cerebral density of the GFAP+ astrocytes occurred with acute death prior (1 to 24 hours) and the lowest in the chronic period (over 2 weeks). Conclusions. The gradual and differentiated appearance of the reactive astrocytes in close relation with the cerebral posttraumatic interval, with specific lesional and perilesional distribution as well as in surrounding area, clearly demonstrates that the state of the reactive astrocitose may constitute an objective index for evaluation of the elapsed time after the posttraumatic event