Senescence and Death of Primitive Cells and Myocytes Lead to Premature Cardiac Aging and Heart Failure

Abstract

Abstract-Chronological myocardial aging is viewed as the inevitable effect of time on the functional reserve of the heart.Cardiac failure in elderly patients is commonly interpreted as an idiopathic or secondary myopathy superimposed on the old heart independently from the aging process. Thus, aged diseased hearts were studied to determine whether cell regeneration was disproportionate to the accumulation of old dying cells, leading to cardiac decompensation. Endomyocardial biopsies from 19 old patients with a dilated myopathy were compared with specimens from 7 individuals of similar age and normal ventricular function. Ten patients with idiopathic dilated cardiomyopathy were also analyzed to detect differences with aged diseased hearts. Senescent cells were identified by the expression of the cell cycle inhibitor p16 INK4a and cell death by hairpin 1 and 2. Replication of primitive cells and myocytes was assessed by MCM5 labeling, myocyte mitotic index, and telomerase function. Aged diseased hearts had moderate hypertrophy and dilation, accumulation of p16INK4a positive primitive cells and myocytes, and no structural damage. Cell death markedly increased and occurred only in cells expressing p16INK4a that had significant telomeric shortening. Cell multiplication, mitotic index and telomerase increased but did not compensate for cell death or prevented telomeric shortening. Idiopathic dilated cardiomyopathy had severe hypertrophy and dilation, tissue injury, and minimal level of p16INK4a labeling. In conclusion, telomere erosion, cellular senescence, and death characterize aged diseased hearts and the development of cardiac failure in humans. Key Words: aging Ⅲ telomeric shortening and telomerase activity Ⅲ p16INK4a marker of cellular senescence Ⅲ cardiac primitive cells Ⅲ heart failure M yocardial aging in humans has been studied extensively and two major conclusions have been reached. Aging effects decrease the functional reserve of the heart 1,2 and loss of myocytes 3 contributes to the attenuation of the response of the old heart to sudden changes in ventricular loading. However, the selection of patients or hearts to be analyzed has always been based on the chronological age of otherwise healthy individuals. [1][2][3] This understandable approach has neglected several variables of the aging process that cannot be easily quantified but may have a significant impact on organ and/or organism aging. It is a wellestablished fact that chronological age and physical age do not necessarily coincide. An 80-year-old man or woman may appear as young as a 60-year-old person. Similarly, organism and organ age do not proceed at the same pace. 4 -6 In general, there is little appreciation of these unpredictable factors and aged patients with cardiac decompensation are diagnosed according to classified diseases, excluding that aging per se can be the etiology of the pathological condition.To establish whether aging alone results in a dilated myopathy with characteristics different from idiopathic dilated cardiomyopathy (...

Mitochondria are required for pro‐ageing features of the senescent phenotype

“…This latter study, together with other more recent reports (Hancock et al , 2011; Lanza et al , 2012; Price et al , 2012), has questioned early associations between CR and enhanced mitochondrial content (Nisoli et al , 2005). Furthermore, despite evidence suggesting that increased mitochondrial abundance can be an advantageous adaptive response to energy deficit, genetically induced mitochondrial biogenesis has been associated with age‐related diseases such as cardiomyopathy (Lehman et al , 2000), renal fibrosis (Hickey et al , 2011) and diabetes (Sawada et al , 2014), all of which have been associated with cellular senescence (Chimenti et al , 2003; Sone & Kagawa, 2005; Ning et al , 2013). …”

Cell death, proliferation and repair in human myocarditis responding to immunosuppressive therapy

“…Morphometric studies, including the assessment of the extent of myocardial fibrosis and the measurement of myocyte diameter at the level of the nucleus with computation of the cross sectional area, were performed on baseline and 6 month follow-up biopsy. 3 The Dallas criteria 4 were adopted for histological diagnosis of myocarditis, supplemented by immunohistochemistry for the characterization of inflammatory infiltrates. 5 …”

“…Two frozen myocardial specimens from each patient were used for PCR and reverse transcriptase PCR analysis to detect cardiotropic DNA (Adenovirus, Epstein Barr virus, Herpes Simplex viruses, Cytomegalovirus, Parvovirus B19) and RNA viruses (Enterovirus, Influenza viruses A and B, Hepatitis C virus), using the primers previously described [2][3][4][5] in baseline and follow-up biopsies. Total RNA extracted from additional left ventricular specimens of responders patients at baseline and 6 month follow-up were used for real-time PCR, using the ABI Prism 7700 Sequence Detection System (Applied Biosystems, Foster City, CA, USA), to detect myosin heavy chain (MHC) a and MHC b.…”

“…In situ ligation of hairpin probes with single-base 3 0 overhangs (hairpin 1) or blunt ends (hairpin 2) were used to measure, respectively, apoptosis and necrosis of myocytes 3,8,9 on baseline and follow-up left ventricular endomyocardial biopsies. The number of proliferating myocytes was evaluated by Ki67 (clone MIB-1, Diagnostic Biosystems, Pleasanton, CA, USA), and MCM5 (Accurate Chemicals, Westbury, NY, USA), two nuclear proteins involved in the cell cycle.…”

“…Specimens were examined with confocal microscope. 3 Control values for myocyte death and proliferation were assessed in 20 surgical specimens of papillary muscles from patients with mitral stenosis and normal left ventricular function. …”