Decline In Ventricular Function Research Articles

Use of Stem Cells to Treat Left Ventricular Hypertrophy

Left Ventricular Hypertrophy is a multifactorial condition involving genetic and signaling pathways. Current recommendations for treating hypertensive LVH include ACE inhibitors, RAS and CCBs. Despite numerous drug therapies for ventricular hypertrophy, patients often deteriorate and experience a decline in ventricular function ultimately leading to heart failure. For this reason, alternative therapies must be investigated. Stem cells possess the potential to divide at a high capacity, self-renew and differentiate into numerous cardiac cell lineages. Furthermore, stem cells are connected to ventricular remodeling and are vital in maintaining the homeostasis of the heart. Further examination of the role of stem cells in LVH could result in the development of targeted therapeutic interventions for prevention or reversal of the phenomenon.

Association Between Progression of Arterial Stiffness and Left Ventricular Remodeling in a Community-Based Cohort

BackgroundCross sectionally measured, elevated arterial stiffness is associated with unfavorable left ventricular (LV) remodeling, suggesting its important role in the pathophysiology of heart failure. However, data linking the degree of arterial stiffness progression with LV remodeling are scarce. ObjectivesThe purpose of this study was to investigate the association between longitudinal change in arterial stiffness and changes in LV remodeling. MethodsSerial measurements of arterial stiffness by cardio-ankle vascular index (CAVI) were performed in 317 participants without cardiovascular disease and with normal arterial stiffness. LV size, mass, and function were assessed by transthoracic echocardiography and including LV global longitudinal strain (LVGLS) by speckle-tracking and tissue Doppler velocity (e’) of the mitral annulus (diastolic function). ResultsDuring a median follow-up of 26.8 mo, there was a significant increase in CAVI (P < 0.001). Generalized estimating equation analyses showed that longitudinal increase in CAVI was associated with impaired LVGLS (estimate 0.46, 95% CI: 0.11-0.82; P = 0.010) after adjustment for demographics and baseline cardiovascular factors, but not with changes of LV mass index and e’ velocity. When controlling for longitudinal change of covariates, CAVI progression remained associated with change in LVGLS (estimate 0.50, 95% CI: 0.16-0.85; P = 0.004). In sex stratified analysis, progression of CAVI was significantly associated with LVGLS deterioration only in women (estimate 0.92, 95% CI: 0.27-1.58; P = 0.006). ConclusionsLongitudinal increase in arterial stiffness is associated with deterioration in LVGLS. Vascular-ventricular coupling plays an important role in the progressive decline in ventricular function even at an early, subclinical stage.

PO-05-026 IMPACT OF LEADLESS PACING ON VENTRICULAR AND VALVULAR FUNCTION

Traditional transvenous pacemakers have been associated with worsening tricuspid valve (TV) function due to lead-related leaflet impingement, as well as ventricular dysfunction related to electromechanical dyssynchrony from right ventricular pacing. The effect of leadless pacing on ventricular and valvular function has not been well established. To describe the impact of leadless pacing on ventricular and valvular function In patients who underwent a leadless pacemaker implant at Duke University Hospital between November 11, 2014 and November 18, 2019 and had pre- and post-procedure echocardiographic imaging, echocardiographic features before and after implant were assessed. Valvular regurgitation was graded ordinally from 0 (none) to 3 (severe). Left ventricular function was quantified by left ventricular ejection fraction (LVEF) and right ventricular function by tricuspid annular plane systolic excursion (TAPSE). Among 54 consecutive patients, the mean age was 70.1 ± 14.3 years, 44% were women, and the most frequent pacing indication was complete heart block (44%). The mean right ventricular pacing burden was 48.6 ± 42.6%. Over a mean echocardiographic follow-up time of 28.7 ± 19.8 months, there was no change in regurgitation severity of the mitral valve (mean change -0.17 ± 1.02, p= 0.24), tricuspid valve (mean change 0.07 ± 1.15, p=0.64), or aortic valve (mean change 0.11 ± 0.77, p=0.29) (Figure). There was no significant change in mean bi-atrial or bi-ventricular chamber size. There was a post-implant decrease in mean LVEF (52.3 ± 9.3 to 47.9 ± 12.1, p=0.0019) and TAPSE (1.8 ± 0.6 to 1.6 ± 0.4, p=0.0437) (Table). Neither change in LVEF nor TAPSE correlated with implant location (apical [n=46] vs non-apical septum [n=7]). Overall, 8 patients (15%) were diagnosed with pacing-related cardiomyopathy and 6 (11%) received an upgrade to a transvenous biventricular pacemaker. Patients with leadless pacemakers experienced no significant change in tricuspid regurgitation post-implant. However, right ventricular leadless pacing was associated with reduction in measures of both right and left ventricular function. These findings may impact selection of a leadless versus transvenous pacing system in patients with pre-existing TR or who are vulnerable to decline in ventricular function.

Highlights From the Circulation Family of Journals.

Highlights From the Circulation Family of Journals.

Abstract 906: Age-Dependent Modifications in Cardiac Myofilament Proteins are Graded by Overall Health, Measured as Frailty, in Aging Male and Female C57BL/6 Mice

Previously, we showed that the age-dependent decline in ventricular function in male mice is proportional to overall health, as quantified with a frailty index (FI) tool. This tool is based on the accumulation of deficits in health across many systems, but not the cardiovascular system per se . Here we investigated whether frailty grades age-dependent modifications in myofilaments in young and aged mice of both sexes. Myofilaments were isolated from ventricles of adult (12-13 mos; n=5 males, 5 females) and aged (22-23 mos; n=6 males, 5 females) mice. FI scores were obtained from all mice. Actomyosin Mg-ATPase activity as a function of increasing calcium concentration and phosphorylation of major myofilament proteins were quantified and compared between groups. Results showed that myofilament calcium sensitivity (EC 50 values) was similar regardless of age or sex and was not affected by FI score. Maximal actomyosin Mg-ATPase activity increased with age in females, but this was not linked to frailty. Hill coefficients declined with age in males only and were lower than females in the older group (p&lt;0.05). However when all mice were examined, Hill coefficients declined as frailty increased (r=0.68, p=0.001). Total phosphorylation levels of myosin-binding protein C (MyBP-C), desmin, tropomyosin and essential myosin light chain (ELC) increased with age, but only in males. Interestingly, phosphorylation of MyBP-C (r=0.49; p=0.03), desmin (r=0.65; p=0.003), tropomyosin (r=0.62; p=0.004) and ELC (r=0.71; p=0.001) were highly correlated with overall health (FI scores). By contrast there was no link between frailty and phosphorylation of actin, troponin T and troponin I. These findings suggest that poor overall health, quantified in an FI, predicts changes in the myofilaments across the life course in both sexes. This may contribute to changes in cardiac contractile function in frail older adults.

Neurohormonal Blockade and Circulating Cardiovascular Biomarkers During Anthracycline Therapy in Breast Cancer Patients: Results From the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) Study.

BackgroundAnthracyclines are associated with cardiotoxic effects. Cardiovascular biomarkers may reflect myocardial injury, dysfunction, inflammation, and fibrosis and may precede and predict the development of left ventricular impairment. The aim of this study was to assess: (1) longitudinal change in circulating cardiovascular biomarkers, (2) the effect of metoprolol succinate and candesartan cilexetil on the biomarker response, and (3) the associations between on‐treatment changes in biomarker concentrations and subsequent left ventricular dysfunction in patients with early breast cancer receiving anthracyclines.Methods and ResultsThis report encompasses 121 women included in the 2×2 factorial, placebo‐controlled, double‐blind PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial with metoprolol and candesartan given concomitantly with anticancer therapy containing the anthracycline, epirubicin (total cumulative dose, 240–400 mg/m2). Cardiovascular magnetic resonance, echocardiography images, and circulating levels of biomarkers were obtained before and after anthracycline treatment. Cardiac troponins I and T, B‐type natriuretic peptide, N‐terminal pro‐B‐type natriuretic peptide, C‐reactive protein, and galectin‐3 increased during anthracycline therapy (all P<0.05). The troponin response was attenuated by metoprolol (P<0.05), but not candesartan. There was no association between change in biomarker concentrations and change in cardiac function during anthracycline therapy.ConclusionsTreatment with contemporary anthracycline doses for early breast cancer is associated with increase in circulating cardiovascular biomarkers. This increase is, however, not associated with early decline in ventricular function. Beta‐blockade may attenuate early myocardial injury, but whether this attenuation translates into reduced risk of developing ventricular dysfunction in the long term remains unclear.Clinical Trial Registration URL: http://www.clinicaltrial.gov. Unique identifier: NCT01434134.

Variable clinical course of identical twin neonates with Alström syndrome presenting coincidentally with dilated cardiomyopathy.

Alström Syndrome (AS) is a rare autosomal recessive disorder caused by mutations in the ALMS1 gene. We report monozygotic twin infants who presented concurrently with symptoms of congestive heart failure (CHF) due to dilated cardiomyopathy (DCM). Following their initial presentation, one twin improved both echocardiographically and functionally while the other twin showed a progressive decline in ventricular function and worsening CHF symptoms requiring multiple hospitalizations and augmentation of heart failure therapy. Concordant findings of nystagmus, vision loss, and developmental delay were noted in both twins. Additional discordant findings included obesity and signs of insulin resistance in one twin. Genetic testing on one sibling confirmed AS. These twins underscore the importance of considering AS in any child presenting with DCM, particularly in infancy, and highlights that, even in monozygotic twins, the clinical course of AS is variable with regard to both the cardiac and non-cardiac manifestations of the disease.

Decline in ventricular function as a result of general anesthesia in pediatric heart transplant recipients.

Echocardiography is frequently performed under anesthesia during procedures such as cardiac catheterization with EMB in pediatric HTx recipients. Anesthetic agents may depress ventricular function, resulting in concern for rejection. The aim of this study was to compare ventricular function as measured by echocardiography before and during GA in 17 pediatric HTx recipients. Nearly all markers of ventricular systolic function were significantly decreased under GA, including EF (-4.2% ±1.2, P<.01) and RV FAC (-0.05±0.02, P=.04). Subjects in the first post-transplant year (n=9) trended toward a more significant decrease in EF vs those beyond the first post-transplant year (n=8; -6.0% ±1.2 vs -2.1±2.0, P=.1). This information quantifies a decline in biventricular function that should be expected in pediatric HTx recipients while under GA and can assist the transplant clinician in avoiding unnecessary treatment of transient GA-induced ventricular dysfunction.

Cardiac acetylcholine inhibits ventricular remodeling and dysfunction under pathologic conditions

Autonomic dysfunction is a characteristic of cardiac disease and decreased vagal activity is observed in heart failure. Rodent cardiomyocytes produce de novo ACh, which is critical in maintaining cardiac homeostasis. We report that this nonneuronal cholinergic system is also found in human cardiomyocytes, which expressed choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT). Furthermore, VAChT expression was increased 3- and 1.5-fold at the mRNA and protein level, respectively, in ventricular tissue from patients with heart failure, suggesting increased ACh secretion in disease. We used mice with genetic deletion of cardiomyocyte-specific VAChT or ChAT and mice overexpressing VAChT to test the functional significance of cholinergic signaling. Mice deficient for VAChT displayed an 8% decrease in fractional shortening and 13% decrease in ejection fraction compared with angiotensin II (Ang II)-treated control animals, suggesting enhanced ventricular dysfunction and pathologic remodeling in response to Ang II. Similar results were observed in ChAT-deficient mice. Conversely, no decline in ventricular function was observed in Ang II-treated VAChT overexpressors. Furthermore, the fibrotic area was significantly greater (P < 0.05) in Ang II-treated VAChT-deficient mice (3.61 ± 0.64%) compared with wild-type animals (2.24 ± 0.11%). In contrast, VAChT overexpressing mice did not display an increase in collagen deposition. Our results provide new insight into cholinergic regulation of cardiac function, suggesting that a compensatory increase in cardiomyocyte VAChT levels may help offset cardiac remodeling in heart failure.

Myosin Heads Are Displaced from Actin Filaments in the In Situ Beating Rat Heart in Early Diabetes

Diabetes is independently associated with a specific cardiomyopathy, characterized by impaired cardiac muscle relaxation and force development. Using synchrotron radiation small-angle x-ray scattering, this study investigated in the in situ heart and in real-time whether changes in cross-bridge disposition and myosin interfilament spacing underlie the early development of diabetic cardiomyopathy. Experiments were conducted using anesthetized Sprague-Dawley rats 3 weeks after treatment with either vehicle (control) or streptozotocin (diabetic). Diffraction patterns were recorded during baseline and dobutamine infusions simultaneous with ventricular pressure-volumetry. From these diffraction patterns myosin mass transfer to actin filaments was assessed as the change in intensity ratio (I1,0/I1,1). In diabetic hearts cross-bridge disposition was most notably abnormal in the diastolic phase (p < 0.05) and to a lesser extent the systolic phase (p < 0.05). In diabetic rats only, there was a transmural gradient of contractile depression. Elevated diabetic end-diastolic intensity ratios were correlated with the suppression of diastolic function (p < 0.05). Furthermore, the expected increase in myosin head transfer by dobutamine was significantly blunted in diabetic animals (p < 0.05). Interfilament spacing did not differ between groups. We reveal that impaired cross-bridge disposition and radial transfer may thus underlie the early decline in ventricular function observed in diabetic cardiomyopathy.

Caspase-3 activation and increased procollagen type I in irradiated hearts

The caspase-3-cleaved presence was evaluated in this study in the heart of irradiated rats, during the decline of ventricular function. Female Wistar rats were irradiated with a single dose of radiation (15 Gy) delivered directly to the heart and the molecular, histological and physiological evaluations were performed at thirteen months post-irradiation. The expressions of procollagen type I, TGF-ß1 and caspase-3-cleaved were analyzed using Western blotting. Cardiac structural and functional alterations were investigated by echocardiography and electron microscopy. In the irradiated group, the levels of procollagen type I, TGF-ß1 and caspase-3-cleaved are increased. Significant histological changes (degeneration of heart tissue and collagen deposition) and functional (reduced ejection fraction) were observed. Data suggest that the cardiac function decline after exposure to ionizing radiation is related, in part, to increased collagen and increased caspase-3-cleaved.

Squeezing better function out of the systemic right ventricle by optimizing its pacing site

The morphologic right ventricle (RV) is the systemic pumping chamber predominantly in 2 types of biventricular congenital heart disease: congenitally corrected transposition of the great arteries and following repair of transposition of the great arteries (TGA) using a Senning or Mustard atrial switch procedure. In both conditions, the systemic RV is prone to fail. Indeed, after the atrial switch procedure for TGA, long-term systemic RV function is a major concern and profoundly affects patient outcomes. Roos-Hesselink et al 1 Roos-Hesselink J.W. Meijboom F.J. Spitaels S.E. et al. Decline in ventricular function and clinical condition after Mustard repair for transposition of the great arteries (a prospective study of 22–29 years). Eur Heart J. 2004; 25: 1264-1270 Crossref PubMed Scopus (198) Google Scholar found that while all patients had good RV function 14 years after undergoing an atrial switch procedure, almost two-thirds showed moderate-to-severe systemic RV dysfunction after 25 years. RV dysfunction was associated with QRS prolongation, a decline in exercise capacity and clinical status and presumably increased need for heart transplant. Reduced myocardial strain and other indices of RV performance form the basis for systemic RV failure in this setting. 2 Eyskens B. Weidemann F. Kowalski M. et al. Regional right and left ventricular function after the Senning operation: an ultrasonic study of strain rate and strain. Cardiol Young. 2004; 14: 255-264 Crossref PubMed Scopus (56) Google Scholar Conversely, RV dysfunction is not commonly seen in the subpulmonary RV when TGA is treated with an arterial switch operation. Therefore, it is the systemic position of the RV that predisposes it to failure. Acute hemodynamic benefits of biventricular and single-site systemic ventricular pacing in patients with a systemic right ventricleHeart RhythmVol. 10Issue 5PreviewPatients treated by atrial redirection surgery (Senning or Mustard procedure) for transposition of the great arteries (TGA) have an important risk for heart failure caused by dysfunction of the systemic right ventricle. Conventional nonsystemic ventricular pacing (non-systVP) may even further increase this risk. Full-Text PDF

The cardioprotective efficacy of TVP1022 in a rat model of ischaemia/reperfusion

Because myocardial infarction is a major cause of morbidity and mortality worldwide, protecting the heart from the ischaemia and reperfusion (I/R) damage is the focus of intense research. Based on our in vitro findings showing that TVP1022 (the S-enantiomer of rasagiline, an anti-Parkinsonian drug) possesses cardioprotective effects, in the present study we investigated the hypothesis that TVP1022 can attenuate myocardial damage in an I/R model in rats. The model consisted of 30-min occlusion of the left anterior descending artery followed by 4 or 24 h reperfusion. In addition, we investigated the possible mechanisms of cardioprotection in H9c2 cells and neonatal rat ventricular myocytes (NRVM) exposed to oxidative stress induced by H(2) O(2) . TVP1022 (20 and 40 mg·kg(-1) ) administered 5 min before reperfusion followed by an additional dose 4 h after reperfusion reduced the infarct size and attenuated the decline in ventricular function. TVP1022 also attenuated I/R-induced deterioration in cardiac mitochondrial integrity evaluated by mitochondrial swelling capacity. In vitro, using H9c2 cells and NRVM, TVP1022 attenuated both serum free- and H(2) O(2) -induced damage, preserved mitochondrial membrane potential and Bcl-2 levels, inhibited mitochondrial cytochrome c release and the increase in cleaved caspase 9 and 3 levels, and enhanced the phosphorylation of protein kinase C and glycogen synthase kinase-3β. TVP1022 provided cardioprotection in a model of myocardial infarction, and therefore should be considered as a novel adjunctive therapy for attenuating myocardial damage resulting from I/R injuries.

Transforming Growth Factor-β

Cardiac remodeling is a term that broadly refers to changes in myocardial structure and function in response to injury. Irrespective of the injurious mechanism (ie, myocardial infarction, hypertensive heart disease, valvulopathy, myocarditis, or primary myocyte dysfunction), a decline in ventricular function activates several compensatory pathways designed to sustain tissue perfusion. Among these cascades, the sympathetic nervous system, the renin-angiotensin-aldosterone system, and the transforming growth factor-β (TGF-β) system stimulate myocyte hypertrophy and cardiac fibrosis. Traditionally, this paradigm of cardiac remodeling is applied to subjects with heart failure and reduced left ventricular ejection fraction; however, the precise molecular mechanisms underlying the pathophysiology of heart failure with preserved ejection fraction (HFpEF) are poorly understood. Article see p 44 Although much attention has focused on myocyte biology in heart failure, regulation of cardiac fibrosis in the context of HFpEF remains an area of active investigation. The cardiac fibroblast is the primary cell type responsible for generating extracellular matrix (ECM) within the myocardium. This ECM is composed primarily of type I collagen (80%) and type III collagen (10%). The remaining 10% is composed of type V and type VI collagen, laminin, elastin, glycosaminoglycans, and proteoglycans.1 This collagen network provides mechanical support to the myocardium, organizes muscle contraction, synthesizes and releases growth factors in a paracrine and autocrine fashion, and promotes wound healing. The term fibrosis encompasses several processes including fibroblast proliferation, collagen synthesis and degradation, and conversion of fibroblasts …

Tachycardia-mediated cardiomyopathy: Recognition and management

Tachycardia-mediated cardiomyopathy is a cause of ventricular dysfunction due to, at least partially, persistent tachycardia leading to cellular and extracellular perturbations. Cardiomyopathy may take years to develop, but pharmacologic management to achieve rate control and reverse remodeling, as well as cardioversion or ablative strategies to stop the tachycardia, can result in rapid recovery from symptoms and gradual improvement in left ventricular ejection fraction. However, ultrastructural changes can remain and may lead to a rapid decline in ventricular function if tachycardia recurs. Ultrastructural changes may also explain a propensity toward sudden death even if the ejection fraction normalizes. Although the etiology, pathophysiology, and late clinical manifestations of tachycardia-mediated cardiomyopathy are beginning to be understood, investigation continues, focusing on prevention, early recognition, and acute and long-term management in an attempt to lessen heart failure and prevent risk of sudden death.

Time dependence of estrogen receptor expression in human hearts

Objectives and aims Transcriptional effects of estrogens are primarily mediated by the two nuclear estrogen receptors (ER), ERα and ERβ. Both receptors are present in the vasculature and in the human heart and have been shown to act antiatherogenic and to be protective against the development of cardiac hypertrophy. The aim was to quantify ER mRNA expression in left ventricular specimens from patients with coronary heart disease (CHD, n = 15) and dilated cardiomyopathy (CMP, n = 38) and compare their levels with those from healthy heart donors ( n = 9). Additionally, a possible variation of ERmRNA expression in human hearts in respect to time of day was studied. Methods and results mRNA expression of both ER receptors was detected by real-time PCR in all of the human specimens. There was no difference in the relative quantity of the receptors between CHD and CMP patients. However, control specimens showed significant lower levels of either receptor in the healthy myocardium ( p < .001 each). Analyzing the time dependency of receptor expression with a cosinor analysis showed a significant 8-hour period rhythm for ERβ in CMP- but no rhythm in CHD patients. Due to the low patient number, rhythmic analysis was not possible in controls. Conclusions The increased ERα and ERβ mRNA expression in left ventricular specimens from CHD and CMP patients might reflect a compensatory mechanism to counteract the decline in ventricular function. Furthermore, we provided evidence for a time dependent variation of ERβ receptor expression in the human heart.

Western diet impairs metabolic remodelling and contractile efficiency in cardiac hypertrophy

Metabolic remodelling in cardiac hypertrophy is underscored by a reduction in fatty acid (FA) oxidation. We tested whether this decline in FA oxidation in the presence of enhanced FA supply may predispose the hypertrophied myocardium to lipid accumulation, functional deterioration, and eventually heart failure. and results Left ventricular hypertrophy was induced surgically in Sprague-Dawley rats by inter-renal aortic constriction. Rats were fed a Western diet (WD, 45% kcal from lipids) or standard diet (SD, 12% kcal from fat) for 9 weeks post-surgery. Hearts were perfused in the isovolumic mode with a physiological mixture of substrates including 5 mM 1-(13)C glucose, 1 mM 3-(13)C lactate, and 0.3 mM U-(13)C palmitate, and cardiac function was monitored. Real-time PCR was used to determine transcript levels of peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARalpha-regulated metabolic enzymes. Palmitate oxidation and PPARalpha-regulated gene expression were markedly reduced in the hypertrophied myocardium of rats fed SD. However, 9 weeks of WD normalized both palmitate oxidation and PPARalpha-regulated gene expression but significantly increased glucose and lactate oxidation in the hypertrophied hearts. This was accompanied by cardiac triglyceride accumulation and a decline in ventricular function despite an increase in oxygen consumption. These results highlight that WD-induced dysregulation of FA metabolism has deleterious functional consequences in cardiac hypertrophy.

Down-Regulation of Apoptosis After Left Ventricular Aneurysm Repair

Apoptosis is a common feature of the cardiomyopathic process contributing to progressive decline in ventricular function after transmural myocardial infarction. We hypothesized that left ventricular aneurysm repair (LVAR) down-regulates apoptotic potential of cardiomyocytes in the surviving myocardium. In the rat infarct model, LV aneurysms were repaired by pursestring suture 2 weeks after coronary artery ligation. Cardiac function and myocardial infarction size were assessed by echocardiography and transverse heart sections, respectively, before sacrifice 12 weeks later. Cardiomyocytes and TdT-mediated dUTP terminal nick-end labeling (TUNEL) assays of apoptotic nuclei were analyzed adjacent to and remote from the aneurysm (8 in infarction group, 7 in aneurysm group, and 11 in repair group). Biochemical samples for immunoblot were also obtained from surviving myocardium. A statistically significant increase in apoptotic rate was seen in both adjacent and remote areas (p < 0.01) after aneurysm formation. After LVAR, heart function was improved, and TUNEL assays also show significant decrease when compared with aneurysm group. But significant decreases were noted only in activated caspase-9 and increases in Bcl-2 in immunoblot analysis when comparing repair group with aneurysm group. Down-regulation of apoptosis accounts for the change in the long-term benefit after LVAR. To prevent heart failure, LVAR is indicated when it is large enough, and the infarction area should be excluded as much as possible.

Invited commentary

Surgical ventricular restoration (SVR) was introduced in the 1960s and has been part of the cardiac surgeon’s armamentarium ever since [1Cooley D.A. Henley W.S. Ahmad K.H. Chapman D.W. Ventricular aneurysm following myocardial infarction: results of surgical treatment.Ann Surg. 1959; 150: 595-612Crossref PubMed Scopus (48) Google Scholar, 2Houel J. Serradimigni A. Ruf G. Dor V. Malmejac C. Gosset C. Aneurysm of the left ventricle Resection under extracorporeal circulation.Mem Acad Chir. 1965; 91: 1021-1026PubMed Google Scholar]. Several reports have demonstrated the beneficial effects of this procedure on outcome and cardiac function, which have usually been attributed to restored ventricular geometry and normalized ventricular volume [3Di Donato M. Toso A. Maioli M. et al.Intermediate survival and predictors of death after surgical ventricular restoration.Semin Thorac Cardiovasc Surg. 2001; 13: 468-475PubMed Scopus (91) Google Scholar, 4Athanasuleas C.L. Stanley Jr, A.W.H. Buckberg G.D. et al.Surgical anterior ventricular endocardial restoration (SAVER) for dilated ischemic cardiomyopathy.Sem Thorac Cardiovasc Surg. 2001; 13: 448-458PubMed Scopus (60) Google Scholar]. However, a controversy remains about patient selection and indication for this operation [5Doenst T. Velazquez E.J. Beyersdorf F. et al.To STICH or not to STICH: We know the answer, but do we understand the question?.J Thorac Cardiovasc Surg. 2005; 129: 246-249Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 6Buckberg G.D. Questions and answers about the STICH trial: A different perspective.J Thorac Cardiovasc Surg. 2005; 130: 245-249Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar]. The issues previously mentioned are not the topic of the present work by Hsu and coworkers [7Hsu C.-P. Huang C.-Y. Wang J.-S. Chiang H.-I. Shih C.-C. Down-regulation of apoptosis after left ventricular aneurysm repair.Ann Thorac Surg. 2007; 84: 1279-1287Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. Instead we find an excellent laboratory investigation on the effect of SVR after myocardial infarction on apoptosis of cardiomyocytes in surviving myocardium. To reiterate, the authors compared cardiac function, myocardial infarction size, and rate of apoptosis between animals with and without of left ventricular aneurysm repair in a rat infarction model. They found improved heart function, reduced rate of apoptosis, and a significant decrease in activated caspase-9 in animals with left ventricular aneurysm repair. The significance of apoptosis in various diseases of the heart has been widely investigated since the late 1980s [8James T.N. Normal and abnormal consequences of apoptosis in the human heart From postnatal morphogenesis to paroxysmal arrhythmias.Circulation. 1994; 90: 556-573Crossref PubMed Scopus (306) Google Scholar]. Remarkably this article by Hsu and colleagues [7Hsu C.-P. Huang C.-Y. Wang J.-S. Chiang H.-I. Shih C.-C. Down-regulation of apoptosis after left ventricular aneurysm repair.Ann Thorac Surg. 2007; 84: 1279-1287Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar] is the first to show apoptosis reduction by SVR after myocardial infarction. Some questions remain open, such as why some important measurements of apoptosis, namely caspase-3 and Bax showed no difference between groups despite a significantly different rate of apoptosis. However further research into the possible benefits of SVR on the cellular level may help to elucidate these issues. Greater insight into the cellular effects of SVR may actually widen our perspective on it beyond the focus on ventricular geometry and mechanics. It will be interesting to see whether or not these basic scientific findings will have the potential to inspire the current clinical debate on SVR. Down-Regulation of Apoptosis After Left Ventricular Aneurysm RepairThe Annals of Thoracic SurgeryVol. 84Issue 4PreviewApoptosis is a common feature of the cardiomyopathic process contriuting to progressive decline in ventricular function after transmural myocardial infarction. We hypothesized that left ventricular aneurysm repair (LVAR) down-regulates apoptotic potential of cardiomyocytes in the surviving myocardium. Full-Text PDF

Human thrombopoietin reduces myocardial infarct size, apoptosis, and stunning following ischaemia/reperfusion in rats

Thrombopoietin (Tpo) is known for its ability to stimulate platelet production. However, it is currently unknown whether Tpo plays a physiological function in the heart. We assessed the potential protective role of Tpo in vitro and in vivo in two rat models of myocardial ischaemia/reperfusion. Tpo receptor (c-mpl) message was detected in the heart using RT-PCR, and the Tpo receptor protein was detected using western blotting and immunohistochemistry. Tpo treatment immediately before ischaemia reduced myocardial necrosis, apoptosis, and decline in ventricular function following ischaemia/reperfusion in the rat in a concentration- and dose-dependent manner with an optimal concentration of 1.0 ng/mL in vitro and an optimal dose of 0.05 microg/kg iv in vivo. Tpo also reduced infarct size when given after the onset of ischaemia or at reperfusion. Tpo activated JAK-2 (Janus kinase-2) and p44 MAPK (mitogen-activated protein kinase) during reperfusion but not prior to ischaemia. Inhibition of JAK-2 (AG-490), p42/44 MAPK (PD98059), mitochondrial K(ATP) channels (5-HD), and sarcolemmal K(ATP) channels (HMR 1098) abolished Tpo-induced resistance to injury from myocardial ischaemia/reperfusion. AG-490, PD98059, 5-HD, and HMR1098 alone had no effect on cardioprotection. Treatment with a single dose of Tpo (0.05 or 1.0 microg/kg iv) did not result in the elevation of platelet count or haematocrit over a 16-day period. A single treatment of Tpo confers cardioprotection through JAK-2, p42/44 MAPK, and K(ATP) channels, suggesting a potential therapeutic role of Tpo in the treatment of injury resulting from myocardial ischaemia and reperfusion.