Evaluation of Incidence and Risk Factors of Sudden Cardiac Death in Patients with Chronic Coronary Syndrome Attending Physical Training.

INTRODUCTION: Regular physical activity is recommended to patients with chronic coronary syndrome (CCS). However, vigorous physical exercise occurs as a risk factor of sudden cardiac death (SCD). The effect of short-term and irregular exercise is controversial. The aim of this research is to assess the role of regular training in the incidence of SCD and to identify risk factors among patients with CCS participating in a long-term training program. METHODS: Data of risk factors, therapy, and participation were collected retrospectively for a 10-year period, assessing the length and regularity of participation. The incidence of SCD and related mortality was registered. ANOVA, χ2 test, and multinominal logistic regression and stepwise analysis were performed. RESULTS: The Incidence of chronic kidney disease (CKD) was higher (p < 0.01) and taking beta-blockers (BBs) was lower (p = 0.04) in the SCD group. Irregular training, lack of BBs, smoking, and CKD increased the risk of SCD, while female sex, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers (ACEI/ARBs), and BBs decreased the risk of SCD. CONCLUSIONS: Taking ACEI/ARBs and BBs proved to be a protective factor, emphasizing the use of optimal medical therapy. Assessment of cardiac risk factors and control of comorbidities also proved to be important. The occurrence of SCD was connected to irregular physical activity, probably relating to the adverse effects of ad hoc exercising.

Clinical Study of Metabolic Parameters, Leptin and the SGLT2 Inhibitor Empagliflozin among Patients with Obesity and Type 2 Diabetes.

Obesity is a major public health problem worldwide, and it is associated with many diseases and abnormalities, most importantly, type 2 diabetes. The visceral adipose tissue produces an immense variety of adipokines. Leptin is the first identified adipokine which plays a crucial role in the regulation of food intake and metabolism. Sodium glucose co-transport 2 inhibitors are potent antihyperglycemic drugs with various beneficial systemic effects. We aimed to investigate the metabolic state and leptin level among patients with obesity and type 2 diabetes mellitus, and the effect of empagliflozin upon these parameters. We recruited 102 patients into our clinical study, then we performed anthropometric, laboratory, and immunoassay tests. Body mass index, body fat, visceral fat, urea nitrogen, creatinine, and leptin levels were significantly lower in the empagliflozin treated group when compared to obese and diabetic patients receiving conventional antidiabetic treatments. Interestingly, leptin was increased not only among obese patients but in type 2 diabetic patients as well. Body mass index, body fat, and visceral fat percentages were lower, and renal function was preserved in patients receiving empagliflozin treatment. In addition to the known beneficial effects of empagliflozin regarding the cardio-metabolic and renal systems, it may also influence leptin resistance.

Examination of Self-Esteem, Body Image, Eating Attitudes and Cardiorespiratory Performance in Adolescents.

Self-esteem, body image and eating attitudes are important characteristics regarding adolescent mental health. In our present work, we aimed to investigate these psychological items in adolescent boys and girls examining gender differences and correlations with the BMI-for-age and cardiorespiratory performance. 374 students (209 girls with an average age of 16.4 ± 1.08 years, and 165 boys with an average age of 16.5 ± 1.03 years) underwent investigation using the Rosenberg self-esteem scale, EAT-26 and BAT questionnaires. The BMI-for-age was calculated with BMI growth charts and the cardiorespiratory performance was measured with the 20 m shuttle run test. Our results showed that adolescent girls scored lower self-esteem and higher values for BAT and each scale of eating behaviors, such as uncontrolled eating, cognitive restraints and emotional eating compared to boys despite the fact, that obesity and overweight were more common among boys. No significant correlation was found between BMI and psychological test results in either boys or girls, however, subjective body shape and gender predicted self-esteem and BAT scores and the cognitive restraints in the eating attitudes. Uncontrolled and emotional eating were primarily influenced by gender, in which BMI played only a weaker role. Cardiorespiratory performance was positively associated with self-esteem and body image among boys, and it had a negative correlation regarding BMI in both genders.

The Effects of SGLT2 Inhibitors on Lipid Metabolism.

Sodium glucose co-transporter 2 (SGLT2) inhibitors are effective antihyperglycemic agents by inhibiting glucose reabsorption in the proximal tubule of the kidney. Besides improving glycemic control in patients with type 2 diabetes, they also have additional favorable effects, such as lowering body weight and body fat. Several clinical studies have demonstrated their positive effect in reducing cardiovascular morbidity and mortality. Furthermore, the use of SGLT2 inhibitors were associated with fewer adverse renal outcomes comparing to other diabetic agents, substantiating their renoprotective effect in diabetic patients. SGLT2 inhibitors have also remarkable effect on lipid metabolism acting at different cellular levels. By decreasing the lipid accumulation, visceral and subcutaneous fat, they do not only decrease the body weight but also change body composition. They also regulate key molecules in lipid synthesis and transportation, and they affect the oxidation of fatty acids. Notably, they shift substrate utilization from carbohydrates to lipids and ketone bodies. In this review we intended to summarize the role of SGLT2 inhibitors in lipid metabolism especially on lipoprotein levels, lipid regulation, fat storage and substrate utilization.

Association between Obesity and Overweight and Cardiorespiratory and Muscle Performance in Adolescents.

The high prevalence of obesity in childhood and adolescence has major public health consequences, since it is associated with various chronic diseases in the short- and long-term. The goal of our study was to examine the possible association between obesity and overweight and cardiorespiratory and muscle performance during a 4-year follow up period in adolescents. The body mass index (BMI) and physical performance of adolescents (360 girls and 348 boys) between 14-18 years of age was measured twice a year, and the possible correlation between overweight and obesity and cardiorespiratory and muscle performances were investigated. Our results revealed that cardiorespiratory performance increased significantly in boys during the 4 years (p < 0.001), but the aerobic performance of girls only showed seasonal fluctuation. Muscle performance significantly increased both in boys and girls (p < 0.001). Inverse association between obesity and cardiorespiratory and muscle performance was proved. Overweight was also inversely correlated with cardiorespiratory performance, but it demonstrated no correlation with muscle strength. Avoiding increased BMI and decreased physical fitness is essential for adolescents' health to prevent short- and long-term adverse effects.

["Risk factors of childhood depression" research grant - past, present, future].

The authors summarize the last 10 years of an ongoing collaborative study between the Universities of Szeged and Pittsburgh on early onset major depression. First, the "Risk factors of childhood depression" grant is presented briefly as an initial research study in which the subjects of the current studies were recruited. This is a prominently large clinical sample in the field of child psychiatry even on an international level. In addition to the follow-up of the prognosis of the disorder, recent studies continue to explore the early onset depression in two directions. On the one hand, two studies investigate the role of biobehavioral inflexibility markers in the development of major depression ("Biobehavioral inflexibility and risk for juvenile-onset depression" and "Biobehavioral inflexibility and risk for juvenile-onset depression - renewal grant"). On the other hand, the authors would like to have a better understanding of the possible relationship between the major depression and cardiovascular diseases ("Pediatric depression and subsequent cardiac risk factors: a longitudinal study"). The most significant aims of the three studies will be demonstrated, as well as how the studies were prepared and organized along with the already existing experience concerning research management and involvement of new collaborating partners and experts.

Impact of home- and center- based physical training program on cardio-metabolic health and IGF-1 level in elderly women.

BACKGROUND: Data in the literature concerning the effects of physical activity on lipid and IGF-1levels are controversial in postmenopausal women. The aim of the present study was to determine the combined effects of a 12 weeks home-based walking program aiming to achieve 10,000 steps daily and a center- based aerobic exercise training on functional capacity, some important cardio-metabolic parameters, IGF-1 level and psychological items among elderly female patients. Sixty female patients (67.4 ± 5 years) with moderate to high cardiovascular risk were randomly assigned either to an exercise training program for 12 weeks or to the control group. RESULTS: Our organized training program resulted in a significantly improved daily physical activity (4232 [IQR: 3162-7219] to 8455 [IQR: 6757-11,488]; p < 0.001 ft-steps), functional capacity (MET) (8.17 ± 1.57 to 8.87 ± 1.76) (p = 0.002), metabolic status including total cholesterol (5.17 ± 1.13 to 4.77 ± 1.12 mmol/l), LDL cholesterol (3.37 ± 1.05 to 2.81 ± 0.98 mmol/l), triglyceride (1.68 ± 0.71 to 1.28 ± 0.71 mmol/l) and HgbA1c (6.24 ± 0.67 to 6.06 ± 0.58 mmol/l), as well as IGF-1 (59.68 ± 27.37 to 66.79 ± 22.74 ng/ml) levels (p < 0.05) in the training group. From psychological tests only physical functionality improved significantly (p = 0.03) in the training group. The training group significantly differed from the control group in four parameters including MET (p = 0.003), LDL-cholesterol (p = 0.046), triglyceride (p = 0.001) and IGF-1 levels (p < 0.001) after the intervention. CONCLUSION: The applied home-, and- center based training program effectively increased the daily physical activity of the elderly female patients and improved several cardio-metabolic parameters. Further investigations are needed on larger patient population to establish our findings and examine how these positive changes may decrease CV events and mortality.

[Performance indicators of cardiac rehabilitation in Hungary]. / A kardiológiai rehabilitáció teljesítménymutatói Magyarországon.

INTRODUCTION: With the improvement of the survival of acute cardiac events and the increasing age, there is a higher demand for cardiac rehabilitation care. AIM: The aim of our study is to analyse the performance indicators of cardiac inpatient rehabilitation care in Hungary financed by the statutory public health insurance system. DATA AND METHODS: Data were derived from the financial database of the National Health Insurance Fund of Hungary. We analysed the period between 2014 and 2017. We investigated the distribution of cardiac rehabilitation hospital beds, the patient turnover and the rehabilitation rate following acute care. RESULTS: In 2017, there were 1765 publicly financed cardiac rehabilitation hospital beds in Hungary (1.8 beds/10 000 population). We observed the lowest number of hospital bed number in Szabolcs-Szatmár-Bereg (0.27 beds/10 000 population), Hajdú-Bihar (0.28) and Fejér (0.6) counties. We found the highest number of hospital beds in Veszprém (11.47 beds/10 000 population), Gyor-Moson-Sopron (4.94) counties and in Budapest (2.27). Between 2014 and 2017, the annual number of patients was between 24 834 and 26 146, while the number of nursing days varied between 510 thousand and 542 thousand. The average length of stay showed a moderate increase from 19.2 days/patient (2014) to 20.2 days/patient (2017). Only 6.6-7.6% of the patients who underwent acute myocardial infarction received cardiac rehabilitation care. CONCLUSION: We found significant regional inequalities in both the capacities and the access to and utilization of cardiac rehabilitation healthcare services, which should be mitigated by health policy activities. The low proportion (6.6-7.6%) of patients who underwent acute myocardial infarction and received cardiac rehabilitation care, should be increased. Orv Hetil. 2019; 160(Suppl 1): 6-12.

Association of Exercise Capacity with Physical Functionality and Various Aspects of Fatigue in Patients with Coronary Artery Disease.

The aim of this study was to examine associations between exercise capacity-indexed as the metabolic equivalent of the task-and various aspects of subjective fatigue, physical functionality, and depression in patients with coronary artery disease. A cross-sectional design was used. Patients with stable coronary artery disease (N = 240) underwent an exercise stress test and completed self-report assessments of depression, subjective physical limitations, vital exhaustion, and the impact of fatigue on physical, social, and cognitive functions. Associations between exercise capacity and these self-report variables were assessed using bivariate correlations and a series of multivariate regressions. Exercise capacity was negatively associated with vital exhaustion, physical limitations, and impact of fatigue on physical and social functioning but not on cognitive functioning. There was a marginal association between exercise capacity and depression. The associations between exercise capacity and fatigue remained significant even after controlling for effects of age, body mass index, gender, education, and comorbid diabetes mellitus. The main conclusion of the study is that in patients with coronary artery disease, exercise capacity has the strongest predictability for physical fatigue, but, importantly, it also independently predicts the feeling of loss of energy and malaise.

Cardioprotective Effect of Resveratrol in a Postinfarction Heart Failure Model.

Despite great advances in therapies observed during the last decades, heart failure (HF) remained a major health problem in western countries. In order to further improve symptoms and survival in patients with heart failure, novel therapeutic strategies are needed. In some animal models of HF resveratrol (RES), it was able to prevent cardiac hypertrophy, contractile dysfunction, and remodeling. Several molecular mechanisms are thought to be involved in its protective effects, such as inhibition of prohypertrophic signaling molecules, improvement of myocardial Ca2+ handling, regulation of autophagy, and the reduction of oxidative stress and inflammation. In our present study, we wished to further examine the effects of RES on prosurvival (Akt-1, GSK-3ß) and stress signaling (p38-MAPK, ERK 1/2, and MKP-1) pathways, on oxidative stress (iNOS, COX-2 activity, and ROS formation), and ultimately on left ventricular function, hypertrophy and fibrosis in a murine, and isoproterenol- (ISO-) induced postinfarction heart failure model. RES treatment improved left ventricle function, decreased interstitial fibrosis, cardiac hypertrophy, and the level of plasma BNP induced by ISO treatment. ISO also increased the activation of P38-MAPK, ERK1/2Thr183-Tyr185, COX-2, iNOS, and ROS formation and decreased the phosphorylation of Akt-1, GSK-3ß, and MKP-1, which were favorably influenced by RES. According to our results, regulation of these pathways may also contribute to the beneficial effects of RES in HF.

Doxycycline protects against ROS-induced mitochondrial fragmentation and ISO-induced heart failure.

In addition to their anti-bacterial action, tetracyclines also have complex biological effects, including the modification of mitochondrial protein synthesis, metabolism and gene-expression. Long-term clinical studies have been performed using tetracyclines, without significant side effects. Previous studies demonstrated that doxycycline (DOX), a major tetracyclin antibiotic, exerted a protective effect in animal models of heart failure; however, its exact molecular mechanism is still unknown. Here, we provide the first evidence that DOX reduces oxidative stress-induced mitochondrial fragmentation and depolarization in H9c2 cardiomyocytes and beneficially alters the expression of Mfn-2, OPA-1 and Drp-1 -the main regulators of mitochondrial fusion and fission-in our isoproterenol (ISO)-induced heart failure model, ultimately decreasing the severity of heart failure. In mitochondria, oxidative stress causes a shift toward fission which leads to mitochondrial fragmentation and cell death. Protecting mitochondria from oxidative stress, and the regulation of mitochondrial dynamics by drugs that shift the balance toward fusion, could be a novel therapeutic approach for heart failure. On the basis of our findings, we raise the possibility that DOX could be a novel therapeutic agent in the future treatment of heart failure.

Comparison of hemorheological changes in patients after acute coronary events, intervention and ambulatory rehabilitation.

During the past decades, our group have investigated the hemorheological parameters (HPs) of more than 1,000 patients with various forms of ischemic heart disease (IHD). Our data indicate that HPs are altered in patients with IHD and the extent of the alterations is in good correlation with the clinical severity of the disease. Our findings have also proven that HPs play a critical role in the pathogenesis of myocardial ischemia.The lack of regular exercise is an important cardiovascular risk factor. Regular physical activity - as part of the cardiovascular rehabilitation training program (CRP) - is recommended for the treatment of IHD and the prevention of first or further cardiovascular events. To estimate the beneficial hemorheological effects of CRP, compared to patients after a coronary event or intervention and not participating in CRP, the data of four of our prospective studies (three non-CRP and one CRP-participating) were evaluated.Hematocrit (Hct), plasma and whole blood viscosity (WBV), Hct/WBV ratio significantly (p < 0.05) increased in the non-CRP groups during the 6-12 months follow-up, while in the CRP group they significantly decreased (p < 0.05). Red blood cell aggregation decreased in a much greater manner in the CRP group.Our results indicate that CRP has beneficial hemorheological effects and is able to reverse the deterioration of HPs after coronary events or intervention.

[Cardiovascular prevention - 2016]. / Cardiovascularis prevenció - 2016.

Cardiovascular diseases are the main causes of premature death worldwide despite the fact that cardiovascular mortality decreased significantly in the last few decades in financially developed countries. This reduction is partly due to the modern medical and revascularisation treatments, and partly because of the effectiveness of prevention strategies such as lowering blood pressure and cholesterol level, as well as successful strategies against smoking. However, this positive trend is undermined by the striking growth in obesity and in type 2 diabetes mellitus, which could also be successfully controlled by lifestyle changes. This summary is based on an overview of the recent (2016) European Guideline for the Prevention of Cardiovascular Diseases. Here the authors describe preventive strategies and goals to be achieved, the most important lifestyle suggestions, and the secondary prevention medical treatment for patients with already established cardiovascular disease. Orv. Hetil., 2016, 157(38), 1526-1531.

Effects of moderate aerobic exercise training on hemorheological and laboratory parameters in ischemic heart disease patients.

BACKGROUND AND DESIGN: In this study we set out to determine the effects of long-term physical training on hemorheological, laboratory parameters, exercise tolerability, psychological factors in cardiac patients participating in an ambulatory rehabilitation program. METHODS: Before physical training, patients were examined by echocardiography, tested on treadmill by the Bruce protocol, and blood was drawn for laboratory tests. The enrolled 79 ischemic heart disease patients joined a 24-week cardiac rehabilitation training program. Blood was drawn to measure hematocrit (Hct), plasma and whole blood viscosity (PV, WBV), red blood cell (RBC) aggregation and deformability. Hemorheological, clinical chemistry and psychological measurements were repeated 12 and 24 weeks later, and a treadmill test was performed at the end of the program. RESULTS: After 12 weeks Hct, PV, WBV and RBC aggregation were significantly decreased, RBC deformability exhibited a significant increase (p<0.05). Laboratory parameters (triglyceride, uric acid, hsCRP and fibrinogen) were significantly decreased (p<0.05). After 24 weeks the significant results were still observed. By the end of the study, IL-6 and TNF-α levels displayed decreasing trends (p<0.06). There was a significant improvement in MET (p<0.001), and the BMI decrease was also significant (p<0.05). The vital exhaustion parameters measured on the fatigue impact scale indicated a significant improvement in two areas of the daily activities (p<0.05). CONCLUSIONS: Regular physical training improved the exercise tolerability of patients with ischemic heart disease. Previous publications have demonstrated that decreases in Hct and PV may reduce cardiovascular risk, while a decrease in RBC aggregation and an increase in deformability improve the capillary flow. Positive changes in laboratory parameters and body weight may indicate better oxidative and inflammatory circumstances and an improved metabolic state. The psychological findings point to an improvement in the quality of life.

Cardiac arrest in kearns-sayre syndrome.

The prognosis of progressive ophthalmoplegia in patients with large-scale mitochondrial DNA deletions is highly variable and almost unpredictable. The risk to develop cardiac involvement and sudden cardiac death is strikingly high, especially in patients with Kearns-Sayre syndrome (KSS). The most typical cardiac complications of the disease are conduction defects, which usually begin with left anterior fascicular block with or without right bundle branch block (RBBB), progressing sometimes rapidly to complete atrioventricular block. Other cardiac manifestations reported are first or second degree of AV block, QT prolongation, torsades de pointes ventricular tachycardia, and rarely dilated cardiomyopathy. Most frequently syncope, sometimes even sudden cardiac death, is the first clinical sign of the cardiac disease in KSS. Due to these life-threatening cardiac conditions, patients should be carefully monitored for cardiac signs and symptoms and pacemaker implantation should be suggested early to avoid sudden cardiac arrest in KSS.Here, we present two cases of KSS with life-threatening syncope due to complete atrioventricular block. To emphasize the importance of an early pacemaker implantation, we review the literature on cardiac complications in KSS in the last 20 years. In almost all of the reviewed cases, ophthalmoplegia or ptosis was present before the cardiac manifestations. In most of the cases, syncope was the first symptom of the cardiac involvement. There was no correlation between the age of the onset of the disease and the onset of cardiac manifestations.With our current report, we increase awareness for life-threatening cardiac complications in patients with KSS.

Regulation of kinase cascade activation and heat shock protein expression by poly(ADP-ribose) polymerase inhibition in doxorubicin-induced heart failure.

Cardiomyopathy is one of the most severe side effects of the chemotherapeutic agent doxorubicin (DOX). The formation of reactive oxygen species plays a critical role in the development of cardiomyopathies, and the pathophysiological cascade activates nuclear enzyme poly(ADP-ribose) polymerase (PARP), and kinase pathways. We characterized the effects of the PARP-inhibitor and kinase-modulator compound L-2286 in DOX-induced cardiac injury models. We studied the effect of the established superoxide dismutase-mimic Tempol and compared the effects of this agent with those of the PARP inhibitor. In the rat H9C2 cardiomyocytes, in which DOX-induced poly(ADP-ribosyl)ation, L-2286 protected them from the DOX-induced injury in a concentration-dependent manner. In the in vivo studies, mice were pretreated (for 1 week) with L-2286 or Tempol before the DOX treatment. Both the agents improved the activation of cytoprotective kinases, Akt, phospho-specific protein kinase C ϵ, ζ/λ and suppressed the activity of cell death promoting kinases glycogen synthase kinase-3ß, JNK, and p38 mitogen-activated protein kinase, but the effect of PARP inhibitor was more pronounced and improved the survival as well. L-2286 activated the phosphorylation of proapoptotic transcription factor FKHR1 and promoted the expression of Hsp72 and Hsp90. These data suggest that the mode of the cytoprotective action of the PARP inhibitor may include the modulation of kinase pathways and heat shock protein expression.

Use of octreotide in the treatment of chylopericardium.

Chylopericardium involves the pericardial effusion of chyle, which can be a primary (idiopathic) or secondary condition to injury or obstruction of the thoracic duct. We present a case of isolated chylopericardium that appeared after coronary artery bypass grafting in a 46-year-old woman. After failure of the usual conservative therapy for chylopericardium, ie, pericardial drainage and a low-fat, medium-chain triglyceride diet, her treatment was completed with octreotide, a long-acting somatostatin analog. Octreotide was used subcutaneously at a 3 × 100 µg daily dose for 2 weeks. The production of pericardial fluid decreased gradually, and had normalized by the end of treatment. No side effects were evident during therapy.

PARP inhibition delays transition of hypertensive cardiopathy to heart failure in spontaneously hypertensive rats.

AIMS: Oxidative stress followed by abnormal signalling can play a critical role in the development of long-term, high blood pressure-induced cardiac remodelling in heart failure (HF). Since oxidative stress-induced poly(ADP-ribose)polymerase (PARP) activation and cell death have been observed in several experimental models, we investigated the possibility that inhibition of nuclear PARP improves cardiac performance and delays transition from hypertensive cardiopathy to HF in a spontaneously hypertensive rat (SHR) model of HF. METHODS AND RESULTS: SHRs were divided into two groups: one received no treatment (SHR-C) and the other (SHR-L) received 5 mg/kg/day L-2286 (PARP-inhibitor) orally for 46 weeks. A third group was a normotensive age-matched control group (CFY) and a fourth was a normotensive age-matched group receiving L-2286 treatment 5 mg/kg/day (CFY+L). At the beginning of the study, systolic function was similar in both CFY and SHR groups. In the SHR-C group at the end of the study, eccentric hypertrophy with poor left ventricular (LV) systolic function was observed, while PARP inhibitor treatment preserved systolic LV function. Due to these favourable changes, the survival rate of SHRs was significantly improved (P < 0.01) by the administration of the PARP inhibitor (L-2286). The PARP inhibitor used did not affect the elevated blood pressure of SHR rats, but moderated the level of plasma-BNP (P < 0.01) and favourably influenced all the measured gravimetric parameters (P < 0.05) and the extent of myocardial fibrosis (P < 0.05). The inhibition of PARP increased the phosporylation of Akt-1/GSK-3beta (P < 0.01), ERK 1/2 (P < 0.01), and PKC epsilon (P < 0.01), and decreased the phosphorylation of JNK (P < 0.05), p-38 MAPK (P < 0.01), PKC pan betaII and PKC zeta/lambda (P < 0.01), and PKC alpha/betaII and delta (P < 0.05). CONCLUSION: These data demonstrate that chronic inhibition of PARP induces long-term favourable changes in the most important signalling pathways related to oxidative stress. PARP inhibition also prevents remodelling, preserves systolic function, and delays transition of hypertensive cardiopathy to HF in SHRs.

PARP inhibition prevents postinfarction myocardial remodeling and heart failure via the protein kinase C/glycogen synthase kinase-3beta pathway.

The inhibition of glycogen synthase kinase-3beta (GSK-3beta) via phosphorylation by Akt or protein kinase C (PKC), or the activation of mitogen-activated protein kinase (MAPK) cascades can play a pivotal role in left ventricular remodeling following myocardial infarction. Our previous data showed that MAPK and phosphatidylinositol-3-kinase/Akt pathways could be modulated by poly(ADP-ribose)polymerase (PARP) inhibition raising the possibility that cardiac hypertrophic signaling responses may be favorably influenced by PARP inhibitors. A novel PARP inhibitor (L-2286) was tested in a rat model of chronic heart failure following isoproterenol-induced myocardial infarction. Subsequently, cardiac hypertrophy and interstitial collagen deposition were assessed; additionally, mitochondrial enzyme activity and the phosphorylation state of GSK-3beta, Akt, PKC and MAPK cascades were monitored. PARP inhibitor (L-2286) treatment significantly reduced the progression of postinfarction heart failure attenuating cardiac hypertrophy and interstitial fibrosis, and preserving the integrity of respiratory complexes. More importantly, L-2286 repressed the hypertrophy-associated increased phosphorylation of panPKC, PKC alpha/betaII, PKC delta and PKC epsilon, which could be responsible for the activation of the antihypertrophic GSK-3beta. This work provides the first evidence that PARP inhibition beneficially modulates the PKC/GSK-3beta intracellular signaling pathway in a rat model of chronic heart failure identifying a novel drug target to treat heart failure.

The role of Akt and mitogen-activated protein kinase systems in the protective effect of poly(ADP-ribose) polymerase inhibition in Langendorff perfused and in isoproterenol-damaged rat hearts.

Blocking poly(ADP-ribosyl)ation of nuclear proteins protects the heart from ischemia-reperfusion injury. In addition, activation of Akt and mitogen-activated protein kinase (MAPK) cascades also plays a pivotal role in the survival of cardiomyocytes during ischemia-reperfusion; however, the potential interplay between these pathways is yet to be elucidated. We therefore tested the hypothesis whether poly(ADP-ribose) polymerase (PARP) inhibition can modulate Akt and MAPK signaling of ischemic-reperfused rat hearts. A novel PARP inhibitor, L-2286 [2-[(2-piperidin-1-yletil)thio]quinazolin-4(3H)-one] was administered during ischemia-reperfusion in Langendorff perfused rat hearts and in isoproterenol-induced myocardial infarction. Thereafter, the cardiac energy metabolism, oxidative damage, and the phosphorylation state of Akt and MAPK cascades were monitored. L-2286 exerted significant protective effect against ischemia-reperfusion-induced myocardial injury in both experimental models. More importantly, L-2286 facilitated the ischemia-reperfusion-induced activation of Akt, extracellular signal-regulated kinase, and p38-MAPK in both isolated hearts and in vivo cardiac injury. By contrast, isoproterenol-induced rapid c-Jun N-termainal kinase activation was repressed by L-2286. Here, we provide evidence for the first time that PARP inhibition beneficially modulates the cardiac Akt and MAPK signaling in ex vivo and in vivo ischemia-reperfusion models. We therefore propose that this novel mechanism may contribute to the cardioprotective properties of PARP inhibitors.