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Cancer therapies induce cardiac injury and increase cardiovascular disease (CVD) risk. In non-cancer populations, higher diet quality is associated with protection against CVD, but the relationship between diet and cardiac function in cancer survivors is unknown. This cross-sectional analysis from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort included 113 cancer survivors (55 breast, 53 prostate, three lung, and three blood) and 4233 non-cancer controls. Dietary intake was reported via validated food frequency questionnaire. Alternate healthy eating index (AHEI) was calculated as a measure of quality. Cardiac function, determined as left ventricular ejection fraction (LVEF), was assessed by cardiac magnetic resonance. Cancer survivors had a lower LVEF compared to controls (61.3 ± 6.5% v 62.4 ± 6.1%, p = 0.04). In all participants, total fat (β ± SE: −0.04 ± 0.01, p = 0.004), saturated fat (−0.11 ± 0.03, p < 0.001), and trans-fat (−0.36 ± 0.12, p = 0.002) intake were inversely associated with LVEF while AHEI (0.03 ± 0.01, p < 0.001) was positively associated with LVEF. Among cancer survivors only, sucrose intake was negatively related to LVEF (−0.15 ± 0.06, p = 0.02), and the ratio of unsaturated fat to saturated fat (2.7 ± 1.1, p = 0.01) and fiber intake (0.42 ± 0.14, p = 0.003) were positively related to LVEF. In cancer survivors, improved dietary fat and carbohydrate quality (i.e., greater consumption of unsaturated fatty acids and fiber) was associated with favorable cardiac function, while higher sucrose was associated with worse cardiac function. Further research is needed to confirm these findings and test whether changes in the identified dietary factors will modulate cardiac function in cancer survivors. [ABSTRACT FROM AUTHOR]

• Nonalcoholic fatty liver disease (NAFLD) severity on liver biopsy has an inverse relationship with Lp(a) level. Patients with non-alcoholic steatohepatitis (NASH) on histology had 50% lower Lp(a) compared to patients with nonalcoholic fatty liver (NAFL). • Conversely, NAFLD severity has a direct relationship with other markers of atherogenic dyslipidemia, including HDL-C, triglycerides, apolipoprotein-B (ApoB), and low-density lipoprotein particle concentration (LDL-P). • This relationship may have implications for prognosticating cardiovascular disease risk in patients with NAFLD. Nonalcoholic fatty liver disease (NAFLD) is associated with atherogenic dyslipidemia and an increased risk of cardiovascular events. Previous studies have suggested an inverse relationship between NAFLD severity and lipoprotein(a) [Lp(a)] level, but contemporary data from the U.S. are lacking. Lp(a), lipid profile, apolipoproteins, and nuclear magnetic resonance-based lipoprotein particle concentrations were measured in 151 patients with biopsy-proven NAFLD. Levels were compared between those with nonalcoholic fatty liver (NAFL) on histology and non-alcoholic steatohepatitis (NASH). Median age was 55 [48, 62] years, 67% of patients were women, 83% were White, 43% had NAFL, and 57% had NASH. Triglyceride level was higher and high-density lipoprotein-cholesterol (HDL-C) was lower among those with NASH as compared with NAFL. Circulating apolipoprotein-B (ApoB) and low-density lipoprotein particle concentration (LDL-P) were 9% and 17% higher in the NASH group as compared with NAFL, respectively. Contrastingly, Lp(a) concentration was 50% lower in NASH relative to NAFL group. Hepatocyte ballooning, lobular inflammation, and fibrosis on histology were inversely associated with Lp(a) concentration. NAFLD severity has a discordant association with Lp(a) and other markers of atherogenic dyslipidemia. This relationship may have implications for prognosticating cardiovascular disease risk in patients with NAFLD. [ABSTRACT FROM AUTHOR]

Despite significant advances and the continuous development of novel, effective therapies to treat a variety of malignancies, cancer therapy-induced cardiotoxicity has been identified as a prominent cause of morbidity and mortality, closely competing with secondary malignancies. This unfortunate limitation has prompted the inception of the field of cardio-oncology with its purpose to provide the necessary knowledge and key information on mechanisms that support the use of the most efficacious cancer therapy with minimal or no interruption while paying close attention to preventing cardiovascular related morbidity and mortality. Several mechanisms that contribute to cancer therapy-induced cardiotoxicity have been proposed and studied. These mainly involve mitochondrial dysfunction and reactive oxygen species-induced oxidative stress, lysosomal damage, impaired autophagy, cell senescence, DNA damage, and sterile inflammation with the formation and activation of the NLRP3 inflammasome. In this review, we focus on describing the principal mechanisms for different classes of cancer therapies that lead to cardiotoxicity involving the NLRP3 inflammasome. We also summarize current evidence of cardio-protection with inflammasome inhibitors in the context of heart disease in general, and further highlight the potential application of this evidence for clinical translation in at risk patients for the purpose of preventing cancer therapy associated cardiovascular morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background In the heart, slow delayed rectifier channels provide outward currents (I Ks) for action potential (AP) repolarization in a region- and context-dependent manner. In diseased hearts, chronic elevation of angiotensin II (Ang II) may remodel I Ks in a region-dependent manner, contributing to atrial and ventricular arrhythmias of different mechanisms. Objective The purpose of this study was to study whether/how chronic in vivo Ang II administration remodels I Ks in atrial and ventricular myocytes. Methods We used the guinea pig (GP) model whose myocytes express robust I Ks. GPs were implanted with minipumps containing Ang II or vehicle. Treatment continued for 4–6 weeks. We used patch clamp, immunofluorescence/confocal microscopy, and immunoblots to evaluate changes in I Ks function and to explore the underlying mechanisms. Results We confirmed the pathologic state of the heart after chronic Ang II treatment. I Ks density was increased in atrial myocytes but decreased in ventricular myocytes in Ang II- vs vehicle-treated animals. The former was correlated with an increase in KCNQ1/KCNE1 colocalization in myocyte periphery, whereas the latter was correlated with a decrease in KCNQ1 protein level. Interestingly, these changes in I Ks were not translated into expected alterations in AP duration or plateau voltage, indicating that other currents were involved. In atrial myocytes from Ang II–treated animals, the L-type Ca channel current was increased, contributing to AP plateau elevation and AP duration prolongation. Conclusion I Ks is differentially modulated by chronic in vivo Ang II administration between atrial and ventricular myocytes. Other currents remodeled by Ang II treatment also contribute to changes in action potentials. [ABSTRACT FROM AUTHOR]

The hormone relaxin has long been recognized for its involvement in maternal adaptation during pregnancy. However, discoveries during the past two decades on the mechanism of action of relaxin, its family of receptors, and newly described roles in attenuating ischemia/reperfusion (I/R) injury, inflammation, and arrhythmias have prompted vast interest in exploring its therapeutic potential in cardiovascular disease. These observations inspired recently concluded clinical trials in patients with acute heart failure. This review discusses our current understanding of the protective signaling pathways elicited by relaxin in the heart, and highlights important new breakthroughs about relaxin signaling that may pave the way to more carefully designed future trials. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is common in patients with heart failure with preserved ejection fraction (HFpEF). While PH-HFpEF may affect more than a million patients in the United States alone, it has been difficult to study its epidemiology and response to treatment due to difficulty in properly defining the illness. While chronic remodeling of the pulmonary vasculature is related to chronic passive congestion of the pulmonary circulation from the pulmonary veins, there are likely other contributors to the development of PH-HFpEF. We explore the potential direct contributions of obesity, diabetes mellitus, genetics, and sleep apnea on the pulmonary circulation in those with PH-HFpEF, and we discuss the potential role of exercise testing or fluid challenge during diagnostic testing. [ABSTRACT FROM AUTHOR]

Thermogenic fat differentiation and function can be promoted through multiple pathways, resulting in a common cell phenotype characterized by the expression of Uncoupling Protein-1 and the ability to dissipate energy, but local and systemic stimuli are necessary to promote adequate thermogenic fat vascularization, which is a precondition for the transport of substrate and the dissipation of heat. Angiopoietin-2 is an important driver of vascularization, and its transcription is in part promoted by estrogen signaling. In this study we demonstrate that adipose tissue-specific knock out of Angiopoietin-2 causes a female-specific reduced thermogenic fat differentiation and function, resulting in obesity and impaired glucose tolerance with end-organ features consistent with metabolic syndrome. In humans, angiopoietin-2 levels are higher in females than in males, and are inversely correlated with adiposity and age more strongly in pre-menopause when compared to post-menopause. Collectively, these data indicate a novel and important role for estrogen-mediated Angiopoietin-2 adipose tissue production in the protection against calorie overload in females, and potentially in the development of postmenopausal weight gain. • Angiogenesis plays a permissive role in inducible thermogenic fat function. • Estrogen-driven adipose tissue angiogenesis controls metabolism in mice and humans. • Adipose tissue Angiopoietin-2 deletion is a novel model of female-specific obesity. • In humans, the interaction between ANG2 levels, age, and adiposity is sex-specific. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H 2 S) has been long recognized as a highly poisonous gas that is rapidly lethal in intoxicating dosage. However, discoveries during the last decade on the endogenous synthesis of H 2 S in the mammalian system and its protective role in combating cellular necrosis, apoptosis, oxidative stress, inflammation as well as promoting angiogenesis and modulation of mitochondrial respiration in the setting of myocardial ischemia and reperfusion injury have prompted vast interest in the possibility of developing new therapies based around mimicry or facilitation of endogenous H 2 S for cardioprotection. These observations have inspired rapid development of H 2 S-releasing drugs in hopes of swift clinical translation in patients with cardiovascular disease. This review will discuss our current understanding of the protective signaling pathways elicited by H 2 S in the heart with an emphasis on the versatile benefits of this gasotransmitter and its potential for clinical translation in patients with cardiovascular disease. [ABSTRACT FROM AUTHOR]

Cyclic guanosine monophosphate (cGMP) is an important intracellular second messenger that mediates multiple tissue and cellular responses. The cGMP pathway is a key element in the pathophysiology of the heart and its modulation by drugs such as phosphodiesterase (PDE)-5 inhibitors and guanylate cyclase activators may represent a promising therapeutic approach for acute myocardial infarction, cardiac hypertrophy, heart failure, and doxorubicin cardiotoxicity in patients. In addition, PDE-5 inhibitors may prove to be innovative therapeutic agents for enhancing the chemosensitivity of doxorubicin while providing concurrent cardiac benefit. [ABSTRACT FROM AUTHOR]

Abstract: Ischemia/reperfusion (I/R) unleashes cellular events that threaten organ survival. I/R affects endoplasmic reticulum (ER) integrity and initiates the unfolded protein response (UPR). The adaptive arm of the UPR attenuates ER stress by increasing expression of chaperones promoting proper protein folding. However, failure to resolve ER stress leads to apoptotis. We recently showed that prolyl hydroxylase inhibition (PHI) attenuated post-ischemic cardiac injury. We hypothesized that PHI attenuated myocardial I/R injury through modulation of the UPR. We show for the first time that PHI activates all three regulatory arms of the UPR in murine microvascular endothelial cells and in mouse hearts. Cardiac I/R activated expression of pro-apoptotic CHOP (2.8 fold, n =3, p <0.01). PHI significantly decreased CHOP expression (50%, n =3, p <0.05) in post-ischemic hearts. PHI also induced activating transcription factor 4 (3.5 fold, n =3, p <0.001), glucose-regulated protein 78 (6 fold, n =3, p <0.001) and ER degradation-enhancing α-mannosidase-like protein (2.8 fold, n =3, p <0.001) expression in reperfusing hearts. Thus PHI resulted in significant reduction of apoptosis in post-ischemic myocardium. Our studies suggest that PHI induces protective ER stress proteins and attenuates post-ischemic myocardial damage by decreasing the pro-apoptotic components of the UPR. [Copyright &y& Elsevier]

Abstract: The phosphodiesterase type-5 (PDE5) inhibitor, sildenafil, is the first drug developed for treatment of erectile dysfunction in patients. Experimental data in animals show that sildenafil has a preconditioning-like cardioprotective effect against ischemia/reperfusion injury in the intact heart. Mechanistic studies suggest that sildenafil exerts cardioprotection through NO generated from eNOS/iNOS, activation of protein kinase C/ERK signaling and opening of mitochondrial ATP-sensitive potassium channels. Additional studies show that the drug attenuates cell death resulting from necrosis and apoptosis, and increases the Bcl2/Bax ratio through NO signaling in adult cardiomyocytes. Emerging new data also suggest that sildenafil may be used clinically for treatment of pulmonary arterial hypertension and endothelial dysfunction. Future demonstration of the cardioprotective effect in patients with the relatively safe and effective FDA-approved PDE5 inhibitors such as sildenafil could have an enormous impact on bringing the long-studied phenomenon of ischemic and pharmacologic preconditioning to the clinical forefront. [Copyright &y& Elsevier]

Background: In the heart, slow delayed rectifier channels provide outward currents (IKs) for action potential (AP) repolarization in a region- and context-dependent manner. In diseased hearts, chronic elevation of angiotensin II (Ang II) may remodel IKs in a region-dependent manner, contributing to atrial and ventricular arrhythmias of different mechanisms.Objective: The purpose of this study was to study whether/how chronic in vivo Ang II administration remodels IKs in atrial and ventricular myocytes.Methods: We used the guinea pig (GP) model whose myocytes express robust IKs. GPs were implanted with minipumps containing Ang II or vehicle. Treatment continued for 4-6 weeks. We used patch clamp, immunofluorescence/confocal microscopy, and immunoblots to evaluate changes in IKs function and to explore the underlying mechanisms.Results: We confirmed the pathologic state of the heart after chronic Ang II treatment. IKs density was increased in atrial myocytes but decreased in ventricular myocytes in Ang II- vs vehicle-treated animals. The former was correlated with an increase in KCNQ1/KCNE1 colocalization in myocyte periphery, whereas the latter was correlated with a decrease in KCNQ1 protein level. Interestingly, these changes in IKs were not translated into expected alterations in AP duration or plateau voltage, indicating that other currents were involved. In atrial myocytes from Ang II-treated animals, the L-type Ca channel current was increased, contributing to AP plateau elevation and AP duration prolongation.Conclusion: IKs is differentially modulated by chronic in vivo Ang II administration between atrial and ventricular myocytes. Other currents remodeled by Ang II treatment also contribute to changes in action potentials. [ABSTRACT FROM AUTHOR]

The phosphodiesterase 5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), and tadalafil (Cialis™) have been developed for treatment of erectile dysfunction. Moreover, sildenafil and tadalafil are used for the management of pulmonary arterial hypertension in patients. Since our first report showing the cardioprotective effect of sildenafil in 2002, there has been tremendous growth of preclinical and clinical studies on the use of PDE5 inhibitors for cardiovascular diseases and cancer. Numerous animal studies have demonstrated that PDE5 inhibitors have powerful protective effect against myocardial ischemia/reperfusion (I/R) injury, doxorubicin cardiotoxicity, ischemic and diabetic cardiomyopathy, cardiac hypertrophy, Duchenne muscular dystrophy and the improvement of stem cell efficacy for myocardial repair. Mechanistically, PDE5 inhibitors protect the heart against I/R injury through increased expression of nitric oxide synthases, activation of protein kinase G (PKG), PKG-dependent hydrogen sulfide generation, and phosphorylation of glycogen synthase kinase-3β — a master switch immediately proximal to mitochondrial permeability transition pore and the end effector of cardioprotection. In addition, PDE5 inhibitors enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs, including doxorubicin. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular and anti-cancer benefits. Despite mixed results of these clinical trials, there is a continuing strong interest by basic scientists and clinical investigators in exploring their new clinical uses. It is our hope that future new mechanistic investigations and carefully designed clinical trials would help in reaping additional benefits of PDE5 inhibitors for cardiovascular disease and cancer in patients. [ABSTRACT FROM AUTHOR]

Abstract: Diabetic patients exhibit increased risk for the development of cardiovascular diseases primarily because of impaired nitric oxide (NO) bioavailability. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil restores NO signaling and protects against ischemia/reperfusion (I/R) injury. In this study, we determined the effect of the long-acting PDE-5 inhibitor tadalafil on diabetes-associated complications and its role in attenuating oxidative stress after I/R injury in type 2 diabetic db/db mice. Adult male db/db mice (n=40/group) were randomized to receive dimethyl sulfoxide (10% DMSO, 0.2ml, ip) or tadalafil (1mg/kg in 10% DMSO, ip) for 28 days. After 28 days treatment, the hearts were isolated and subjected to 30min global ischemia followed by 60min reperfusion in the Langendorff mode. Infarct size was measured using computer morphometry of tetrazolium-stained sections. Cardiomyocytes were isolated from a subset of hearts and subjected to 40min simulated ischemia followed by 1h of reoxygenation (SI/RO). Dichlorodihydrofluorescein diacetate and JC-1 staining was used to measure reactive oxygen species (ROS) generation and mitochondrial membrane potential (Δψm), respectively. Another subset of hearts was used for the estimation of lipid peroxidation, glutathione, and the expression of myocardial pRac1, Rac1, gp91phox, p47phox, and p67phox by Western blot. Tadalafil treatment improved the metabolic status and reduced infarct size compared to the untreated db/db mice (21.2±1.8% vs 45.8±2.8%; p<0.01). The db/db mice showed enhanced oxidative stress in cardiomyocytes as indicated by a significant increase in ROS production. Cardiac NAD(P)H oxidase activity, lipid peroxidation, and oxidized glutathione were also increased in db/db mice compared to nondiabetic control animals. Tadalafil treatment in db/db mice suppressed oxidative stress, attenuated myocardial expression of pRac1 and gp91phox, and also preserved the loss of Δψm in cardiomyocytes after SI/RO. In conclusion, these results demonstrate that chronic treatment with tadalafil attenuates oxidative stress and improves mitochondrial integrity while providing powerful cardioprotective effects in type 2 diabetes. [Copyright &y& Elsevier]

Background: Sacubitril/valsartan (SAC/VAL) is approved by the U.S. Food and Drug Administration for heart failure with reduced ejection fraction (HFrEF).Objectives: This study investigated the effects of SAC/VAL on acute myocardial infarction (MI) and cardiac remodeling in a translational rabbit model of MI.Methods: New Zealand White rabbits were sedated and underwent conscious MI (45-min ischemia) by balloon inflation (previously implanted surgically) followed by 72 h (acute protocol) or 10 weeks (chronic protocols) of reperfusion. "Infarct-sparing" protocol: SAC/VAL, VAL, or placebo were randomly allocated and administered at reperfusion. "HFrEF-treatment" protocol: rabbits were randomized, and treatment commenced after echocardiography-confirmed left ventricular ejection fraction (LVEF) ≤40%. "HFrEF-prevention" protocol: treatment started at reperfusion and continued daily throughout the study.Results: Compared with placebo, SAC/VAL and VAL significantly reduced infarct size (TTC staining) and plasma troponin levels; however, only SAC/VAL preserved LVEF at 72 h post-MI. In the HFrEF-treatment protocol, LVEF improvement was observed with SAC/VAL compared with both placebo and VAL starting 2 weeks post-treatment, a benefit that persisted throughout study duration. In the HFrEF-prevention protocol, SAC/VAL and VAL attenuated the decline in LVEF post-MI, although SAC/VAL offered better functional protection. The functional improvement observed in both treatment protocols was paralleled by significant reduction in left ventricular (LV) scar size (Picrosirius red staining) in the SAC/VAL groups.Conclusions: Reperfusion therapy with SAC/VAL or VAL offers robust acute infarct-sparing benefits; however, SAC/VAL treatment offered superior short-term and long-term benefits in preventing MI-induced LV dysfunction compared with VAL. SAC/VAL also significantly attenuated LV scar size following MI compared with placebo, whereas VAL did not reach statistical significance in scar reduction. [ABSTRACT FROM AUTHOR]

Background Successful reperfusion is the most effective strategy to reduce ischemic injury in acute myocardial infarction (AMI). Ischemic injury, however, also triggers a secondary ischemia–independent injury, known as reperfusion injury, contributing to the overall infarct size. We hypothesize that inhibition of the Nod-like Receptor Protein-3 (NLRP3) inflammasome limits infarct size following myocardial ischemia/reperfusion (I/R), by inhibiting the inflammatory component of the reperfusion injury. Methods CD-1 male mice underwent transient ligation of the left anterior descending coronary artery for 30 or 75 min followed by reperfusion. Infarct size was measured at 1, 3 and 24 h. A NLRP3 inflammasome inhibitor (NLRP3inh) or vehicle was administrated immediately at time of reperfusion or with a delay of 1 or 3 h of reperfusion. Results A time-dependent increase in infarct size was measured at 1, 3, and 24 h after reperfusion (11 ± 2%, 30 ± 5% and 43 ± 4% of the area at risk respectively; P < 0.001 for trend). NLRP3 myocardial expression was significantly increased at 24 h and 6 h vs 3 h (P < 0.01). Administration of the NLRP3inh at reperfusion did not reduce infarct size at 3 h, while it significantly reduced infarct size at 24 h (− 56% vs vehicle, P < 0.01). The NLRP3inh given 1 h after reperfusion also significantly decreased caspase-1 activity and infarct size measured at 24 h, whereas the NLRP3inh did not when given with a delay of 3 h. Conclusions Pharmacological inhibition of the NLRP3 inflammasome within 1 h of reperfusion limits the secondary inflammatory injury and infarct size following myocardial ischemia–reperfusion in the mouse. [ABSTRACT FROM AUTHOR]

Elevated mammalian target of rapamycin (mTOR) signaling contributes to the pathogenesis of diabetes, with increased morbidity and mortality, mainly because of cardiovascular complications. Because mTOR inhibition with rapamycin protects against ischemia/reperfusion injury, we hypothesized that rapamycin would prevent cardiac dysfunction associated with type 2 diabetes (T2D). We also investigated the possible mechanisms and novel protein targets involved in rapamycin-induced preservation of cardiac function in T2D mice. Adult male leptin receptor null, homozygous db/db, or wild type mice were treated daily for 28 days with vehicle (5% DMSO) or rapamycin (0.25 mg/kg, intraperitoneally). Cardiac function was monitored by echocardiography, and protein targets were identified by proteomics analysis. Rapamycin treatment significantly reduced body weight, heart weight, plasma glucose, triglyceride, and insulin levels in db/db mice. Fractional shortening was improved by rapamycin treatment in db/db mice. Oxidative stress as measured by glutathione levels and lipid peroxidation was significantly reduced in rapamycin-treated db/db hearts. Rapamycin blocked the enhanced phosphorylation of mTOR and S6, but not AKT in db/db hearts. Proteomic (by two-dimensional gel and mass spectrometry) and Western blot analyses identified significant changes in several cytoskeletal/contractile proteins (myosin light chain MLY2, myosin heavy chain 6, myosin-binding protein C), glucose metabolism proteins (pyruvate dehydrogenase E1, PYGB, Pgm2), and antioxidant proteins (peroxiredoxin 5, ferritin heavy chain 1) following rapamycin treatment in db/db heart. These results show that chronic rapamycin treatment prevents cardiac dysfunction in T2D mice, possibly through attenuation of oxidative stress and alteration of antioxidants and contractile as well as glucose metabolic protein expression. [ABSTRACT FROM AUTHOR]

Expression of the STAT3 transcription factor in the heart is cardioprotective and decreases the levels of reactive oxygen species. Recent studies indicate that a pool of STAT3 resides in the mitochondria where it is necessary for the maximal activity of complexes I and II of the electron transport chain. However, it has not been explored whether mitochondrial STAT3 modulates cardiac function under conditions of stress. Transgenic mice with cardiomyocyte-specific overexpression of mitochondria-targeted STAT3 with a mutation in the DNA-binding domain (MLS-STAT3E) were generated. We evaluated the role of mitochondrial STAT3 in the preservation of mitochondrial function during ischemia. Under conditions of ischemia heart mitochondria expressing MLS-STAT3E exhibited modest decreases in basal activities of complexes I and II of the electron transport chain. In contrast to WT hearts, complex I-dependent respiratory rates were protected against ischemic damage in MLS-STAT3E hearts. MLS-STAT3E prevented the release of cytochrome c into the cytosol during ischemia. In contrast to WT mitochondria, ischemia did not augment reactive oxygen species production in MLS-STAT3E mitochondria likely due to an MLS-STAT3E-mediated partial blockade of electron transport through complex I. Given the caveat of STAT3 overexpression, these results suggest a novel protective mechanism mediated by mitochondrial STAT3 that is independent of its canonical activity as a nuclear transcription factor. [ABSTRACT FROM AUTHOR]

Acute myocarditis is an acute inflammatory syndrome characterized by acute myocardial damage and dysfunction followed by a variable recovery over time with some patients progressing toward severe dilated cardiomyopathy. Cardiomyocyte apoptosis, a key pathologic feature of heart failure, may play a critical role in functional recovery in patients with acute myocarditis. The aim of the study was to investigate whether apoptosis predicts functional recovery in patients with acute myocarditis. Sixteen patients with biopsy-documented acute myocarditis were followed for 1 year with serial transthoracic echocardiography. Functional recovery was defined as 12-month left ventricular ejection fraction >40%. Cardiomyocyte apoptosis, leukocyte infiltration, and cell proliferation was assessed in all samples. A group of cases in which the diagnosis of acute myocarditis was made after death was also selected for comparison, and morphologically normal hearts from patients who died from a noncardiac cause were selected as controls. Six patients (38%) had functional recovery at 12 months, whereas 10 (62%) did not. The 2 groups had similar characteristics except for lower baseline left ventricular ejection fraction in the group with functional recovery. Apoptotic rate was found to be significantly higher in patients with acute myocarditis than in control hearts, and, unexpectedly, patients with functional recovery had significantly higher apoptotic rates than patients without recovery (3.2% vs 0.5%, p = 0.001). None of the patients with apoptotic rates below the median had functional recovery versus 86% of patients with apoptotic rates above the median (p <0.001). In conclusion, higher rates of cardiomyocyte apoptosis in patients with acute myocarditis are associated with functional recovery at 1 year. [Copyright &y& Elsevier]

Cardiac remodeling after acute myocardial infarction (AMI) is characterized by molecular and cellular mechanisms involving both the left (LV) and right ventricular (RV) walls. Cardiomyoycte apoptosis in the peri-infarct and remote LV myocardium has a central role in cardiac remodeling. Whether apoptosis also occurs in the right ventricle of patients with ischemic heart disease has not been investigated. The aim of the present study was to investigate the presence of cardiomyocyte apoptosis in the right ventricle in patients with AMI. We assessed the number of apoptotic cardiomyocytes using multiple samplings in the LV and RV walls of 12 patients selected at autopsy who died 4 to 42 days after AMI. Five patients without cardiac disease were also selected at autopsy as controls. Apoptotic rates were calculated from the number of cardiomyocytes showing double positive staining for in situ end-labeling of DNA fragmentation (TUNEL) and for activated caspase-3. Potentially false-positive results (DNA synthesis and RNA splicing) were excluded from cell counts. The apoptotic rate in the right ventricle in patients with AMI was significantly higher than in control hearts (median 0.8%, interquartile range 0.3 to 1.0 vs median 0.01%, interquartile range 0.01 to 0.03, p <0.001). RV apoptosis significantly correlated with such parameters of global adverse remodeling as cardiac diameter to LV free wall thickness (R = +0.57, p = 0.050). RV apoptosis was significantly higher in five cases (42%) with infarct involving the ventricular septum and an adjacent small area of the RV walls (median 1.0%, interquartile range 0.8 to 2.2 vs median 0.5%, interquartile range 0.2 to 1.0, p = 0.048, p <0.001 vs controls). The association between apoptotic rate in the right ventricle and cardiac remodeling was apparent even after exclusion of cases with RV AMI involvement (R = +0.82, p = 0.023 for diameter to LV wall thickness ratio and R = −0.91, p = 0.002 for RV free wall thickness). In conclusion, patients with cardiac remodeling after AMI had a significant increase in RV apoptosis even when ischemic involvement of the RV wall was not apparent. [Copyright &y& Elsevier]

Objectives: The aim of the study was to analyze the molecular mechanisms activated during postinfarction remodeling in human hearts. Background: The molecular mechanisms of initial response to ischemic insult in the heart and the pathways involved in compensation and remodeling are still largely unknown. Methods: Up-regulation or down-regulation of gene expression in the human viable peri-infarct (vs. remote) myocardial region was investigated by complementary deoxyribonucleic acid array technology and confirmed at a single-gene/protein level with reverse transcriptase polymerase chain reaction and immunohistochemistry. An in vitro model of cardiomyocyte hypoxia in HL1 cells was used to validate anti-apoptotic effects of the candidate gene/protein and to assess the associated downstream cascade. Finally, a mouse model of myocardial infarction was used to test the in vivo effects of exogenous transfection with the candidate gene/protein. Results: Protein disulfide isomerase (PDI), a member of the unfolded protein response, is 3-fold up-regulated in the viable peri-infarct myocardial region, and in a postmortem model, its expression is significantly inversely correlated with apoptotic rate and with presence of heart failure (HF) and biventricular dilatation. Induced PDI expression in HL1 cells conferred protection from hypoxia-induced apoptosis. Adenoviral-mediated PDI gene transfer to the mouse heart resulted in 2.5-fold smaller infarct size, significantly reduced cardiomyocyte apoptosis in the peri-infarct region, and smaller left ventricular end-diastolic diameter versus mice treated with a transgene-null adenoviral vector. Conclusions: These results suggest that PDI promotes survival after ischemic damage and that zinc-superoxide dismutase is one of the PDI molecular targets. Pharmacological modulation of this pathway might prove useful for future prevention and treatment of HF. [Copyright &y& Elsevier]

Acute myocardial infarction (AMI) initiates an intense inflammatory response in which interleukin-1 (IL-1) plays a central role. The IL-1 receptor antagonist is a naturally occurring antagonist, and anakinra is the recombinant form used to treat inflammatory diseases. The aim of the present pilot study was to test the safety and effects of IL-1 blockade with anakinra on left ventricular (LV) remodeling after AMI. Ten patients with ST-segment elevation AMI were randomized to either anakinra 100 mg/day subcutaneously for 14 days or placebo in a double-blind fashion. Two cardiac magnetic resonance (CMR) imaging and echocardiographic studies were performed during a 10- to 14-week period. The primary end point was the difference in the interval change in the LV end-systolic volume index (LVESVi) between the 2 groups on CMR imaging. The secondary end points included differences in the interval changes in the LV end-diastolic volume index, and C-reactive protein levels. A +2.0 ml/m2 median increase (interquartile range +1.0, +11.5) in the LVESVi on CMR imaging was seen in the placebo group and a −3.2 ml/m2 median decrease (interquartile range −4.5, −1.6) was seen in the anakinra group (p = 0.033). The median difference was 5.2 ml/m2. On echocardiography, the median difference in the LVESVi change was 13.4 ml/m2 (p = 0.006). Similar differences were observed in the LV end-diastolic volume index on CMR imaging (7.6 ml/m2, p = 0.033) and echocardiography (9.4 ml/m2, p = 0.008). The change in C-reactive protein levels between admission and 72 hours after admission correlated with the change in the LVESVi (R = +0.71, p = 0.022). In conclusion, in the present pilot study of patients with ST-segment elevation AMI, IL-1 blockade with anakinra was safe and favorably affected by LV remodeling. If confirmed in larger trials, IL-1 blockade might represent a novel therapeutic strategy to prevent heart failure after AMI. [Copyright &y& Elsevier]