Pathophysiology Of Heart Disease Research Articles

Potential Role of Novel Cardiovascular Biomarkers in Pediatric Patients with Chronic Kidney Disease.

Cardiovascular Disease is the leading cause of death in adult and pediatric patients with Chronic Kidney Disease (CKD) and its pathogenesis involves the interaction of multiple pathways. As Inflammatory mechanisms play a critical role in the vascular disease of CKD pediatric patients, there are several biomarkers related to inflammation strongly associated with this comorbidity. This review provides available evidence on the link between several biomarkers and the pathophysiology of heart disease in patients with CKD. The data were obtained independently by the authors, who carried out a comprehensive and non-systematic search in PubMed, Cochrane, Scopus, and SciELO databases. The search terms were "Chronic Kidney Disease", "Cardiovascular Disease", "Pediatrics", "Pathophysiology", "Mineral and Bone Disorder (MBD)", "Renin Angiotensin System (RAS)", "Biomarkers", "BNP", "NTproBNP", "CK-MB", "CXCL6", "CXCL16", "Endocan-1 (ESM-1)", "FABP3", "FABP4", h-FABP", "Oncostatin- M (OSM)", "Placental Growth Factor (PlGF)" and "Troponin I". The pathogenesis of CKD-mediated cardiovascular disease is linked to inflammatory biomarkers, which play a critical role in the initiation, maintenance, and progression of cardiovascular disease. There are several biomarkers associated with cardiovascular disease in pediatric patients, including BNP, NTproBNP, CK-MB, CXCL6, CXCL16, Endocan-1 (ESM-1), FABP3, FABP4, Oncostatin- M (OSM), Placental Growth Factor (PlGF), and Troponin I. The pathogenesis of CKD-mediated cardiovascular disease is not completely understood, but it is linked to inflammatory biomarkers. Further studies are required to elucidate the pathophysiological and potential role of these novel biomarkers.

Abstract P2005: Mechanosensitive Piezo-1 Channel Aggravates Ischemia Induced Adverse Cardiac Remodeling And Dysfunction

Background: Mechanotransduction is a physiological process through which mechanical forces are sensed and converted to biological responses. It is fundamental for morphogenesis during early development and organ functions during adult life. An injured heart undergoes dynamic phases of structural and functional remodeling, exposing cardiac cells to the fluctuating mechanical environment. Piezo-1 (PZO1) is a recently discovered mechanosensitive ion channel with widespread physiological importance. However, its role in the pathophysiology of heart disease is not fully understood. Methods and Results: The qPCR analysis confirmed that PZO-1 expression increases in cardiomyocytes (CM) post-MI. To evaluate the role of CM-PZO1 in MI-induced adverse cardiac remodeling, conditional CM-specific PZO1 KO mice were generated using tamoxifen-inducible α-MHC promoter driven MerCreMer transgene. At 12 weeks of age, mice were subjected to a well-established tamoxifen diet protocol followed by MI surgery. Cardiac function was monitored by serial echocardiography. In the control group, EF and FS declined from 2 weeks post-MI, indicating systolic dysfunction. These changes were associated with the development of structural remodeling as reflected by a significant increase in LVIDs, HW/TL ratio, CM CSA, and hypertrophy markers (ANP, BNP). Interestingly, all these parameters were essentially normalized in CM-PZO1 KO mice, confirming that CM-specific PZO1 deletion prevents the progression of pathological hypertrophy and systolic dysfunction in MI heart. Moreover, CM-PZO1 KO displayed significant alterations in gene expression of ECM proteins such as connective tissue growth factor (CTGF), latent TGF-β binding protein 2 (LTBP2), cartilage oligomeric matrix protein (COMP), cartilage intermediate layer protein (CILP) while collagen and fibronectin levels were comparable between control and KO groups. These observations indicate a potential role of CM-PZO1 in modulating cardiac ECM and scar properties under pathological conditions. Conclusion: Our findings suggest that PZO1 serves as a key cardiac mechanotransducer under pathological condition and represent a novel therapeutic target for treating heart diseases.

The therapeutic potential of targeting cardiac RGS4.

G protein-coupled receptors (GPCRs) play pivotal roles in regulation of cardiac function and homeostasis. To function properly, every cell needs these receptors to be stimulated only when a specific extracellular stimulus is present, and to be silenced the moment that stimulus is removed. The regulator of G protein signaling (RGS) proteins are crucial for the latter to occur at the cell membrane, where the GPCR normally resides. Perturbations in both activation and termination of G protein signaling underlie numerous heart pathologies. Although more than 30 mammalian RGS proteins have been identified, each RGS protein seems to interact only with a specific set of G protein subunits and GPCR types/subtypes in any given tissue or cell type, and this applies to the myocardium as well. A large number of studies have provided substantial evidence for the roles various RGS proteins expressed in cardiomyocytes play in cardiac physiology and heart disease pathophysiology. This review summarizes the current understanding of the functional roles of cardiac RGS proteins and their implications for the treatment of specific heart diseases, such as heart failure and atrial fibrillation. We focus on cardiac RGS4 in particular, since this isoform appears to be selectively (among the RGS protein family) upregulated in human heart failure and is also the target of ongoing drug discovery efforts for the treatment of a variety of diseases.

Study the association of microRNA polymorphisms (miR-146a, miR-4513) with the risk of coronary heart diseases in Egyptian population.

Coronary heart disease (CHD) is the most prevalent cause of cardiovascular mortality in the world. It is well established that microRNAs (miRNAs) and their variants have an essential role in regulating the development of cardiovascular physiology, thus impacting the pathophysiology of heart diseases. This study was designed to determine the possible association of miRNA polymorphisms (miRNA-146a rs2910164C/G and miR-4513 rs2168518G/A) with susceptibility to CHD in Egyptian patients and their correlation with different biochemical parameters. The study comprised 300 participants, including 200 unrelated patients with CHD and 100 healthy controls. Anthropometric and blood biochemical parameters were measured as well genetic analysis for rs2910164C/G and rs2168518G/A polymorphisms were performed for all subjects using TaqMan real-time PCR assay. Our results revealed that the biomedical parameters have a significant correlation between CHD patients and healthy controls with a p < 0.05. Analyses of genotype distribution for (rs2910164 and rs2168518) revealed a significant association with CHD [odd ratio = 4.54, confidence interval (CI 95%) = (2.41-8.53)] and [odd ratio = 0.88, (CI 95%) = (0.83-0.92)], respectively. Furthermore, a statistically significant difference was detected between lipid profile levels and both rs2910164 and rs2168518 polymorphisms. The present study's findings indicated that the selected polymorphisms, miR-146a rs2910164 and miR-4513 rs2168518 could represent a useful biomarker for susceptibility to CHD in the Egyptian population. These genetic characteristics and personal habits and environmental factors may contribute to the development of CHD.

COLOCALIZATION AND REMODELING OF HEART- AND LUNG-PROJECTING STELLATE GANGLION NEURONS IN BLEOMYCIN-INDUCED PULMONARY FIBROSIS

COLOCALIZATION AND REMODELING OF HEART- AND LUNG-PROJECTING STELLATE GANGLION NEURONS IN BLEOMYCIN-INDUCED PULMONARY FIBROSIS

The feasibility and safety of a simple method for coronary sinus blood sampling during catheter ablation of arrhythmias.

BackgroundCoronary sinus (CS) blood sampling gives an insight into the localized pathophysiology of heart diseases. However, additional specifically-designed or modified catheters were needed in most previous studies, making the convenience of clinical application unsatisfactory. This study aimed to introduce a simple method for CS blood sampling without using additional catheters during catheter ablation (CA) of arrhythmias, and to investigate its feasibility and safety.MethodsA total of 119 patients undergoing CA were prospectively enrolled, including 25 with paroxysmal supraventricular tachycardia (PSVT), 30 with premature ventricular complexes (PVC), and 64 with atrial fibrillation (AF). Cannulation and sampling of CS was performed via the femoral vein using a conventional 8F SR0TM or 8.5F SL1TM introducer sheath (St. Jude Medical) guided by a 6F steerable diagnostic catheter (St. Jude Medical). The success rate and any suspicious complications were recorded. Untargeted liquid chromatograph-mass spectrometer (LC-MS)-based metabonomics of CS samples versus peripheral venous samples were also performed.ResultsCS blood samples were successfully collected from 114 patients, with an overall success rate of 95.8%. Among patients with different arrhythmias, the success rates were similar, with 96.0% in PSVT, 96.7% in PVC, and 95.3% in AF (P=0.223). Adverse events occurred in four (3.4%) patients, including two patients with occasional atrial ectopic beats without causing any discomfort, and two patients with new-onset paroxysmal AF lasting for about 2 min. No serious complications were noted. Metabonomics analysis showed that CS samples provided a number of different metabolites (93 in PVST, 217 in PVC, and 109 in AF) versus peripheral samples.ConclusionsOur method for CS blood sampling during CA is feasible and safe, and can provide useful cardiometabolic information that is significantly different from a peripheral sample.

Anesthetic Management in Adults with Congenital Heart Disease.

Adults with congenital heart disease (ACHD) are a complex and growing population that presents numerous challenges for anesthetic management. This review summarizes special considerations for anesthetic management in ACHD. The adult patient with congenital heart disease may require anesthetic care for multiple surgeries and interventions throughout their lifetime. The cardiac and extracardiac manifestations of ACHD have important perioperative implications that affect anesthetic management. Recent American Heart Association/American College of Cardiology and European Society of Cardiology guidelines endorse a multidisciplinary, team-based approach to care. The cardiac anesthesiologist, endorsed as part of this multidisciplinary team, must have a thorough understanding of congenital heart disease pathophysiology and common extra-cardiac manifestations of ACHD. Safe anesthetic management in adult congenital heart disease should incorporate a multi-disciplinary approach to patient care. Anesthesiologists and centers with special expertise in ACHD care should be utilized or consulted whenever possible.

Modified Algorithm Using Total Count for Calculating Myocardial Washout Rate in Single-Photon Emission Computerized Tomography.

Background: The arithmetic mean of washout rate (WR) (namely, AMWR) of each segment is a commonly used algorithm for calculating WR from a polar map in single-photon emission computerized tomography (SPECT). However, in this algorithm, uneven radiotracer uptake among segments affects WR calculation. To solve this possible issue, we formulated a modified algorithm for calculating WR based on the total count (namely, TCWR). Methods: The WR of iodine-123-β-methyl-p-iodophenylpentadecanoic acid (BMIPP) was calculated using TCWR and AMWR, and WR values using TCWR and AMWR were compared by disease. Participants included those without cardiovascular diseases (normal), those with CD36 deficiency, triglyceride deposit cardiomyovasculopathy (TGCV), TGCV with old myocardial infarction (OMI), and non-TGCV with OMI. Results: WR values using TCWR and AMWR did not differ significantly in the following groups: normal, 27.4±8.5 and 27.3±8.5% (p=0.97); CD36 deficiency, -3.2±6.5 and -4.1±7.4% (p=0.81); TGCV, 2.4±6.3 and 2.2±6.3% (p=0.93); and TGCV with OMI, -0.9±7.6 and -3.7±8.4% (p=0.32). However, AMWR showed a lower WR than TCWR in non-TGCV with OMI (4.8±8.7 and 18.9±6.7%, p=0.0008). Conclusions: TCWR is suitable for calculating WR using SPECT polar maps even in cases with heterogeneous radiotracer uptake, such as OMIs. TCWR may be applied to measuring the WR of radiopharmaceuticals other than BMIPP in investigating the pathophysiology of heart diseases.

Cardiac Left Ventricle Mitochondrial Dysfunction After Neonatal Exposure to Hyperoxia: Relevance for Cardiomyopathy After Preterm Birth.

Individuals born preterm present left ventricle changes and increased risk of cardiac diseases and heart failure. The pathophysiology of heart disease after preterm birth is incompletely understood. Mitochondria dysfunction is a hallmark of cardiomyopathy resulting in heart failure. We hypothesized that neonatal hyperoxia in rats, a recognized model simulating preterm birth conditions and resulting in oxygen-induced cardiomyopathy, induce left ventricle mitochondrial changes in juvenile rats. We also hypothesized that humanin, a mitochondrial-derived peptide, would be reduced in young adults born preterm. Sprague-Dawley pups were exposed to room air (controls) or 80% O2 at postnatal days 3 to 10 (oxygen-induced cardiomyopathy). We studied left ventricle mitochondrial changes in 4 weeks old males. In a cohort of young adults born preterm (n=55) and age-matched term (n=54), we compared circulating levels of humanin. Compared with controls, oxygen-exposed rats showed smaller left ventricle mitochondria with disrupted integrity on electron microscopy, decreased oxidative phosphorylation, increased glycolysis markers, and reduced mitochondrial biogenesis and abundance. In oxygen-exposed rats, we observed lipid deposits, increased superoxide production (isolated cardiomyocytes), and reduced Nrf2 gene expression. In the cohort, left ventricle ejection fraction and peak global longitudinal strain were similar between groups however humanin levels were lower in preterm and associated with left ventricle ejection fraction and peak global longitudinal strain. In conclusion, neonatal hyperoxia impaired left ventricle mitochondrial structure and function in juvenile animals. Serum humanin level was reduced in preterm adults. This study suggests that preterm birth-related conditions entail left ventricle mitochondrial alterations that may underlie cardiac changes perpetuated into adulthood. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03261609.

Interleukin-1 blockade in cardiac sarcoidosis: study design of the multimodality assessment of granulomas in cardiac sarcoidosis: Anakinra Randomized Trial (MAGiC-ART)

BackgroundSarcoidosis is an inflammatory disease characterized by the formation of granulomas, which involve the heart in up to 25% of patients. Cardiac sarcoidosis can lead to life threatening arrhythmias and heart failure. While corticosteroids have been used as a treatment for over 50 years, they are associated with hypertension, diabetes, and weight gain, further increasing cardiovascular risk. Interleukin-1 (IL-1) is the prototypical proinflammatory cytokine that works to activate the nuclear transcription factor NF-kB, one of the targets of glucocorticoids. IL-1 also plays an important role also in the pathophysiology of heart disease including atherosclerosis, myocardial infarction, and myocarditis.MethodsBuilding on a network of research collaborators developed in the Cardiac Sarcoidosis Consortium, we will investigate the feasibility and tolerability of treatment of CS with anakinra at two National Institute of Health Clinical and Translational Science Award (CTSA) hubs with expertise in cardiac sarcoidosis. In this pilot study, up to 28 patients with cardiac sarcoidosis will be recruited to compare the administration of an IL-1 blocker, anakinra, 100 mg daily on top of standard of care versus standard of care only for 28 days and followed for 180 days. Utilizing surrogate endpoints of changes in systemic inflammatory biomarkers and cardiac imaging, we aim to determine whether IL-1 blockade with anakinra can combat systemic and cardiac inflammation in patients with cardiac sarcoidosis.DiscussionThe current trial demonstrates an innovative collaborative approach to clinical trial development in a rare, understudied disease that disproportionately affects females and minorities.Trial Registration The trial was registered prospectively with ClinicalTrials.gov on July 12, 2019, identifier NCT04017936.

Tenascin-C in Heart Diseases-The Role of Inflammation.

Tenascin-C (TNC) is a large extracellular matrix (ECM) glycoprotein and an original member of the matricellular protein family. TNC is transiently expressed in the heart during embryonic development, but is rarely detected in normal adults; however, its expression is strongly up-regulated with inflammation. Although neither TNC-knockout nor -overexpressing mice show a distinct phenotype, disease models using genetically engineered mice combined with in vitro experiments have revealed multiple significant roles for TNC in responses to injury and myocardial repair, particularly in the regulation of inflammation. In most cases, TNC appears to deteriorate adverse ventricular remodeling by aggravating inflammation/fibrosis. Furthermore, accumulating clinical evidence has shown that high TNC levels predict adverse ventricular remodeling and a poor prognosis in patients with various heart diseases. Since the importance of inflammation has attracted attention in the pathophysiology of heart diseases, this review will focus on the roles of TNC in various types of inflammatory reactions, such as myocardial infarction, hypertensive fibrosis, myocarditis caused by viral infection or autoimmunity, and dilated cardiomyopathy. The utility of TNC as a biomarker for the stratification of myocardial disease conditions and the selection of appropriate therapies will also be discussed from a clinical viewpoint.

Thrombospondin‐1 Plays an Essential Role in Hippo Signaling During the Early Phase of Trypanosoma cruzi Infection in Heart Endothelial Cells

Trypanosoma cruzi is an obligate intracellular hemoflagellate parasite which cause Chagas disease. This neglected tropical disease causes severe morbidity and mortality in endemic regions. 30% of chronically infected people suffer from cardiac disorder. Chagas heart diseasecan lead to sudden death due to cardiac arrhythmias or progressive heart failure. Invasive trypomastigotes released from infected cells can be carried in vascular endothelial system to infect neighboring and distant cells. During the process of cellular infection, the parasite induces host cells to increase the levels of host thrombospondin-1 (TSP-1) to enable the process of infection. TSP-1 plays important roles in the functioning of vascular cells including vascular endothelial cells with important implications in cardiovascular health. Hippo signaling components, including yes-associated protein 1 (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ), which are upstream of TSP-1 have been linked to the pathophysiology of heart disease. The molecular mechanisms by which T. cruzi signals and eventually infect heart endothelial cells remain unknown. To evaluate the importance of TSP-1 expression in heart endothelial cells during the process of T. cruzi infection, we challenge heart endothelial cells prepared from Wild Type and TSP-1 Knockout mouse (MHEC) to invasive T. cruzi trypomastigotes at different time points and evaluated changes in the Hippo signaling cascade using immunoblotting and immunofluorescence assays. We found that the parasite turned off the hippo signaling pathway in TSP-1KO heart endothelial cells. The levels of SAV1 and MOB1A increased to a maximum of 2.70±0.23 and 5.74±1.45 fold at 3 and 6 h, respectively, in TSP-1KO MHEC compared to WT MHEC following parasite challenge. This was accompanied by a significant continuous increase in the nuclear translocation of downstream effector molecule YAP to a maximum mean nuclear fluorescence intensity of 10.14±0.40 at 6 h compared to wild type cells. Besides this, we found that increased nuclear translocated YAP significantly colocalized with the transcription co-activator molecule pan-TEAD with a maximum Pearson's correlation coefficient of 0.51±0.06 at 6 h compared to YAP-Pan-TEAD colocalization in the WT MHEC, which decreased significantly with to a minimum Pearson's correlation coefficient of 0.30±0.01 at 6 h. Our finding suggests that upregulated TSP-1 is essential for the regulation of the hippo signaling pathway during the early phase of infection. These studies advance our understanding of the Host-Parasite molecular interactions occurring between heart endothelial cells and T. cruzi in the presence and absence of TSP-1. Taken together, this further supports our concept that an increase in the level of TSP-1 induced by the parasite is essential for T. cruzi infection and pathogenesis.

S‐acyltransferase zDHHC9 Promotes Pathogenic Signaling in the Heart

Heart disease remains a leading cause of mortality, contributing to over 600,000 deaths per year in the United States. Notwithstanding, the molecular mechanisms underlying the pathophysiology of heart disease remain largely elusive. Receptors, ion channels, and signaling proteins that regulate cardiac contractility and physiology are modified by post-translational modifications such as phosphorylation. Recent research into the roles of S-acylation or palmitoylation, the reversible post-translational modification of proteins with fatty acids, has demonstrated critical functions in the regulation of intracellular signaling in physiology and disease. Palmitoylation, which is catalyzed by the zinc finger Asp-His-His-Cys (zDHHC) family of S-acyltransferases, has been implicated in trafficking, stability, sorting and binding of proteins to cofactors. However, the roles of palmitoylation in cardiac signal transduction and cardiac pathogenesis are not well understood. Our preliminary work indicates that cardiac-specific transgenic overexpression of the Golgi-specific acyl transferase zDHHC9 (TgZdhhc9) results in cardiac hypertrophy and severe cardiomyopathy at six and eight months of age respectively in mice. Furthermore, using unbiased palmitoyl proteomics, we discovered that zDHHC9 palmitoylates Rab3 GTPase-activating protein catalytic subunit (Rab3gap1) that hydrolyzes the active GTP-bound form of Rab3 GTPase protein (Rab3) and inactivates Rab3 function. More so, mice subjected to transverse aortic constriction surgery, a pressure-overload model of pathological cardiac hypertrophy, showed increased palmitoylation of Rab3gap1, compared to sham controls. In addition, we observed that overexpression of zDHHC9 resulted in retention of Rab3gap1 at the Golgi and post-Golgi vesicles in cardiomyocytes and TgZdhhc9 hearts showed increased levels of Rab3a-GTP prior to disease onset, suggesting enhancement of cardiac Rab3a activity. Ongoing research will identify which hypertrophic signaling effectors are modulated by the zDHHC9/ Rab3gap1/Rab3a cascade in the heart. Altogether, these data suggest zDHHC9-mediated palmitoylation of Rab3gap1 may contribute to hypertrophic signaling and heart disease.

Giovanni Maria Lancisi (1654-1720) and the modern cardiovascular physiology.

Giovanni Maria Lancisi (1654-1720) was one of the most important Italian physicians of the modern age. Orphaned of his mother, he spent his early years in the city of Orvieto; when he was 12, his father brought him back to Rome and enrolled him to study medicine at the Sapienza University in Rome. His dedication to study and work soon led him to increasingly important positions. Within a few years, the fame of Lancisi became such that he was appointed the personal physician of three popes. In De Subitaneis Mortibus (1707), he described the pathophysiology of heart diseases, identifying the cause of sudden deaths in structural anomalies of the heart, lungs, and brain. He also wrote about cerebral localizations and first discussed the physiological mechanisms of urine formation and excretion. In 1717, Lancisi described the pathogenesis of malaria and the close correlation between its onset and the swampy waters of the Tiber River, proposing the draining of marshes to eradicate malaria. In the posthumous De Motu Cordis et Aneurysmatibus (1728) he described for the first time heart dilatation and aneurysms of the great vessels, providing a fundamental contribution to the history of cardiovascular physiology. Proof of his interest in medical education is the establishment of an academy and the donation of a library to the hospital, bridging the gap between theory and practice in medical training. Over the centuries, Lancisi's memory has faded, but his work is still relevant for anyone practicing the medical profession.

Role of Selected miRNAs as Diagnostic and Prognostic Biomarkers in Cardiovascular Diseases, Including Coronary Artery Disease, Myocardial Infarction and Atherosclerosis.

Cardiovascular diseases are the leading cause of death worldwide in different cohorts. It is well known that miRNAs have a crucial role in regulating the development of cardiovascular physiology, thus impacting the pathophysiology of heart diseases. MiRNAs also have been reported to be associated with cardiac reactions, leading to myocardial infarction (MCI) and ultimately heart failure (HF). To prevent these heart diseases, proper and timely diagnosis of cardiac dysfunction is pivotal. Though there are many symptoms associated with an irregular heart condition and though there are some biomarkers available that may indicate heart disease, authentic, specific and sensitive markers are the need of the hour. In recent times, miRNAs have proven to be promising candidates in this regard. They are potent biomarkers as they can be easily detected in body fluids (blood, urine, etc.) due to their remarkable stability and presence in apoptotic bodies and exosomes. Existing studies suggest the role of miRNAs as valuable biomarkers. A single biomarker may be insufficient to diagnose coronary artery disease (CAD) or acute myocardial infarction (AMI); thus, a combination of different miRNAs may prove fruitful. Therefore, this review aims to highlight the role of circulating miRNA as diagnostic and prognostic biomarkers in cardiovascular diseases such as coronary artery disease (CAD), myocardial infarction (MI) and atherosclerosis.

Platelet proteome changes in dogs with congestive heart failure

BackgroundPlatelets play a central role in the development of cardiovascular diseases and changes in their proteins are involved in the pathophysiology of heart diseases in humans. There is lack of knowledge about the possible role of platelets in congestive heart failure (CHF) in dogs. Thus, this study aimed to investigate the changes in global platelet proteomes in dogs with CHF, to clarify the possible role of platelets in the physiopathology of this disease. Healthy-dogs (n = 10) and dogs with acute CHF due to myxomatous mitral valve disease (MMVD, n = 10) were used. Acute CHF was defined based on the clinical (increased respiratory rate or difficulty breathing) and radiographic findings of pulmonary edema. Dogs Blood samples were collected into tubes with acid-citrate-dextrose, and platelet-pellets were obtained by centrifuge and washing steps. Platelet-proteomes were identified using LC-MS based label-free differential proteome expression analysis method and matched according to protein database for Canis lupus familiaris.ResultsTotally 104 different proteins were identified in the platelets of the dogs being 4 out of them were significantly up-regulated and 6 down-regulated in acute CHF dogs. Guanine-nucleotide-binding protein, apolipoproteins (A-II and C-III) and clusterin levels increased, but CXC-motif-chemokine-10, cytochrome-C-oxidase-subunit-2, cathepsin-D, serine/threonine-protein-phosphatase-PP1-gamma-catalytic-subunit, creatine-kinase-B-type and myotrophin levels decreased in acute CHF dogs. These proteins are associated with several molecular functions, biological processes, signaling systems and immune-inflammatory responses.ConclusionThis study describes by first time the changes in the protein composition in platelets of dogs with acute CHF due to MMVD. Our findings provide a resource for increase the knowledge about the proteome of canine platelets and their roles in CHF caused by MMVD and could be a tool for further investigations about the prevention and treatment of this disease.

Ischemic Heart Disease Pathophysiology Paradigms Overview: From Plaque Activation to Microvascular Dysfunction.

Ischemic heart disease still represents a large burden on individuals and health care resources worldwide. By conventions, it is equated with atherosclerotic plaque due to flow-limiting obstruction in large–medium sized coronary arteries. However, clinical, angiographic and autoptic findings suggest a multifaceted pathophysiology for ischemic heart disease and just some cases are caused by severe or complicated atherosclerotic plaques. Currently there is no well-defined assessment of ischemic heart disease pathophysiology that satisfies all the observations and sometimes the underlying mechanism to everyday ischemic heart disease ward cases is misleading. In order to better examine this complicated disease and to provide future perspectives, it is important to know and analyze the pathophysiological mechanisms that underline it, because ischemic heart disease is not always determined by atherosclerotic plaque complication. Therefore, in order to have a more complete comprehension of ischemic heart disease we propose an overview of the available pathophysiological paradigms, from plaque activation to microvascular dysfunction.

Role of collagen turnover biomarkers in the noninvasive assessment of myocardial fibrosis: an update.

The pro-fibrotic milieu, as the result of the extracellular matrix remodeling, is a central feature in the pathophysiology of heart disease and contributes to its high morbidity and mortality. Fibrosis is a recognized risk factor for development of heart failure and arrythmias and is usually detected by cardiac magnetic resonance or endomyocardial biopsy. Collagen type I and type III are major components of the collagen network, and the assessment of their derived biomarkers could serve as estimate of the myocardial fibrotic content. This reviewsummarizes data from numerous studies in which these biomarkers have proven their diagnostic and prognostic utility, setting the stage for further randomized clinical trialsthat might translate into early implementation of antifibrotic therapies.

Effect of Abengourou forastero cocoa against doxorubicin-induced cardiotoxicity in experimental rats

Oxidative stress is a determining factor in the pathophysiology of heart disease. This study aimed at evaluating the protective activity of Abengourou Forastero cocoa in doxorubicin-induced cardiotoxicity in rats. Thirty (30) wistar rats divided into 5 groups were orally pretreated with distilled water, resveratrol (25 mg/kg/day) or defatted Abengourou Forastero cocoa powder (1000 and 1500 mg/kg/day) for sixty (60) consecutive days. A single dose of doxorubicin (15 mg/kg/day) was administered on day 59 by intraperitoneal route. The biochemical parameters were assessed and a histological examination of the heart was performed. This study showed that doxorubicin treated animals exhibited a significant increase of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, phosphocreatine kinases, creatine kinases, total cholesterol, triglycerides, and LDL-cholesterol levels in serum. However, a decrease of HDL-cholesterol and an alteration of cardiac tissue were noticed. Preventive treatment with Abengourou Forastero cocoa at doses of 1000 and 1500 mg/kg significantly reduced the biochemical and histological alterations induced by doxorubicin. Results showed that Abengourou Forastero cocoa protects and prevents against doxorubicin-induced cardiac damage.

ZDHHC9‐mediated palmitoylation promotes hypertrophic signaling in the heart

Heart disease remains a leading cause of mortality in the United States, contributing to over 600,000 deaths per year in the United States. Notwithstanding, the molecular mechanisms underlying the pathophysiology of heart disease remain largely elusive. Receptors, ion channels, and signaling proteins that regulate cardiac contractility and physiology are modified by post‐translational modifications such as phosphorylation. Recent research into the roles of S‐acylation or palmitoylation, the reversible post‐translational modification of proteins with fatty acids, has demonstrated critical functions in the regulation of intracellular signaling in physiology and disease. Palmitoylation, which is catalyzed by the zinc finger Asp‐His‐His‐Cys (zDHHC) family of S‐acyl transferases, has been implicated in trafficking, stability, sorting and binding of proteins to cofactors. However, the roles of palmitoylation in cardiac signal transduction and cardiac pathogenesis are not well understood. In HEK‐293 cells, the Golgi‐localized acyl transferase, zDHHC9, was shown to palmitoylate and induce plasma membrane localization and activation of H‐Ras and N‐Ras, members of the Ras family of membrane‐localized GTPases. Activation of Ras enhances the activity of downstream pathways such as the ERK/MAP kinase pathway and c‐Jun N‐terminal kinases (JNK), which induce pathological cardiac remodeling in the heart. To investigate the potential roles of zDHHC9 in cardiac pathogenesis, we generated a transgenic mouse model with cardiomyocyte‐specific overexpression of zDHHC9 (Tg‐Zdhhc9). These mice exhibited cardiac hypertrophy with increased ventricular wall thickness at 6 months of age. At 8 months of age, Tg‐Zdhhc9 mice showed impaired cardiac contractile function and severe dilated cardiomyopathy. Interestingly, there were no significant differences in palmitoylation of H‐Ras in Tg‐Zdhhc9 hearts compared to control hearts, indicating that zDHHC9‐triggered cardiac hypertrophy may be due to palmitoylation of other substrates in cardiomyocytes. Ongoing work is utilizing unbiased quantitative palmitoyl proteomics to identify novel zDHHC9 substrates that mediate activation of hypertrophic signaling in the cardiomyocytes. Altogether, these data suggest zDHHC9‐mediated palmitoylation contributes to hypertrophic signaling and heart disease.Support or Funding InformationThis work was supported by National Heart, Lung and Blood Institute grant R00‐HL‐36695 (MJB).