Increased Heart Weight Research Articles

Comparison of ANP and BNP Granular Density in Atria of Rats After Physiological and Pathological Hypertrophy.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones located in atria granules. Both peptides respond to cardiac pressure and volume dynamics and accordingly serve as translation biomarkers for the clinical treatment of heart failure. Serum ANP and BNP play central secretary roles in blood pressure and cardiac output regulation and have proven utility as differential biomarkers of cardiovascular proficiency and drug-induced maladaptation, yet both peptides are impervious to exercise-induced hypertrophy. We employed immunoelectron microscopy to examine the effects of 28 days of chronic swim exercise or administration of a PPARγ agonist on atrial granules and their stored natriuretic peptides in Sprague Dawley rats. Chronic swimming and drug treatment both resulted in a 15% increase in heart weight compared with controls, with no treatment effects on perinuclear granule area in the left atria (LAs). Drug treatment resulted in larger size granules with greater BNP density in the right atria. Comparing swimming and PPARγ agonist treatment effects on ANP:BNP granule density ratios between atrial chambers revealed a shift toward a greater proportion of ANP than BNP in LAs of swim-trained rats. These data suggest a distinction in the population of ANP and BNP after chronic swim or PPARγ that makes it a novel metric for the differentiation of pathological and physiological hypertrophy.

Long-term Dexamethasone Treatment Increases Cardiac Galectin-3 Levels.

Glucocorticoids, which are widely prescribed around the world, cause cardiac remodeling in long-term treatment by triggering insulin resistance and increasing blood pressure. However, its role in cardiac remodeling remains unclear. Galectin-3 (gal-3) is a member of a beta-galactoside-binding animal lectins, upregulated as a result of insulin resistance and in the pressure-overloaded myocardium and regulate cardiac remodeling. We hypothesized that gal-3 may be upregulated in the myocardium with prolonged use of glucocorticoids and associated with cardiac hypertrophy. To examine the involvement of glucocorticoids in gal-3 levels in rat myocardium, sixteen female Wistar Albino rats were assigned to control (C; n = 8) and dexamethasone (Dex; n = 8) groups. Daily dexamethasone was injected subcutaneously for 28days at a dose of 1mg.kg-1. Control animals were injected with the same volume of saline. The body weight and heart weights were determined. Gal-3 levels in myocardium were determined by Western blot. Our data shows that dexamethasone administration resulted in significant increase in heart weight (p < 0.05) and HW/BW ratios (p < 0.001) and 28days of dexamethasone administration with the dose of 1mg.kg-1 caused a twofold increase in the gal-3 expression in the left ventricle (p < 0.001). The finding of the current study is the first to show that dexamethasone causes an increase in gal-3 levels in myocardium. Our study provides an important step in the development of possible therapeutics by determining that dexamethasone causes an increase in gal-3 levels in the myocardium and raises awareness about the follow-up of patients receiving long-term glucocorticoid therapy.

Maternal obesity causes fetal cardiac hypertrophy and alters adult offspring myocardial metabolism in mice.

Obesity in pregnant women causes fetal cardiac dysfunction and increases offspring cardiovascular disease risk, but its effect on myocardial metabolism is unknown. We hypothesized that maternal obesity alters fetal cardiac expression of metabolism-related genes and shifts offspring myocardial substrate preference from glucose towards lipids. Female mice were fed control or obesogenic diets before and during pregnancy. Fetal hearts were studied in late gestation (embryonic day (E) 18.5; term≈E21), and offspring were studied at 3, 6, 9 or 24months postnatally. Maternal obesity increased heart weight and peroxisome proliferator activated receptor gamma (Pparg) expression in female and male fetuses and caused left ventricular diastolic dysfunction in the adult offspring. Cardiac dysfunction worsened progressively with age in female, but not male, offspring of obese dams, in comparison to age-matched control animals. In 6-month-old offspring, exposure to maternal obesity increased cardiac palmitoyl carnitine-supported mitochondrial respiration in males and reduced myocardial 18 F-fluorodeoxyglucose uptake in females. Cardiac Pparg expression remained higher in adult offspring of obese dams than control dams and was correlated with contractile and metabolic function. Maternal obesity did not affect cardiac palmitoyl carnitine respiration in females or 18 F-fluorodeoxyglucose uptake in males and did not alter cardiac 3 H-oleic acid uptake, pyruvate respiration, lipid content or fatty acid/glucose transporter abundance in offspring of either sex. The results support our hypothesis and show that maternal obesity affects offspring cardiac metabolism in a sex-dependent manner. Persistent upregulation of Pparg expression in response to overnutrition in utero might underpin programmed cardiac impairments mechanistically and contribute to cardiovascular disease risk in children of women with obesity. KEY POINTS: Obesity in pregnant women causes cardiac dysfunction in the fetus and increases lifelong cardiovascular disease risk in the offspring. In this study, we showed that maternal obesity in mice induces hypertrophy of the fetal heart in association with altered expression of genes related to nutrient metabolism. Maternal obesity also alters cardiac metabolism of carbohydrates and lipids in the adult offspring. The results suggest that overnutrition in utero might contribute to increased cardiovascular disease risk in children of women with obesity.

Bone, microbiological and intestinal characteristics of piglets fed diets containing Lithothamnium calcareum

The aim of this study was to assess the effect of calcitic seaweed (CS), calcitic limestone (CL) and monodicalcium phosphate (DP) fed to piglets in various combinations on their gastrointestinal tract and bones. A total of 128 piglets (21 days old, 5.50 ± 0.49 kg bodyweight (BW) were assigned to treatments in a randomized complete block design and eight replications to one of four diets: D1: with CL + DP, D2: with CL, CS + DP, D3, similar to D2, but with 30% less calcium from CS and DP, and D4: with CS + DP. Treatments affected the metatarsal bones, mineral concentration in the heart and liver, and pH in the cecum and colon.Piglets fed D4 tended to have a greater Enterobacteriaceae count in the jejunum and ileum compared withD1 (4.82 vs 4.79 CFU/g). Piglets fed D1 and D3 had a greater Enterobacteriaceae count in their cecum than D4 (4.79 and 4.80 vs 4.76). The D2 and D1 treatments produced greater crypt depth (CD) in the duodenum and ileum compared with D3 and D4, respectively. Feeding D3 resulted in a greater villus height (VH) to CD ratio in the duodenum compared with D2 and showed a 24.5% increase in heart weight compared with fed D1. In conclusion, CS could be an alternative source of calcium source for piglets. The inconsistent findings of the present study suggest the need for further studies to better understand the interplay of effects of Ca2+ source and level on its metabolism.

Pirfenidone attenuates cardiac hypertrophy against isoproterenol by inhibiting activation of the janus tyrosine kinase-2/signal transducer and activator of transcription 3 (JAK-2/STAT3) signaling pathway

ABSTRACT Cardiovascular risk factors have attracted increasing attention in recent years with the acceleration of population aging, amongst which cardiac hypertrophy is the initiating link to heart failure. Pirfenidone is a promising agent for the treatment of idiopathic pulmonary fibrosis and has recently proven to exert inhibitory effects on the inflammatory response. This study proposes to explore the potential pharmacological action of pirfenidone in treating cardiac hypertrophy in a rodent model. Four groups of mice were used in the present study: the control, ISO (5 mg/kg/day) for 7 days, pirfenidone (200 mg/kg/day) for 14 days, and spironolactone (SPI) (200 mg/kg/day) for 14 days groups. Increased heart weight index, left ventricle (LV) weight index, LV wall thickness, declined LV volume, and elevated serum levels of CK-MB, AST, and LDH were observed in ISO-challenged mice, all of which were dramatically reversed by the administration of pirfenidone or SPI. Furthermore, an elevated cross-sectional area of cardiomyocytes in the wheat germ agglutinin (WGA) staining of heart cross-sections, upregulated atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), β-Myosin Heavy Chain (β-MHC), and excessively released tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) in cardiac tissues were observed in the ISO group but greatly alleviated by pirfenidone or SPI. Lastly, the promoted expression levels of p-JAK-2/JAK-2 and p-STAT3/STAT-3 in the cardiac tissues of ISO-challenged mice were significantly repressed by pirfenidone or SPI. Collectively, our data reveals a therapeutic property of pirfenidone on ISO-induced cardiac hypertrophy in mice.

Chronic High‐Rate Pacing Induces Heart Failure with Preserved Ejection Fraction‐Like Phenotype in Obese Ossabaw Swine

The lack of pre‐clinical large animal models of heart failure with preserved ejection fraction (HFpEF) remains a growing, yet unmet obstacle to improving understanding of this complex condition. This study tested the hypothesis that chronic, high‐rate pacing induces a HFpEF‐like phenotype in obese Ossabaw swine. Swine were fed standard chow or an excess calorie, high‐fat, high‐fructose diet for ~18 weeks. Obese swine were implanted with a pacemaker to increase heart rate to 180 beats/min for 4 weeks (obese HF). Compared to lean swine, chronic pacing did not affect baseline (un‐paced) blood pressure or heart rate, but increased heart weight (P= 0.03), fibrosis (P&lt; 0.001), and tended to reduce capillary density (P= 0.06). Cardiac output was increased in obese HF (P= 0.02) and associated with ~45% increase in ventricular stroke volume (P= 0.01), elevated end‐diastolic pressure (25 ± 2 mmHg; P&lt; 0.001), and a normal ejection fraction of 56 ± 7% (P= 0.57). Baseline coronary blood flow was increased in obese HF (P= 0.03); however, MVO2 (P= 0.48) and coronary venous PO2 (P= 0.14) remained unchanged. Hemorrhage studies revealed impairment of the chronotropic response (59 ± 10 to 158 ± 19 bpm in lean control vs. 70 ± 5 vs. 84 ± 5 bpm in obese HF; P&lt; 0.001) and augmented reductions in coronary blood flow (0.39 ± 0.03 to 0.19 ± 0.04 ml/min/g in lean control vs. 0.60 ± 0.05 to 0.21 ± 0.04 ml/min/g in obese HF) as blood pressure decreased from 109 ± 3 to 42 ± 1 mmHg in lean control vs. 102 ± 4 to 42 ± 1 mmHg in obese HF swine. These findings support that chronic high‐rate pacing of obese Ossabaw swine induces key phenotypic features of the human HFpEF condition and provides a distinct preclinical tool for future mechanistic and therapeutic study.

Pivotal role of adipocyte‐Na/K‐ATPase Signaling in the pathogenesis of Experimental Uremic Cardiomyopathy by fat transplantation

ObjectiveMounting evidence highlights the role of adipose tissue in the development of systemic inflammation that contributes to various metabolic abnormalities. We have recently demonstrated that administration of NaKtide, antagonist of Na/K‐ATPase (NKA) signaling, coupled to adipocyte specific promoter can improve adipocyte phenotype and further attenuated experimental uremic cardiomyopathy. Studies have shown that transplanting brown adipose tissue from C57BL6 mice reduced obesity and improved whole energy metabolism. Therefore, the objective of the present study is to explore the specific role of adipocyte function in systemic inflammation and associated pathologies of uremic cardiomyopathy using adipose tissue transplantation studies.HypothesisIn the present study, we hypothesize that, the transplantation of NaKtide transfected subcutaneous fat into mice with partial nephrectomy (PNx) may help to provide a deeper understanding of adipocyte‐NKA signaling, that modulate the progression of uremic cardiomyopathy.MethodsFollowing 4 weeks of PNx or Sham surgery and lenti‐adiponectin‐Naktide in C57BL6 mice, 200 mg of subcutaneous fat pads were dissected and subcutaneously transplanted into the dorsal interscapular region of the recipient mice at the time of the PNx surgery. The tissues were harvested for morphological and molecular analyses after 8 weeks of transplantation. Statistical analysis of the data were performed by one‐way analysis of variance.ResultsThe immunofluorescence staining showed high expression of NaKtide in fat tissues of mice transplanted with NaKtide transfected fat. The pSrc protein expression in the fat tissue was significantly upregulated in PNx, which was significantly down‐regulated by PNx+NaKtide fat transplantation (p&lt;0.01). The adipose tissue dysfunction during PNx was assessed by the level of protein carbonylation and mRNA expression of IL‐1β and Sirt2, which were significantly reversed by NaKtide transfected fat (p&lt;0.01). The transplantation of NaKtide transfected adipose tissue significantly improved the systemic inflammation (p&lt;0.01). The altered plasma miRNA expressions in PNx were also normalized by NaKtide transfected fat transplantation. PNx mice developed cardiomyopathy characterized by increased heart weight and decreased cardiac function, assessed by echocardiography measurements (p&lt;0.01). These alterations were reversed by the transplantation of adipose tissues from PNx+NaKtide donor mice (p&lt;0.01). The mice transplanted with the fat tissue of PNx+NaKtide showed significantly decreased cardiac fibrosis, when compared to PNx heart, which was further confirmed by the mRNA expression of major fibrotic genes in cardiac tissues.ConclusionThe study demonstrates that, the inhibition of adipocyte‐NKA signaling in uremic cardiomyopathy could modulate the adipocyte redox state that resulted in the manipulation of systemic inflammatory milieu and associated pathophysiological mechanisms, which can be used as a clinical target for therapeutic intervention of uremic cardiomyopathy.

Cardiomyocyte‐specific deletion of Med13 &amp; Med13L results in dysregulated gene expression and lethal systolic heart failure

The Mediator co‐activation complex is an important component in RNA Pol II‐dependent gene expression that functions to integrate intracellular signals, allowing for optimized cellular response to (patho)physiological states. The Mediator kinase submodule functions to fine‐tune these molecular transitions. The kinase submodule consists of four proteins, including Med13, Med12, Cdk8, and Cyclin C. Also involved is the Med13 paralog, Med13‐like (Med13L), which is both mutually exclusive in the submodule and partially redundant. Approximately 22% of reported human mutations in MED13 or MED13L have congenital heart defects often resulting in dysregulated cardiac metabolism and aberrant cardiovascular physiology. Therefore, we hypothesize that the acute loss of Med13 and Med13L in cardiomyocytes results in disrupted Mediator kinase submodule formation leading to altered gene expression and subsequent pathogenesis of heart failure. To investigate this, we created a Tamoxifen‐inducible cardiomyocyte‐specific Med13/Med13L double knockout mouse model and treated mice for two weeks with Tamoxifen beginning at eight‐weeks‐old. Following treatment, mice had significant progressive decreased ejection fraction consistent with severe heart failure. Survival studies demonstrate rapid mortality—50% of Med13/Med13L cardiac knockout mice die within four weeks. Post‐mortem analysis showed increased heart weight and heart‐weight‐to‐body‐weight ratio as well as gross histology consistent with dilated hypertrophy. To begin elucidating the mechanistic processes underlying these findings, mRNA sequencing was performed prior to observed declines in cardiac function and showed that cardiac stress response pathways were differentially expressed. Specifically, the Wnt‐β‐catenin pathway was activated, while basal transcription was unchanged. Taken together, Med13 and Med13L are critical for normal Mediator‐regulated RNA Pol II‐dependent transcription and subsequent cardiac physiology. Therefore, disruptions cause significant cardiac dysfunction and death as sequelae of heart failure.

Pentacyclic triterpene oleanolic acid protects against cardiac aging through regulation of mitophagy and mitochondrial integrity

Advanced aging exhibits altered cardiac geometry and function involving mitochondrial anomaly. Natural compounds display promises in the regulation of cardiac homeostasis via governance of mitochondrial integrity in aging. This study examined the effect of oleanolic acid (OA), a natural pentacyclic triterpenoid with free radical scavenging and P450 cyclooxygenase-regulating properties, on cardiac aging and mechanisms involved with a focus on mitophagy. Young (4–5 month-old) and old (22–24 month-old) mice were treated with OA for 6 weeks prior to assessment of cardiac function, morphology, ultrastructure, mitochondrial integrity, cell death and autophagy. Our data revealed that OA treatment alleviated aging-induced changes in myocardial remodeling (increased heart weight, chamber size, cardiomyocyte area and interstitial fibrosis), contractile function and intracellular Ca2+ handling, apoptosis, necroptosis, inflammation, autophagy and mitophagy (LC3B, p62, TOM20 and FUNDC1 but not BNIP3 and Parkin). OA treatment rescued aging-induced anomalies in mitochondrial ultrastructure (loss of myofilament alignment, swollen mitochondria, increased circularity), mitochondrial biogenesis and O2− production without any notable effect at young age. Interestingly, OA-offered benefit against cardiomyocyte aging was nullified by deletion of the mitophagy receptor FUNDC1 using FUNDC1 knockout mice, denoting an obligatory role for FUNDC1 in OA-elicited preservation of mitophagy. OA reconciled aging-induced changes in E3 ligase MARCH5 but not FBXL2, and failed to affect aging-induced rises in IP3R3. Taken together, our data indicated a beneficial role for OA in attenuating cardiac remodeling and contractile dysfunction in aging through a FUNDC1-mediated mechanism.

Impact of Chronic Use of Whey Protein Isolate in Two Doses Using an Experimental Model

There is limited evidence in the scientific literature regarding the chronic use of whey protein and its potentially adverse effects or toxicity. We evaluated the impact of chronic use of whey protein in two doses using an experimental model. Adult male Wistar rats (n = 30) were supplemented with two different doses: 3125 mg/kg and 6250 mg/kg of whey protein isolate for 90 days. Biochemical, hematological, tissue, morphological, and behavioral analysis were evaluated. The whey-treated groups significantly increased their weight compared to the control (p &lt; 0.05). Biochemical and hematological parameters were unchanged, except for glucose, higher in the 6250 mg/kg group (p &lt; 0.05). The behavioral analysis showed no relevant difference (p &gt; 0.05). The organs analysis showed an absolute increase in liver, right kidney, and heart weights in the whey-treated group compared to the control (p &lt; 0.05). This study suggests that whey protein isolate has no toxicity when supplemented at such doses for 90 days. These doses also appeared to have the same effect regarding weight gain and absolute organs weight. This research corroborates with current literature; however, further work is needed to safely investigate the chronic use of whey supplements at a higher dose.

Preserved Left Ventricular Function despite Myocardial Fibrosis and Myopathy in the Dystrophin-Deficient D2.B10-Dmd mdx /J Mouse.

Duchenne muscular dystrophy involves an absence of dystrophin, a cytoskeletal protein which supports cell structural integrity and scaffolding for signalling molecules in myocytes. Affected individuals experience progressive muscle degeneration that leads to irreversible loss of ambulation and respiratory diaphragm function. Although clinical management has greatly advanced, heart failure due to myocardial cell loss and fibrosis remains the major cause of death. We examined cardiac morphology and function in D2.B10-Dmdmdx/J (D2-mdx) mice, a relatively new mouse model of muscular dystrophy, which we compared to their wild-type background DBA/2J mice (DBA/2). We also tested whether drug treatment with a specific blocker of mitochondrial permeability transition pore opening (Debio-025), or ACE inhibition (Perindopril), had any effect on dystrophy-related cardiomyopathy. D2-mdx mice were treated for six weeks with Vehicle control, Debio-025 (20 mg/kg/day), Perindopril (2 mg/kg/day), or a combination (n = 8/group). At 18 weeks, compared to DBA/2, D2-mdx hearts displayed greater ventricular collagen, lower cell density, greater cell diameter, and greater protein expression levels of IL-6, TLR4, BAX/Bcl2, caspase-3, PGC-1α, and notably monoamine oxidases A and B. Remarkably, these adaptations in D2-mdx mice were associated with preserved resting left ventricular function similar to DBA/2 mice. Compared to vehicle, although Perindopril partly attenuated the increase in heart weight and collagen at 18 weeks, the drug treatments had no marked impact on dystrophic cardiomyopathy.

Inhalation of PM2.5 from diesel exhaust promote impairment of mitochondrial bioenergetics and dysregulate mitochondrial quality in rat heart: implications in isoproterenol-induced myocardial infarction model

Aim: Ambient exposure of PM2.5 from diesel exhaust (termed as diesel particulate matter [DPM]) can induce cardiotoxicity that can be manifested into myocardial ischemia/infarction, where the survival depends on mitochondrial function. The mechanism for DPM-induced mitochondrial dysfunction is yet to be elucidated and the consequential impact of impaired mitochondria on the severity of myocardial infarction (MI) has not been established. Materials and methods: Female Wistar rats were exposed to DPM (0.5 mg/ml) for 3 h daily (to achieve a PM2.5 concentration of 250 µg/m3) for 21 d trailed by an induction of MI using isoproterenol (ISO). Conclusion: DPM exposure altered the basal ECG pattern and increased heart weight (HW) to body weight (BW) ratio from control. Loss of mitochondrial quality in the cardiac tissue was observed in DPM exposed animals, measured via declined ETC enzyme activity, reduced ATP levels, high oxidative stress, low mitochondrial copy number, and low expression of the mitochondrial genes involved in mitophagy (PINK and PARKIN) and mitochondrial fusion (MFN-1). Subsequent induction of MI in DPM exposed animals (DPM + ISO) further deteriorated the normal sinus rhythm, accompanied by elevated plasma CK and LDH level, increased myocardial caspase activity, downregulation of Peroxisome proliferator-activated receptor-gamma coactivator (PGC1-α), transcription factor A (TFAM), DNA polymerase subunit gamma (POLG), and other mitochondrial quality control genes. Based on these results, we conclude that DPM alters the electrophysiology and ultrastructure of the heart that aggravates the MI-induced cardiotoxicity, where the diminished mitochondrial quality can be the potential contributor.

Protective Effects of Chrysin against Cyclophosphamide-Induced Cardiotoxicity in Rats: A Biochemical and Histopathological Approach.

Mounting evidences have indicated that cyclophosphamide (CyC)a potent anticancer and cytotoxic agent is associated with various organ and systemic toxicities and the cytotoxic effects observed after administration of CyC still challenges its clinical use. Chrysin (Chy) is a dietary flavonoid with prevailing antioxidant and anti-inflammatory properties. This study evaluated the protective properties of Chy against CyC-induced cardiotoxicity in rats. The animals were orally treated with Chy (25 and 50 mg/kg/day) for 35 days and exposed to CyC (i. p., 100 mg/kg) once a week for four weeks. The results indicated that CyC caused significant cardiotoxicity as manifested by notable increases in heart weight, cardiac function biomarkers such as lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), troponin T and aspartate transaminase (AST). In addition, cardiac malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), interleukin 1β (IL1 β) and interleukin 6 (IL-6) levels were considerably increased. Meanwhile, cardiac antioxidant enzymes activities such as superoxide dismutase (SOD) and catalase (CAT), as well as glutathione (GSH) level were suppressed, while H&E stained histopathological assessment showed marked alterations in cardiac tissues. CyC also significantly lowered red blood cells (RBC) and white blood cells (WBC) parameters, whereas treatment with Chy significantly restored the altered biochemical and histopathological features. Conclusively, aforementioned results inferred that Chy offered cardioprotective potentials against CyC-induced cardiotoxicity which may be due to its antioxidant, and anti-inflammatory properties.

Treadmill running alleviates adipose tissue browning and lipolysis in rats with heart failure.

This study observed the effects of treadmill running on adipose tissue browning and lipolysis in rats with induced heart failure and elucidated the possible mechanism. Rats underwent abdominal aortic constriction as a model of heart failure. Cardiac function was detected by echocardiography. We detected serum levels of norepinephrine and interleukin 6, cardiac atrial natriuretic peptide and brain natriuretic peptide and marker genes of browning, white adipose tissue (WAT), and lipolysis in adipose tissue. Rats with heart failure showed typical symptoms such as increased heart weight and mRNA levels of atrial natriuretic peptide and brain natriuretic peptide and decreased left ventricular ejection fraction. Exercise partially improved left ventricular diastolic function and significantly decreased atrial natriuretic peptide expression. Rats with heart failure showed significantly reduced body weight and ratios of muscle and fat weight to body weight. Exercise significantly increased body weight and the ratio of muscle weight to body weight. Heart failure stimulated the expression of proliferator-activated receptor-gamma coactivator-1-alpha and uncoupling protein 1 in epididymal WAT, inguinal WAT, and brown adipose tissue but decreased that of adiponectin and leptin in inguinal WAT. Lipolysis, characterized by high adipose triglyceride lipase and hormone-sensitive lipase expression, was activated in all adipose tissues. Exercise reduced browning and lipolysis in adipose tissues. Rats with heart failure had abnormally high levels of serum norepinephrine and interleukin 6, which could be suppressed by exercise. Exercise may improve cardiac cachexia and inhibit the browning and lipolysis of adipose tissue by downregulating sympathetic nervous system activity and inflammation.

Utilidad del pliegue diagonal del lóbulo de la oreja en enfermedad coronaria, un signo simple y eficaz

Different publications have pointed out the predictive value of the presence of the diagonal earlobe crease (DELC) for coronary artery disease (CAD) irrespective of gender, although its usefulness in patients over 60 years has been discussed. Despite the simplicity of its evaluation, it is not commonly used in clinical/forensic practice. METHODS: Systematic evaluation of the presence of DELC in forensic autopsies. RESULTS: 247 cases with 177 men (72%), mean age 64±16.3 years, violent death in 85 cases (34%), natural in 158 cases (64%) and undetermined in 4 cases (2%), 17% DM, 33% hypertension, 41% severe CAD, 51% sudden cardiovascular death (SCD-CV) and 26% sudden death due to ischemic heart disease (SCD-I). The presence of severe CAD was significantly associated with men, age ≥60 years, hypertension, increased heart weight and DELC; in multivariate analyses, only DELC and increased heart weight maintained their association with severe CAD. The same multivariate analyses were performed to predict SCD-CV and SCD-I. In the first case, only the male sex, increased heart weight and DELC, and in the second case only the male sex, hypertension and increased heart weight maintained statistical significance. Finally, we separately analyzed the age groups &lt;60 years (N=91) and ≥60 years (N=156), estimating the utility of the DELC with Sensitivity=39 and 56%, Specificity=88 and 75%, Positive predictive value= 53 and 70%, Negative predictive value=81 and 62% respectively. CONCLUSIONS: Checking for the presence of PDL is easy, fast and cheap. Its strong and consistent independent association with severe CAD and CV death should position this trait as an important finding in the physical examination of patients with suspected CAD. In our series, this association was repeated in the group &gt;60 years, although with less weight than in young people.

Vasorin deficiency leads to cardiac hypertrophy by targeting MYL7 in young mice

Vasorin (VASN) is an important transmembrane protein associated with development and disease. However, it is not clear whether the death of mice with VASN deficiency (VASN −/−) is related to cardiac dysfunction. The aim of this research was to ascertain whether VASN induces pathological cardiac hypertrophy by targeting myosin light chain 7 (MYL7). VASN −/− mice were produced by CRISPR/Cas9 technology and inbreeding. PCR amplification, electrophoresis, real‐time PCR and Western blotting were used to confirm VASN deficiency. Cardiac hypertrophy was examined by blood tests, histological analysis and real‐time PCR, and key downstream factors were identified by RNA sequencing and real‐time PCR. Western blotting, immunohistochemistry and electron microscopy analysis were used to confirm the downregulation of MYL7 production and cardiac structural changes. Our results showed that sudden death of VASN −/− mice occurred 21–28 days after birth. The obvious increases in cardiovascular risk, heart weight and myocardial volume and the upregulation of hypertrophy marker gene expression indicated that cardiac hypertrophy may be the cause of death in young VASN −/− mice. Transcriptome analysis revealed that VASN deficiency led to MYL7 downregulation, which induced myocardial structure abnormalities and disorders. Our results revealed a pathological phenomenon in which VASN deficiency may lead to cardiac hypertrophy by downregulating MYL7 production. However, more research is necessary to elucidate the underlying mechanism.

Idarubicin-induced oxidative stress and apoptosis in cardiomyocytes: An in vitro molecular approach.

Idarubicin (IDA) is an anthracycline antibiotic, frequently used for the treatment of various human cancers. In vivo rodent model studies have identified a variety of possible adverse outcomes from IDA including heart effects like increased heart weights, myocardial histopathological injury, electrocardiogram abnormalities, and cardiac dysfunction. Despite significant investigations, the molecular mechanisms responsible for the cardiotoxicity of IDA have not been fully clarified. The aim of the current study was to investigate the effects of IDA on the HL-1 cardiac muscle cell. Different concentrations of IDA (10-6, 10-5, 10-4, and 10-3M) were used at different time (6, 12, 24, and 48 h) periods, and the Cell Counting Kit-8 (CCK-8); 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) probe method; and enzyme-linked immunosorbent assay (ELISA) were used to detect the oxidative stress level. In addition, we used network analysis to predict IDA-induced cardiotoxicity. The TUNEL assay, qRT-PCR, ELISA assay, and Western blotting detection of related apoptotic factors including caspase family, Bax, and Bcl-2. Overall, we found that IDA was generally more toxic at high concentrations or extended durations of exposure. At the same time, IDA can increase the content of reactive oxygen species (ROS), malondialdehyde (MDA), and decrease the level of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) in cells, and increase the content of lactate dehydrogenase (LDH) and nitric oxide synthase (NOS) in the medium. Network analysis showed that the apoptosis signaling pathway was activated; specifically, the caspase family was involved in the signal pathway. The results of the TUNEL assay, qRT-PCR, ELISA, and Western blot found that IDA can activate apoptotic factors. The mechanism may be related to the activation of apoptosis signaling pathway. These results indicate that the cardiotoxic effects of IDA are most likely associated with oxidative stress and ROS formation, which finally ends in apoptotic factors' activation and induction of cell apoptosis.

Abstract 14091: Systemic Hypoxemia Induces Cardiomyocyte Cell Cycle Re-Entry but Few Myocytes Appear to Truly Divide

Rationale: The adult mammalian heart has a very limited capacity to regenerate cardiomyocytes that die from pathological damage. Several studies suggest that those few new myocytes found after injury are derived from pre-existing cardiomyocytes. A recent study suggests that systemic hypoxemia in adult mice can induce their cardiac myocytes to reenter the cell cycle and form two daughter cells. The goal of the present experiments was to determine if hypoxemia can induce adult murine cardiomyocytes to reenter the cell cycle and divide. Hypothesis: Hypoxia induces adult cardiomyocytes to complete the cell cycle and form new cardiac myocytes. Methods and Results: EdU mini pumps were implanted in 2-month-old C57BL/6 mice. Mice were then placed in a hypoxia chamber and the oxygen was lowered by 1% every day for 14 days to reach a final concentration of 7% oxygen. The animals remained in hypoxia (7% Oxygen) for 2 weeks and then were euthanized. Hypoxic mice had an increase in heart weight and echocardiography documented an increase in cardiac pump function and LV wall thickness when compared to control mice. Analysis of isolated cardiac myocytes in C57BL/6 animals showed an increase in EdU+ cardiomyocytes in hypoxemia and DAPI fluorescence intensity was also increased in these EdU+ myocytes which may indicate DNA synthesis. In fixed heart tissue sections, hypoxic mice contained more EdU+ myocytes and had an increase in the total amount of EdU+ cells in the heart. To further evaluate cardiomyocyte proliferation, we employed a mosaic mouse model with double markers (MADM) in which myocytes entering the cell cycle express both red fluorescent protein (RFP) and green fluorescent protein (GFP) and therefore are yellow in color. When cells complete the cell cycle and divide they express only RFP or GFP. MADM mice were exposed to hypoxia at 7% Oxygen as described above. MADM mice subjected to hypoxemia had increased numbers of yellow myocytes versus controls. There was a much smaller number of hypoxic myocytes with just RFP or GFP. Conclusion: Systemic hypoxia induces cardiac myocyte cell cycle re-entry and DNA synthesis, but it seems that very few of these myocytes complete the cell cycle and divide into two daughter cells.

Abstract 10928: Chlorogenic Acid Ameliorates Pressure Overload-Induced Cardiac Hypertrophy in Mouse Models

Introduction: Cardiac hypertrophy leading to heart failure is one of the critical causes of morbidity and mortality. Although social interest in treatment and prevention of cardiovascular disease is high, sufficient outcome has not been obtained yet. Chlorogenic acid (CGA) is one of the most abundant phenolics in plants, and is called caffeic acid. Recently, the cardioprotective effects of CGA which ameliorate isoproterenol-induced hypertrophy in vitro research have been reported. However, it has not been elucidated whether CGA affects cardiac hypertrophy in vivo models with TAC. Hypothesis: We assessed the hypothesis that the administration of CGA has protective effect on TAC-induced cardiac hypertrophy. Methods: We used mouse models of cardiac hypertrophy induced by TAC for four weeks. Mice were randomly assigned to sham, TAC, and TAC+CGA groups. CGA was administered at dose of 40mg/kg intraperitoneally once a day for four weeks after the TAC operation. cardioprotective effect was investigated by echocardiography and histological analysises. In addition, immunoblot and metabolome analysises and biomedical assays were conducted in excised hearts. Statistical analysis was performed by one-way ANOVA. All data are expressed as mean ± SD. Statistical significance was defined as P &lt; 0.05. Results: We evaluated sham group (n=8), TAC group (n=7), TAC+CGA group (n=7) four weeks after TAC operation. TAC group showed an increase of heart weight, which was attenuated by CGA (120.3±9.3mg, 148.8±9.0mg, 126.6±6.2mg, p&lt;0.05). Consistently, echocardiography revealed that the change of myocardial diastolic wall thickness (0.79±0.1mm, 1.13±0.1mm, 0.93±0.1mm, p&lt;0.05). Histological analysis indicated that fibrosis induced by TAC was alleviated by CGA. According to immunoblot analysis, TAC group showed overexpression of TGF-β, IL-6, and TNF-α. In addition, the enhancements of glycolysis and TCA cycle were indicated in metabolome analysis. These changes were modulated by CGA administration. Conclusion: In conclusion, the present study revealed that CGA administration ameliorates pressure overload-induced cardiac hypertrophy in rodent model. As a key factor, expression of inflammatory cytokines and modulation of glucose metabolism were observed.

Abstract 13218: CITED4 is Required for Exercise-Induced Cardiac Growth and Cardiomyogenesis in Mice

Introduction: CITED4 (CBP/p300-interacting transactivators with E [glutamic acid]/D [aspartic acid]-rich-carboxylterminal domain 4) is a transcriptional regulator which limits pathologic remodeling after ischemic and pressure overload models of cardiac stress. It is also upregulated in the heart with exercise, an effective intervention which induces physiological hypertrophy and cardiomyogenesis in adult mice. We hypothesized that CITED4 is required for exercise-induced cardiac growth and cardiomyogenesis. Methods and Results: Eight- to ten-week-old mice with cardiomyocyte-specific CITED4 knockout (C4KO) and littermate controls underwent 8 weeks of voluntary wheel running in comparison to sedentary controls. 5-Ethynyl-2′-deoxyuridine (EdU) was injected subcutaneously every two days for the first two weeks. There were no significant differences in cardiac size and function at baseline between C4KO and control mice. In control mice, running increased heart weight to tibial length ratio (HW/TL, 6.26±0.25 vs 7.37±0.75, p=0.01, n=5-9 per group), heart weight to body weight ratio (HW/BW, 4.08±0.40 vs 4.93±0.48, p=0.01), and cardiomyocyte (CM) size without affecting fractional shortening (FS), consistent with physiologic remodeling. There was also a nonsignificant trend to increased EdU+ CMs in the control exercised mice (2.96±2.34% vs 5.23±6.28%, p=0.44), suggestive of previously documented exercise-induced cardiomyogenesis. In contrast, running did not change HW/TL and CM size in C4KO mice (HW/TL, 6.44±0.48 vs 6.66±0.29, p=0.22, n= 0-13 per group) but reduced %FS (58.78±3.27 vs 53.67±4.59, p=0.03) and increased chamber size (LVIDs, 1.32±0.13 vs 1.50±0.17, p=0.032), suggesting maladaptive cardiac remodeling with exercise, confirming prior findings observed in a more extreme swim-exercise model. Rather than the expected increase, hearts from exercised C4KO mice had fewer EdU+ CMs compared to sedentary C4KO mice (3.76±2.60% vs 2.11±0.76%, p=0.05) and reduced expression of cell cycle genes Cdkn1b, Cyclin B1, Cdkn2a, and Ki-67. Conclusions: CITED4 is required for exercise-induced cardiomyogenesis, CM hypertrophy, and adaptive remodeling. CITED4 deficiency leads to maladaptive cardiac remodeling with physiologic stress.