Myocyte Hypertrophy Research Articles

Histological features of endomyocardial biopsies in patients undergoing hemodialysis: Comparison with dilated cardiomyopathy and hypertensive heart disease

Heart failure is a frequently occurring complication in patients on maintenance hemodialysis (HD). However, the histological features of right ventricular endomyocardial biopsy (RVEMB) samples remain unclear. The clinical characteristics and histological findings of consecutive patients undergoing HD with available RVEMB samples (HD group; n=28) were retrospectively compared with those of patients with dilated cardiomyopathy (n=56) and hypertensive heart disease (n=15). The mean myocyte diameter was significantly larger in the HD group than in the other groups (P<.001), whereas the mean percent area of fibrosis did not differ among the three groups. Immunohistochemical analysis revealed that the capillary density was significantly lower in the HD group compared with the other groups (P<.001), and it was positively associated with left ventricular ejection fraction (P=.014). The number of CD68-positive macrophages, which was significantly higher in the HD group compared with the other two groups (P<.001), was associated with cardiovascular mortality (P=.020; log-rank test). Myocyte hypertrophy, macrophage infiltration, and reduced capillary density were characteristic histological features of the RVEMB samples in patients undergoing HD, which may be related to the pathogenesis of cardiac dysfunction.

Training-Induced Deactivation of the AT1 Receptor Pathway Drives Autonomic Control and Heart Remodeling During the Transition From the Pre- to Hypertensive Phase in Spontaneously Hypertensive Rats.

The effects of hypertension and exercise training (T) on the sequential interplay between renin-angiotensin system (RAS), autonomic control and heart remodeling during the development of hypertension in spontaneously hypertensive rats (SHR), was evaluated.Methods and Results:Time course changes of these parameters were recorded in 4-week-old SHR submitted to a T or sedentary (S) protocol. Wistar Kyoto rats served as controls. Hemodynamic recordings were obtained in conscious rats at experimental weeks 0, 1, 2, 4, and 8. The left ventricle (LV) was collected to evaluate RAS gene and protein expression, cardiomyocytes' hypertrophy and collagen accumulation. Pre-hypertensive SHR exhibited augmented AT1R gene expression; at 5 weeks, they presented with elevated pressure, increased LV angiotensinogen and ACE mRNA expression, followed by sympathoexcitation (from the 8thweek onwards). Marked AT1R protein content, myocytes's hypertrophy, collagen deposition and increased pressure variability were observed in 12-week-old sedentary SHR. In addition to attenuating all these effects, T activated Mas receptor expression augmented parasympathetic modulation of the heart, and delayed the onset and reduced the magnitude, but did not block the development of genetic hypertension. The close temporal relationship between changes in the LV ACE-Ang II-AT1R axis, autonomic control and cardiac remodeling at both the establishment of hypertension and during exercise training reveals the essential role played by the AT1R pathway in driving cardiac remodeling and autonomic modulation during the transition from the pre- to hypertensive phase.

Ursolic Acid Improves Monocrotaline-Induced Right Ventricular Remodeling by Regulating Metabolism.

Pulmonary arterial hypertension (PAH) is a progressive and malignant disease characterized by pulmonary small arteries and right ventricle (RV) remodeling that can lead to severe RV dysfunction and death. The current therapeutic targets for RV dysfunction, which is strongly linked to mortality, are far from adequate. Therefore, we investigated the effect of ursolic acid (UA), a pentacyclic triterpenoid carboxylic acid, on PAH-induced RV remodeling and its underlying mechanism. We established a PAH model by injecting Sprague Dawley rats with monocrotaline (MCT, 60 mg/kg, ip), as verified by echocardiography and hemodynamic examination. Proteomic analysis was performed on RV samples using a Q Exactive high-field mass spectrometer, followed by KEGG enrichment analysis. The effect of 4 weeks of UA (50 mg/kg) treatment on RV remodeling was explored based on ultrasound, hemodynamic parameters, and histological changes, with the mechanism verified in vivo and in vitro by qRT-PCR and western blotting. RV hypertrophy, fibrosis, increased apoptosis, and abnormal metabolism were induced by MCT and suppressed by UA via a mechanism that changed the expression of key markers. UA also attenuated the Phenylephrine-induced hypertrophy of neonatal rat ventricular myocytes and upregulated peroxisome proliferator-activated receptor-alpha (PPARα), a key fatty acid metabolism regulator, and its downstream factor carnitine palmitoyl transferase 1b. In conclusion, UA exerts beneficial effects on PAH-induced RV dysfunction and remodeling by regulating PPARα-dependent fatty acid metabolism.

Higenamine Improves Cardiac and Renal Fibrosis in Rats With Cardiorenal Syndrome via ASK1 Signaling Pathway

The pathogenesis of cardiorenal syndrome (CRS) is very complex, and currently there is no effective treatment for CRS. Higenamine (HI) has been shown to improve cardiac function in rats with heart failure. However, the role of higenamine in CRS remains unknown. Here, in vitro, higenamine treatment markedly reduced neonatal rat cardiac fibroblast collagen synthesis and inhibited neonatal rat cardiac myocyte hypertrophy. In our study, a rat model of type 2 CRS was induced by left anterior descending coronary artery ligation combined with 5/6 subtotal nephrectomy (STNx). Higenamine treatment decreased serum creatinine (Scr), blood urea nitrogen, and brain natriuretic peptide levels and was capable of improving left ventricular remodeling and systolic function in CRS rats, accompanied with decreased expression of transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (α-SMA) and collagen I (Col1A1). Moreover, higenamine significantly inhibited the protein expression of phosphorylated apoptosis signal-regulated kinase 1 (p-ASK1) and downstream mitogen-activated protein kinases (MAPK) (ERK, P38)/NF-κB in cardiorenal tissues of CRS rats and neonatal rat cardiac fibroblast/neonatal rat cardiac myocyte cells. Our study demonstrated that higenamine improved cardiorenal function in CRS rats and attenuated heart and kidney fibrosis possibly via targeting ASK1/MAPK (ERK, P38)/NF-κB signaling pathway. This finding extends our knowledge on the role of higenamine in cardiorenal fibrosis, providing a potential target to prevent the progression of CRS.

P311Hypertrophic cardiomyopathy and other forms of left ventricular hypertrophy. The P wave can make the difference

Abstract Background Structural disarray of hypertrophied myocytes and interstitial fibrosis characterize hypertrophic cardiomyopathy (HCM). These morphological changes also affect atrial myocytes and, together with hemodynamic alterations because of HCM, may lead to atrial cardiomyopathy. Purpose To investigate the incremental value of P-wave parameters to differentiate left ventricular hypertrophy (LVH) because of HCM from LVH in hypertensive heart disease (HHD) and athletes heart. Methods In a prospective study, we compared electrocardiographic (including signal-averaged ECG of the P wave) and echocardiographic data of patients with HCM, HHD and athletes heart. We developed a predictive model with a simple scoring system to identify HCM. Results We compared data of 27 patients with HCM (70% males, 49.8 ± 14.5 years), 324 patients with HHD (52% males, 74.8 ± 5.5 years), and 215 subjects with athletes heart (72% males, 42.3 ± 7.5). The table shows the significant differences among the 3 groups. We included the following parameters into a predictive score to differentiate HCM from other forms of LVH: QRS width (&amp;gt;88ms = 1 point), P-wave integral (&amp;gt;688µVs = 1 point) and septum thickness (&amp;gt;12mm = 2 points). A score &amp;gt;2 (Youden index 0.626) correctly classified HCM in 81% of the cases with a sensitivity and specificity of 82% an 81%, respectively. Conclusion Differentiation of HCM from other forms of LVH is improved by including atrial parameters. A simple scoring system including septum thickness, QRS width and P wave integral allowed identification of patients with HCM with a sensitivity and specificity of &amp;gt;80%. This score needs to be validated prospectively. Table 1 HCM HHD Athletes P-value HCM vs HHD* HCM vs Athletes* 95%-CI P-value 95%-CI P-value P-wave duration [ms] 152.7 ± 25.8 143.9 ± 16.5 133.5 ± 14.2 &amp;lt;0.001 -16.9 -24.6 to -9.1 &amp;lt;0.001 -16.3 -22.7 to -9.9 &amp;lt;0.001 P-wave integral [µVs] 850.4 ± 272.4 672.0 ± 235.4 773.1 ± 260.1 &amp;lt;0.001 -198.6 -320.8 to -76.3 0.002 -68.2 -169.7 to 33.2 0.187 QRS [ms] 110.3 ± 27.3 96.9 ± 20.3 95.1 ± 9.8 &amp;lt;0.001 -16.4 -24.7 to -8.1 &amp;lt;0.001 -13.8 -20.8 to -6.9 &amp;lt;0.001 QTc [ms] 447.9 ± 27.2 438.6 ± 24.5 414.0 ± 22.9 &amp;lt;0.001 -21.1 -32.7 to -9.5 &amp;lt;0.001 -30.8 -40.5 to -21.2 &amp;lt;0.001 LVMMI [g/m2] 153.6 ± 55.5 133.5 ± 30.3 98.6 ± 19.7 &amp;lt;0.001 -15.3 -29.7 to -0.9 0.038 -56.1 -67.7 to -44.6 &amp;lt;0.001 IVS [ms] 16.8 ± 4.2 11.8 ± 2.2 10.3 ± 1.5 &amp;lt;0.001 -5.2 -6.3 to -4.1 &amp;lt;0.001 -6.4 -7.3 to -5.6 &amp;lt;0.001 LAVI [ml/m2] 43.2 ± 13.9 30.5 ± 9.7 30.8 ± 9.5 &amp;lt;0.001 -14.6 -20.0 to -9.3 &amp;lt;0.001 -12.2 -16.6 to -7.9 &amp;lt;0.001 The table shows the study result after univariate and multivariate (*; adjusting for age and sex) analysis. Abstract Figure 1

Atrial remodeling and atrial fibrillation in acquired forms of cardiovascular disease.

Atrial fibrillation (AF) is prevalent in common conditions and acquired forms of heart disease, including diabetes mellitus (DM), hypertension, cardiac hypertrophy, and heart failure. AF is also prevalent in aging. Although acquired heart disease is common in aging individuals, age is also an independent risk factor for AF. Importantly, not all individuals age at the same rate. Rather, individuals of the same chronological age can vary in health status from fit to frail. Frailty can be quantified using a frailty index, which can be used to assess heterogeneity in individuals of the same chronological age. AF is thought to occur in association with electrical remodeling due to changes in ion channel expression or function as well as structural remodeling due to fibrosis, myocyte hypertrophy, or adiposity. These forms of remodeling can lead to triggered activity and electrical re-entry, which are fundamental mechanisms of AF initiation and maintenance. Nevertheless, the underlying determinants of electrical and structural remodeling are distinct in different conditions and disease states. In this focused review, we consider the factors leading to atrial electrical and structural remodeling in human patients and animal models of acquired cardiovascular disease or associated risk factors. Our goal is to identify similarities and differences in the cellular and molecular bases for atrial electrical and structural remodeling in conditions including DM, hypertension, hypertrophy, heart failure, aging, and frailty.

Caloric restriction reverses left ventricular hypertrophy through the regulation of cardiac iron homeostasis in impaired leptin signaling mice

Leptin-deficient and leptin-resistant mice manifest obesity, insulin resistance, and left ventricular hypertrophy (LVH); however, LVH’s mechanisms are not fully understood. Cardiac iron dysregulation has been recently implicated in cardiomyopathy. Here we investigated the protective effects of caloric restriction on cardiac remodeling in impaired leptin signaling obese mice. RNA-seq analysis was performed to assess the differential gene expressions in the heart of wild-type and ob/ob mice. In particular, to investigate the roles of caloric restriction on iron homeostasis-related gene expressions, 10-week-old ob/ob and db/db mice were assigned to ad libitum or calorie-restricted diets for 12 weeks. Male ob/ob mice exhibited LVH, cardiac inflammation, and oxidative stress. Using RNA-seq analysis, we identified that an iron uptake-associated gene, transferrin receptor, was upregulated in obese ob/ob mice with LVH. Caloric restriction attenuated myocyte hypertrophy, cardiac inflammation, fibrosis, and oxidative stress in ob/ob and db/db mice. Furthermore, we found that caloric restriction reversed iron homeostasis-related lipocalin 2, divalent metal transporter 1, transferrin receptor, ferritin, ferroportin, and hepcidin expressions in the heart of ob/ob and db/db mice. These findings demonstrate that the cardioprotective effects of caloric restriction result from the cellular regulation of iron homeostasis, thereby decreasing oxidative stress, inflammation, and cardiac remodeling. We suggest that decreasing iron-mediated oxidative stress and inflammation offers new therapeutic approaches for obesity-induced cardiomyopathy.

Total flavonoids from Anchusa italica Retz. Improve cardiac function and attenuate cardiac remodeling post myocardial infarction in mice

Ethnopharmacological relevanceThe plant Anchusa italica Retz. (Anchusa azurea Mill.) has been traditionally used in Uygur medicine for the treatment of cardiovascular and cerebrovascular diseases in China. Our previous study showed that total flavonoids from Anchusa italica Retz. (TFAI) exhibited potent cardioprotection in acute ischemia/reperfusion injured rats. Aim of the studyThis study was undertaken to investigate the effects of TFAI on chronic myocardial infarction (MI) in mice and the underlying mechanism. Materials and methodsTotal flavonoids were extracted from the whole herb of Anchusa italica Retz. and were characterized using HPLC-MS analysis. The left anterior descending branch of the coronary artery was ligated to simulate MI injury in mice. After surgery, mice were orally fed with TFAI at the doses of 10, 30 and 50 mg/kg body weight/day for a total of four weeks. Cardiac function and infarct size were measured, and inflammatory mediators were detected. Hematoxylin and eosin (H&E) staining and Masson's trichrome staining were performed on heart sections. The apoptotic factors, such as Bax, Bcl-2 and cleaved caspase 3, as well as the key proteins in the PI3K/Akt/mTOR signaling pathway were examined by Western blot. ResultsThe content of total flavonoids in TFAI was 56.2%. Four weeks following the MI surgery, TFAI enhanced the survival rate in post-MI mice. TFAI treatment at the doses of 30 and 50 mg/kg remarkably reduced infarct size and improved cardiac function as indicated by elevated EF and FS. Assay of the inflammatory factors showed that sera levels of TNF-α, IL-1β and IL-6 were markedly decreased by TFAI treatment compared to the MI group. H&E staining and Masson's trichrome staining demonstrated that TFAI suppressed myocyte hypertrophy and cardiac fibrosis as indicated by the decreased cross-section area and collagen volume. Western blot analysis showed that cleaved caspase 3 and Bax/Bcl-2 were significantly downregulated following TFAI treatment. Furthermore, TFAI treatment significantly suppressed the activation of the PI3K/Akt/mTOR signaling pathway. ConclusionsOur data suggest that TFAI exerts a potent protective effect against chronic MI injury, and its beneficial effects on cardiac function and cardiac remodeling might be attributable, at least in part, to anti-inflammation and inhibition of the PI3K/Akt/mTOR signaling pathway.

Exogenous dihydrosphingosine 1 phosphate mediates collagen synthesis in cardiac fibroblasts through JAK/STAT signalling and regulation of TIMP1

Cardiac fibrosis and myocyte hypertrophy are hallmarks of the cardiac remodelling process in cardiomyopathies such as heart failure (HF). Dyslipidemia or dysregulation of lipids contribute to HF. The dysregulation of high density lipoproteins (HDL) could lead to altered levels of other lipid metabolites that are bound to it such as sphingosine-1- phosphate (S1P). Recently, it has been shown that S1P and its analogue dihydrosphingosine-1-phosphate (dhS1P) are bound to HDL in plasma. The effects of dhS1P on cardiac cells have been obscure. In this study, we show that extracellular dhS1P is able to increase collagen synthesis in neonatal rat cardiac fibroblasts (NCFs) and cause hypertrophy of neonatal cardiac myocytes (NCMs). The janus kinase/signal transducer and activator (JAK/STAT) signalling pathway was involved in the increased collagen synthesis by dhS1P, through sustained increase of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). Extracellular dhS1P increased phosphorylation levels of STAT1 and STAT3 proteins, also caused an early increase in gene expression of transforming growth factor-β (TGFβ), and sustained increase in TIMP1. Inhibition of JAKs led to inhibition of TIMP1 and TGFβ gene and protein expression. We also show that dhS1P is able to cause NCM hypertrophy through S1P-receptor-1 (S1PR1) signalling which is opposite to that of its analogue, S1P. Taken together, our results show that dhS1P increases collagen synthesis in cardiac fibroblasts causing fibrosis through dhS1P-JAK/STAT-TIMP1 signalling.

Caloric restriction reverses left ventricular hypertrophy through the regulation of cardiac iron homeostasis in ob/ob mice

Leptin‐deficient mice manifest obesity, insulin resistance, and left ventricular hypertrophy (LVH); however, LVH’s mechanisms are not fully understood. Cardiac iron dysregulation has been recently implicated in cardiomyopathy. Here we investigated the protective effects of caloric restriction on cardiac remodeling in impaired leptin signaling obese mice. RNA‐seq analysis was performed to assess the differential gene expressions in the heart of wild‐type and ob/ob mice. In particular, to investigate the roles of caloric restriction on iron homeostasis‐related gene expressions, 10‐week‐old ob/ob mice were assigned to ad libitum or calorie‐restricted diets for 12 weeks. Male ob/ob mice exhibited LVH, cardiac inflammation, and oxidative stress. Using RNA‐seq analysis, we identified that an iron uptake‐associated gene, transferrin receptor, was upregulated in obese ob/ob mice with LVH. Caloric restriction attenuated myocyte hypertrophy, cardiac inflammation, fibrosis, and oxidative stress in ob/ob mice. Furthermore, we found that caloric restriction reversed iron homeostasis‐related lipocalin 2, divalent metal transporter 1, transferrin receptor, ferritin, ferroportin, and hepcidin expressions in the heart of ob/ob mice. These findings demonstrate that the cardioprotective effects of caloric restriction result from the cellular regulation of iron homeostasis, thereby decreasing oxidative stress, inflammation, and cardiac remodeling. We suggest that decreasing iron‐mediated oxidative stress and inflammation offers new therapeutic approaches for obesity‐induced cardiomyopathy.Support or Funding InformationThis work was supported by a grant of the Basic Science Research Program through the National Research Foundation of Korea (2015R1A5A2008833).

Saraf-dependent activation of mTORC1 regulates cardiac growth

Pathological cardiac hypertrophy is an independent risk for heart failure (HF) and sudden death. Deciphering signaling pathways regulating intracellular Ca2+ homeostasis that control adaptive and pathological cardiac growth may enable identification of novel therapeutic targets. The objective of the present study is to determine the role of the store-operated calcium entry-associated regulatory factor (Saraf), encoded by the Tmem66 gene, on cardiac growth control in vitro and in vivo. Saraf is a single-pass membrane protein located at the sarco/endoplasmic reticulum and regulates intracellular calcium homeostasis. We found that Saraf expression was upregulated in the hypertrophied myocardium and was sufficient for cell growth in response to neurohumoral stimulation. Increased Saraf expression caused cell growth, which was associated with dysregulation of calcium-dependent signaling and sarcoplasmic reticulum calcium content. In vivo, Saraf augmented cardiac myocyte growth in response to angiotensin II and resulted in increased cardiac remodeling together with worsened cardiac function. Mechanistically, Saraf activated mTORC1 (mechanistic target of rapamycin complex 1) and increased protein synthesis, while mTORC1 inhibition blunted Saraf-dependent cell growth. In contrast, the hearts of Saraf knockout mice and Saraf-deficient myocytes did not show any morphological or functional alterations after neurohumoral stimulation, but Saraf depletion resulted in worsened cardiac function after acute pressure overload. SARAF knockout blunted transverse aortic constriction cardiac myocyte hypertrophy and impaired cardiac function, demonstrating a role for SARAF in compensatory myocyte growth. Collectively, these results reveal a novel link between sarcoplasmic reticulum calcium homeostasis and mTORC1 activation that is regulated by Saraf.

CARDIOPROTECTIVE EFFECT OF CANNABIDIOL IN A NON ISCHEMIC MODEL OF HEART FAILURE

CBD has known anti-inflammatory actions. We assessed the potential benefits of CBD in a non-ischemic murine model of heart failre (HF). CBD was administered subcutaneously (SC) /3rd day/4 weeks. Cardiac tissue was evaluated for fibrosis, myocyte hypertrophy and expression of mRNA markers for

CARDIAC MANIFESTATIONS AND HOSPITALIZATIONS FOR FABRY'S DISEASE: INSIGHTS FROM NATIONWIDE INPATIENT SAMPLE (NIS) DATABASE

Fabry's disease (FD) is a rare X linked lysosomal storage disorder which results in deleterious tissue distribution of glycophospholipids. Cardiac manifestations can occur due to glycophospholipids deposition, signaling for myocytes hypertrophy, outflow tract obstruction, scar formation, valvular,

Impact of hyperthyroidism on cardiac hypertrophy.

The cardiac growth process (hypertrophy) is a crucial phenomenon conserved across a wide array of species and is critically involved in the maintenance of cardiac homeostasis. This process enables an organism to adapt to changes in systemic demand and occurs due to a plethora of responses, depending on the type of signal or stimuli received. The growth of cardiac muscle cells in response to environmental conditions depends on the type, strength and duration of stimuli, and results in adaptive physiological responses or non-adaptive pathological responses. Thyroid hormones (TH) have a direct effect on the heart and induce a cardiac hypertrophy phenotype, which may evolve to heart failure. In this review, we summarize the literature on TH function in the heart by presenting results from experimental studies. We discuss the mechanistic aspects of TH associated with cardiac myocyte hypertrophy, increased cardiac myocyte contractility and electrical remodeling, as well as the associated signaling pathways. In addition to classical crosstalk with the sympathetic nervous system (SNS), emerging work pointing to the new endocrine interaction between TH and the renin-angiotensin system (RAS) is also explored. Given the inflammatory potential of the angiotensin II peptide, this new interaction may open the door for new therapeutic approaches which target the key mechanisms responsible for TH-induced cardiac hypertrophy.

The Effects of Ethanol on the Heart: Alcoholic Cardiomyopathy.

Alcoholic-dilated Cardiomyopathy (ACM) is the most prevalent form of ethanol-induced heart damage. Ethanol induces ACM in a dose-dependent manner, independently of nutrition, vitamin, or electrolyte disturbances. It has synergistic effects with other heart risk factors. ACM produces a progressive reduction in myocardial contractility and heart chamber dilatation, leading to heart failure episodes and arrhythmias. Pathologically, ethanol induces myocytolysis, apoptosis, and necrosis of myocytes, with repair mechanisms causing hypertrophy and interstitial fibrosis. Myocyte ethanol targets include changes in membrane composition, receptors, ion channels, intracellular [Ca2+] transients, and structural proteins, and disrupt sarcomere contractility. Cardiac remodeling tries to compensate for this damage, establishing a balance between aggression and defense mechanisms. The final process of ACM is the result of dosage and individual predisposition. The ACM prognosis depends on the degree of persistent ethanol intake. Abstinence is the preferred goal, although controlled drinking may still improve cardiac function. New strategies are addressed to decrease myocyte hypertrophy and interstitial fibrosis and try to improve myocyte regeneration, minimizing ethanol-related cardiac damage. Growth factors and cardiomyokines are relevant molecules that may modify this process. Cardiac transplantation is the final measure in end-stage ACM but is limited to those subjects able to achieve abstinence.

Autophagy during left ventricular redilation after ventriculoplasty: Insights from a rat model of ischemic cardiomyopathy

ObjectivesMyocardial autophagy has been recognized as an important factor in heart failure. It is not known whether changes in ventricular geometry by left ventriculoplasty influence autophagy in ischemic cardiomyopathy. We hypothesized that myocardial autophagy plays an important role in left ventricular (LV) redilation after ventriculoplasty. MethodsFour weeks after ligation of the left anterior descending artery, ventriculoplasty or sham operation was performed. The animals were euthanized at 2 days (early) or 28 days (late) after the second operation. Ventricular autophagy was evaluated by protein expression of microtubule-associated protein light chain 3 II, an autophagosome marker. Cardiomyocyte area was assessed by histologic examination. LV function was evaluated by echocardiography. To examine the implications of autophagy, an autophagy inhibitor (3-methyladenine) was injected intraperitoneally for 3 weeks before sacrifice. ResultsThe LV was reduced in size early and redilated late after ventriculoplasty. LV systolic function was improved early and later worsened after ventriculoplasty. Light chain 3 II expression decreased early after ventriculoplasty and increased in the late period. Myocyte area increased from the early to late stage after ventriculoplasty. Autophagic inhibition exaggerated the increased myocyte hypertrophy and LV redilation. ConclusionsIn a rat model of myocardial infarction, autophagy decreased early after ventriculoplasty and increased again during LV redilation. These results provide new insights into the mechanism underlying the late failure of ventriculoplasty.

Altered adrenergic response in myocytes bordering a chronic myocardial infarction underlies in vivo triggered activity and repolarization instability.

Key points Ventricular arrhythmias are a major complication after myocardial infarction (MI), associated with sympathetic activation. The structurally heterogeneous peri‐infarct zone is a known substrate, but the functional role of the myocytes is less well known.Recordings of monophasic action potentials in vivo reveal that the peri‐infarct zone is a source of delayed afterdepolarizations (DADs) and has a high beat‐to‐beat variability of repolarization (BVR) during adrenergic stimulation (isoproterenol, ISO).Myocytes isolated from the peri‐infarct region have more DADs and spontaneous action potentials, with spontaneous Ca2+ release, under ISO. These myocytes also have reduced repolarization reserve and increased BVR. Other properties of post‐MI remodelling are present in both peri‐infarct and remote myocytes.These data highlight the importance of altered myocyte adrenergic responses in the peri‐infarct region as source and substrate of post‐MI arrhythmias. Ventricular arrhythmias are a major early complication after myocardial infarction (MI). The heterogeneous peri‐infarct zone forms a substrate for re‐entry while arrhythmia initiation is often associated with sympathetic activation. We studied the mechanisms triggering these post‐MI arrhythmias in vivo and their relation to regional myocyte remodelling. In pigs with chronic MI (6 weeks), in vivo monophasic action potentials were simultaneously recorded in the peri‐infarct and remote regions during adrenergic stimulation with isoproterenol (isoprenaline; ISO). Sham animals served as controls. During infusion of ISO in vivo, the incidence of delayed afterdepolarizations (DADs) and beat‐to‐beat variability of repolarization (BVR) was higher in the peri‐infarct than in the remote region. Myocytes isolated from the peri‐infarct region, in comparison to myocytes from the remote region, had more DADs, associated with spontaneous Ca2+ release, and a higher incidence of spontaneous action potentials (APs) when exposed to ISO (9.99 ± 4.2 vs. 0.16 ± 0.05 APs/min, p = 0.004); these were suppressed by CaMKII inhibition. Peri‐infarct myocytes also had reduced repolarization reserve and increased BVR (26 ± 10 ms vs. 9 ± 7 ms, P < 0.001), correlating with DAD activity. In contrast to these regional distinctions under ISO, alterations in Ca2+ handling at baseline and myocyte hypertrophy were present throughout the left ventricle (LV). Expression of some of the related genes was, however, different between the regions. In conclusion, altered myocyte adrenergic responses in the peri‐infarct but not the remote region provide a source of triggered activity in vivo and of repolarization instability amplifying the substrate for re‐entry. These findings stimulate further exploration of region‐specific therapies targeting myocytes and autonomic modulation.

The disruption of invariant natural killer T cells exacerbates cardiac hypertrophy and failure caused by pressure overload in mice.

What is the central question of this study? We questioned whether the disruption of invariant natural killer T (iNKT) cells exacerbates left ventricular (LV) remodelling and heart failure after transverse aortic constriction in mice. What are the main findings and their importance? Pressure overload induced by transverse aortic constriction increased the infiltration of iNKT cells in mouse hearts. The disruption of iNKT cells exacerbated LV remodelling and hastened the transition from hypertrophy to heart failure, in association with the activation of mitogen-activated protein kinase signalling. Activation of iNKT cells modulated the immunological balance in this process and played a protective role against LV remodelling and failure. Chronic inflammation is involved in the development of cardiac remodelling and heart failure (HF). Invariant natural killer T (iNKT) cells, a subset of Tlymphocytes, have been shown to produce various cytokines and orchestrate tissue inflammation. The pathophysiological role of iNKT cells in HF caused by pressure overload has not been studied. In the present study, we investigated whether the disruption of iNKT cells affected this process in mice. Transverse aortic constriction (TAC) and a sham operation were performed in male C57BL/6J wild-type (WT) and iNKT cell-deficient Jα18 knockout (KO) mice. The infiltration of iNKT cells was increased after TAC. The disruption of iNKT cells exacerbated left ventricular (LV) remodelling and hastened the transition to HF after TAC. Histological examinations also revealed that the disruption of iNKT cells induced greater myocyte hypertrophy and a greater increase in interstitial fibrosis after TAC. The expressions of interleukin-10 and tumour necrosis factor-α mRNA and their ratio in the LV after TAC were decreased in the KO compared with WT mice, which might indicate that the disruption of iNKT cells leads to an imbalance between T-helper type1 and type2 cytokines. The phosphorylation of extracellular signal-regulated kinase was significantly increased in the KO mice. The disruption of iNKT cells exacerbated the development of cardiac remodelling and HF after TAC. The activation of iNKT cells might play a protective role against HF caused by pressure overload. Targeting the activation of iNKT cells might thus be a promising candidate as a new therapeutic strategy for HF.

Load-independent effects of empagliflozin contribute to improved cardiac function in experimental heart failure with reduced ejection fraction

Background and aimsSodium–glucose linked cotransporter-2 (SGLT2) inhibitors reduce the likelihood of hospitalization for heart failure and cardiovascular death in both diabetic and non-diabetic individuals with reduced ejection fraction heart failure. Because SGLT2 inhibitors lead to volume contraction with reductions in both preload and afterload, these load-dependent factors are thought to be major contributors to the cardioprotective effects of the drug class. Beyond these effects, we hypothesized that SGLT2 inhibitors may also improve intrinsic cardiac function, independent of loading conditions.MethodsPressure–volume (P–V) relationship analysis was used to elucidate changes in intrinsic cardiac function, independent of alterations in loading conditions in animals with experimental myocardial infarction, a well-established model of HFrEF. Ten-week old, non-diabetic Fischer F344 rats underwent ligation of the left anterior descending (LAD) coronary artery to induce myocardial infarction (MI) of the left ventricle (LV). Following confirmation of infarct size with echocardiography 1-week post MI, animals were randomized to receive vehicle, or the SGLT2 inhibitor, empagliflozin. Cardiac function was assessed by conductance catheterization just prior to termination 6 weeks later.ResultsThe circumferential extent of MI in animals that were subsequently randomized to vehicle or empagliflozin groups was similar. Empagliflozin did not affect fractional shortening (FS) as assessed by echocardiography. In contrast, load-insensitive measures of cardiac function were substantially improved with empagliflozin. Load-independent measures of cardiac contractility, preload recruitable stroke work (PRSW) and end-systolic pressure volume relationship (ESPVR) were higher in rats that had received empagliflozin. Consistent with enhanced cardiac performance in the heart failure setting, systolic blood pressure (SBP) was higher in rats that had received empagliflozin despite its diuretic effects. A trend to improved diastolic function, as evidenced by reduction in left ventricular end-diastolic pressure (LVEDP) was also seen with empagliflozin. MI animals treated with vehicle demonstrated myocyte hypertrophy, interstitial fibrosis and evidence for changes in key calcium handling proteins (all p < 0.05) that were not affected by empagliflozin therapy.ConclusionEmpagliflozin therapy improves cardiac function independent of loading conditions. These findings suggest that its salutary effects are, at least in part, due to actions beyond a direct effect of reduced preload and afterload.

Taurine protects against cardiac dysfunction induced by pressure overload through SIRT1–p53 activation

BackgroundHeart failure (HF) is an epidemic disease with increased incidence annually. It has been reported that taurine can improve cardiac function. This study investigated the cardioprotective effects of taurine in pressure-loaded HF mice and elucidated the possible mechanism. MethodsHF models were established by transverse aortic constriction (TAC). Animals were treated with either taurine for 9 weeks and/or the SIRT1 inhibitor EX527 (5 mg/kg/day, every 2days) after TAC operation. Cardiac function and geometry were revealed by echocardiography. Myocardial hypertrophy and fibrosis were assessed using Fluorescent wheat germ agglutinin (WGA) staining and Masson's trichrome staining. Western blot and RT-PCR were performed to elucidate the expression of target proteins and genes respectively. Apoptosis in cardiomyocytes was detected by TUNEL staining. Myocardial oxidative stress was assessed by detecting the concentration of myocardial super oxidative dismutase (SOD) and malonyldialdehyde (MDA) and reactive oxygen species (ROS). Taurine concentrations and NAD+/NADH ratio were determined by taurine and NAD+/NADH assay kit. ResultsTaurine notably relieved cardiac dysfunction after TAC. The mechanisms were attributed to reduced myocyte hypertrophy and fibrosis, and alleviated apoptosis and oxidative stress. Meanwhile, taurine increased NAD+/NADH ratio，promoted the expression of SIRT1 and suppressed p53 acetylation. However, EX-527(inhibitor of SIRT1) decreased NAD+/NADH ratio and increased acetyl-p53 levels, and abolished the cardioprotective effects of taurine on mice subjected to TAC and increased apoptosis and oxidative stress. ConclusionThe mechanism responsible for cardiac-protective effects of taurine in HF induced by pressure overload is associated with the activation of the SIRT1–p53 pathway.