Angiotension II directly bind P2X7 receptor to induce myocardial ferroptosis and remodeling by activating human antigen R.

Continuous remodeling of the heart can result in adverse events such as reduced myocardial function and heart failure. Available evidence indicates that ferroptosis is a key process in the emergence of cardiac disease. P2 family purinergic receptor P2X7 receptor (P2X7R) activation plays a crucial role in numerous aspects of cardiovascular disease. The aim of this study was to elucidate any potential interactions between P2X7R and ferroptosis in cardiac remodeling stimulated by angiotensin II (Ang II), and P2X7R knockout mice were utilized to explore the role of P2X7R and elucidate its underlying mechanism through molecular biological methods. Ferroptosis is involved in cardiac remodeling, and P2X7R deficiency significantly alleviates cardiac dysfunction, remodeling, and ferroptosis induced by Ang II. Mechanistically, Ang II interacts with P2X7R directly, and LYS-66 and MET-212 in the in the ATP binding pocket form a binding complex with Ang II. P2X7R blockade influences HuR-targeted GPX4 and HO-1 mRNA stability by affecting the shuttling of HuR from the nucleus to the cytoplasm and its expression. These results suggest that focusing on P2X7R could be a possible therapeutic approach for the management of hypertensive heart failure.

Bradykinin attenuates endothelial-mesenchymal transition following cardiac ischemia-reperfusion injury.

AIMS: Endothelial-mesenchymal transition (EndMT) is a crucial pathological process contributing to cardiac fibrosis. Bradykinin has been found to protect the heart against fibrosis. Whether bradykinin regulates EndMT has not been determined. MATERIALS AND METHODS: Rats were subjected to ligation of the left anterior descending coronary artery for 1 h and subsequent reperfusion to induce cardiac ischemia-reperfusion (IR) injury. Bradykinin (0.5 µg/h) was infused by an osmotic pump implanted subcutaneously at the onset of reperfusion. Fourteen days later, the functional, histological, and molecular analyses were performed to investigate the changes in cardiac fibrosis and EndMT. Human coronary artery endothelial cells were utilized to determine the molecular mechanisms in vitro. RESULTS: Bradykinin treatment improved cardiac function and decreased fibrosis following cardiac IR injury, accompanied by ameliorated EndMT and increased nitric oxide (NO) production. In vitro experiments found that bradykinin mitigated transforming growth factor ß1 (TGFß1)-induced EndMT. Significantly, the bradykinin B2 receptor antagonist or endothelial nitric oxide synthase inhibitor abolished the effects of bradykinin on EndMT inhibition, indicating that the bradykinin B2 receptor and NO might mediate the effects of bradykinin on EndMT inhibition. CONCLUSION: Bradykinin plays an essential role in the process of cardiac fibrosis. Bradykinin preserves the cellular signature of endothelial cells, preventing them from EndMT following cardiac IR injury, possibly mediated by bradykinin B2 receptor activation and NO production.

GLP-1RA may have varying effects on cardiac structure in patients with ASCVD depending on BMI.

Background: Glucagon-like peptide-1 receptor agonist(GLP-1RA) is commonly used in patients with cardiovascular disease due to its significant improvement in the prognosis of atherosclerotic cardiovascular disease (ASCVD). However, previous studies have primarily focused on obese patients, leaving uncertainty regarding whether GLP-1RA can yield similar cardiovascular benefits in individuals with normal or low body weight. Methods: In this study, we enrolled patients with ASCVD to establish a retrospective cohort. Patients receiving GLP-1RA treatment were assigned to the GLP-1RA group, while a control group was formed by matching age and body mass index (BMI) among patients not receiving GLP-1RA treatment. Each group was further divided into subgroups based on baseline BMI levels: normal weight, overweight, and obesity. A six-month follow-up was conducted to assess changes in patient weight, metabolic indicators, and cardiac structure and function. Results: Among the normal weight subgroup, no significant weight change was observed after six months of GLP-1RA treatment (57.4 ± 4.8 vs. 58.7 ± 9.2, p = 0.063). However, significant weight reduction was observed in the other two subgroups (Overweight group: 70.0 ± 9.1 vs. 73.1 ± 8.2, p = 0.003, Obesity group: 90.5 ± 14.3 vs. 95.5 ± 16.6, p<0.001). Regardless of baseline BMI levels, GLP-1RA demonstrated significant glucose-lowering effects in terms of metabolic indicators. However, GLP-1RA have a more significant effect on improving blood lipids in overweight and obese patients. The effects of GLP-1RA on cardiac structure exhibited variations among patients with different baseline BMI levels. Specifically, it was observed that the improvement in atrial structure was more prominent in patients with normal body weight(LAD: 33.0 (30.3, 35.5) vs. 35.0 (32.5, 37.1), p = 0.018, LAA (18.0 (16.0, 21.5) vs. 18.5 (16.5, 20.5), p = 0.008), while the enhancement in ventricular structure was more significant in obese subjects(LEVDD: 49.8 ± 5.8 vs. 50.2 ± 5.0, p < 0.001, LVMI: 65.1 (56.2, 71.4) vs. 65.8 (58.9, 80.4), p < 0.039). Conclusion: According to the study, it was found that the administration of GLP-1RA can have different effects on cardiac structure in patients with different baseline BMI, In obese patients, improvements in ventricular remodeling may be more associated with weight loss mechanisms, while in patients with normal or low BMI, GLP-1RA may directly improve atrial remodeling through GLP-1 receptors in atrial tissue.

The isoproterenol-induced myocardial fibrosis: A biochemical and histological investigation.

The isoproterenol (ISO)-induced myocardial fibrosis is considered a reliable and repeatable experimental model characterized by a relatively low mortality rate. Although is well-known that ISO stimulates the ß1 adrenergic receptors at the myocardial level, a high degree of heterogeneity emerges around the doses and duration of the treatment generating unclear results. Therefore, we propose to gain insights into the progression of ISO-induced myocardial fibrosis, in order to critically analyze and optimize the experimental model. Male Wistar rats (12-14-week-old) were submitted to subcutaneous injection of ISO, in particular, two doses were selected: the commonly used dose of 5 mg/kg and a lower dose of 1 mg/kg, administered for 3 and 6 days. Biochemical and histological examinations were conducted either immediately after the last administration or after a recovering period of 7 or 14 days from the initial administration. Noteworthy, from our investigation emerged that even the lower dose of ISO was able to induce the maximal biochemical and histological alterations, suggesting that lower doses should be considered to control the progression of the damage more precisely and to identify a prodromic phase in which intervention with pharmacological or nutraceutical tools can be effectively attempted.

The Role and Potential Mechanisms of Rehabilitation Exercise Improving Cardiac Remodeling.

Rehabilitation exercise is a crucial non-pharmacological intervention for the secondary prevention and treatment of cardiovascular diseases, effectively ameliorating cardiac remodeling in patients. Exercise training can mitigate cardiomyocyte apoptosis, reduce extracellular matrix deposition and fibrosis, promote angiogenesis, and regulate inflammatory response to improve cardiac remodeling. This article presents a comprehensive review of recent research progress, summarizing the pivotal role and underlying mechanism of rehabilitation exercise in improving cardiac remodeling and providing valuable insights for devising effective rehabilitation treatment programs. Graphical Abstract.

Smoking cessation only partially reverses cardiac metabolic and structural remodeling in mice.

AIMS: Active cigarette smoking is a major risk factor for chronic obstructive pulmonary disease that remains elevated after cessation. Skeletal muscle dysfunction has been well documented after smoking, but little is known about cardiac adaptations to cigarette smoking. The underlying cellular and molecular cardiac adaptations, independent of confounding lifestyle factors, and time course of reversibility by smoking cessation remain unclear. We hypothesized that smoking negatively affects cardiac metabolism and induces local inflammation in mice, which do not readily reverse upon 2-week smoking cessation. METHODS: Mice were exposed to air or cigarette smoke for 14 weeks with or without 1- or 2-week smoke cessation. We measured cardiac mitochondrial respiration by high-resolution respirometry, cardiac mitochondrial density, abundance of mitochondrial supercomplexes by electrophoresis, and capillarization, fibrosis, and macrophage infiltration by immunohistology, and performed cardiac metabolome and lipidome analysis by mass spectrometry. RESULTS: Mitochondrial protein, supercomplex content, and respiration (all p < 0.03) were lower after smoking, which were largely reversed within 2-week smoking cessation. Metabolome and lipidome analyses revealed alterations in mitochondrial metabolism, a shift from fatty acid to glucose metabolism, which did not revert to control upon smoking cessation. Capillary density was not different after smoking but increased after smoking cessation (p = 0.02). Macrophage infiltration and fibrosis (p < 0.04) were higher after smoking but did not revert to control upon smoking cessation. CONCLUSIONS: While cigarette-impaired smoking-induced cardiac mitochondrial function was reversed by smoking cessation, the remaining fibrosis and macrophage infiltration may contribute to the increased risk of cardiovascular events after smoking cessation.

Transcriptome and proteome analyses reveal that upregulation of GSTM2 by allisartan improves cardiac remodeling and dysfunction in hypertensive rats.

Long-term hypertension can lead to hypertensive heart disease, which ultimately progresses to heart failure. As an angiotensin receptor blocker antihypertensive drug, allisartan can control blood pressure, and improve cardiac remodeling and cardiac dysfunction caused by hypertension. The aim of the present study was to investigate the protective effects of allisartan on the heart of spontaneously hypertensive rats (SHRs) and the underlying mechanisms. SHRs were used as an animal model of hypertensive heart disease and were treated with allisartan orally at a dose of 25 mg/kg/day. The blood pressure levels of the rats were continuously monitored, their body and heart weights were measured, and their cardiac structure and function were evaluated using echocardiography. Wheat germ agglutinin staining and Masson trichrome staining were employed to assess the morphology of the myocardial tissue. In addition, transcriptome and proteome analyses were performed using the Solexa/Illumina sequencing platform and tandem mass tag technology, respectively. Immunofluorescence co-localization was conducted to analyze Nrf2 nuclear translocation, and TUNEL was performed to detect the levels of cell apoptosis. The protein expression levels of pro-collagen I, collagen III, phosphorylated (p)-AKT, AKT, p-PI3K and PI3K, and the mRNA expression levels of Col1a1 and Col3a1 were determined by western blotting and reverse transcription-quantitative PCR, respectively. Allisartan lowered blood pressure, attenuated cardiac remodeling and improved cardiac function in SHRs. In addition, allisartan alleviated cardiomyocyte hypertrophy and cardiac fibrosis. Allisartan also significantly affected the 'pentose phosphate pathway', 'fatty acid elongation', 'valine, leucine and isoleucine degradation', 'glutathione metabolism', and 'amino sugar and nucleotide sugar metabolism' pathways in the hearts of SHRs, and upregulated the expression levels of GSTM2. Furthermore, allisartan activated the PI3K-AKT-Nrf2 signaling pathway and inhibited cardiomyocyte apoptosis. In conclusion, the present study demonstrated that allisartan can effectively control blood pressure in SHRs, and improves cardiac remodeling and cardiac dysfunction. Allisartan may also upregulate the expression levels of GSTM2 in the hearts of SHRs and significantly affect glutathione metabolism, as determined by transcriptome and proteome analyses. The cardioprotective effect of allisartan may be mediated through activation of the PI3K-AKT-Nrf2 signaling pathway, upregulation of GSTM2 expression and reduction of cardiomyocyte apoptosis in SHRs.

Electrocardiographic predictors of response to sacubitril/valsartan therapy in heart failure with reduced ejection fraction.

BACKGROUND: Sacubitril/valsartan (SV) is currently recommended as a first-line therapy in patients with heart failure and reduced ejection fraction (HFrEF) due to its significant clinical and prognostic benefit; however, not all patients respond to therapy and predictors of clinical response to SV remain under-studied. AIMS: To identify electrocardiographic (ECG) predictors of response to SV therapy in HFrEF patients. METHODS: A retrospective analysis of a hospital heart failure registry was undertaken. Consecutive HFrEF patients (New York Heart Association class II-III) on maximal-dose SV were studied. Response to SV was defined as ≥10% relative improvement in left ventricular ejection fraction (LVEF) at 3-months post-maximal-dose therapy. Pre-therapy ECGs were retrospectively analyzed for axes and standard wave and interval durations. Logistic regression was used to estimate odds ratios and 95% confidence intervals for associations between predictors and therapeutic response. Backward stepwise regression was employed to develop a parsimonious model. RESULTS: P-wave duration (PWD) 100-120 ms, PWD >120 ms, and QTc >460 ms were associated with response to SV on univariate analysis: OR 18.00 (4.45-122.90), 5.00 (1.47-20.42), and 3.10 (1.18-9.22), respectively. The preferred model that included the former two predictors in combination with pre-therapy creatinine, mineralocorticoid receptor antagonist use, and LVEF was highly selective (area under the ROC curve = 0.868). CONCLUSIONS: Prolongation of both PWD and QTc interval on baseline ECG in HFrEF patients is predictive of therapeutic response to maximal-dose SV therapy and may indicate early cardiac remodeling that is highly amenable to reversal.

Follistatin-like 1 protects against doxorubicin-induced cardiotoxicity by preventing mitochondrial dysfunction through the SIRT6/Nrf2 signaling pathway.

Mitochondrial dysfunction and myocardial remodeling have been reported to be the main underlying molecular mechanisms of doxorubicin-induced cardiotoxicity. SIRT6 is a nicotinamide adenine dinucleotide-dependent enzyme that plays a vital role in cardiac protection against various stresses. Moreover, previous studies have demonstrated that FSTL1 could alleviate doxorubicin-induced cardiotoxicity by inhibiting autophagy. The present study investigated the probable mechanisms of FSTL1 on doxorubicin-induced cardiotoxicity in vivo and in vitro. We confirmed that FSTL1 exerted a pivotal protective role on cardiac tissue in vivo and on doxorubicin-induced cell injury in vitro. Furthermore, FSTL1 can alleviate doxorubicin-induced mitochondrial dysfunction by inhibiting autophagy and apoptosis. Further studies demonstrated that FSTL1 can activate SIRT6 signaling by restoring the SIRT6 protein expression in doxorubicin-induced myocardial injury. SIRT6 activation elevated the protein expression of Nrf2 in doxorubicin-induced H9C2 injury. Treatment with the Nrf2 inhibitor ML385 partially antagonized the cardioprotective role of SIRT6 on doxorubicin-induced autophagy or apoptosis. These results suggested that the protective mechanism of FSTL1 on doxorubicin-induced cardiotoxicity may be related with the inhibition of autophagy and apoptosis, partly through the activation of SIRT6/Nrf2.

Clinical characteristics and long-term outcomes of patients with heart failure with improved ejection fraction. First Polish experience from LECRA-HF registry.

PURPOSE: Heart failure (HF) with improved ejection fraction (HFimpEF) is a new category of HF introduced in the newest European Society of Cardiology guidelines. However, clinical characteristics and long-term outcomes of HFimpEF patients remain insufficiently elucidated. We sought to characterize Polish HFimpEF patients and determine their long-term mortality. MATERIAL AND METHODS: Of 1186 patients enrolled in the single-center Lesser Poland Cracovian Heart Failure (LECRA-HF) registry between 2009 and 2019 and hospitalized due to HF decompensation, 340 (28.7%) were those with HF with reduced ejection fraction (HFrEF). Based on follow-up echocardiography, 61 (17.9%) of them were classified as HFimpEF and the remaining as HFnon-impEF. RESULTS: HFimpEF patients were more frequently females (P â€‹< â€‹0.001), had higher baseline left ventricular ejection fraction (LVEF, P â€‹< â€‹0.001), had less often a history of diabetes (P â€‹= â€‹0.024), severe chronic kidney disease (P â€‹= â€‹0.026) or prior myocardial infarction (P â€‹= â€‹0.008) than HFnon-impEF patients. By multivariable analysis the HFimpEF diagnosis was independently predicted by baseline NYHA I/II (odds ratio [OR] 2.347, 95% confidence interval [95%CI] 1.020-5.405), non-ischemic etiology (OR 3.096, 95%CI 1.587-6.024), lack of diabetes mellitus (OR 2.016, 95%CI 1.059-3.846) and higher baseline LVEF (OR 1.084, 95%CI 1.042-1.126, per 1%). Within the median 49 (25-77) months all-cause mortality was lower in HFimpEF than in HFnon-impEF (10.8 vs 16.4%/year, P â€‹= â€‹0.004). CONCLUSIONS: Our findings indicate that every sixth Polish patient with HFrEF has a chance to improve LVEF during follow-up and to become a HFimpEF patient. Baseline characteristics of HFimpEF patients are different from HFnon-impEF. Simultaneously, the HFimpEF diagnosis is associated with higher long-term survival.

Alterations in Mitochondrial Oxidative Phosphorylation System: Relationship of Complex V and Cardiac Dysfunction in Human Heart Failure.

Heart failure (HF) is a disease related to bioenergetic mitochondrial abnormalities. However, the whole status of molecules involved in the oxidative phosphorylation system (OXPHOS) is unknown. Therefore, we analyzed the OXPHOS transcriptome of human cardiac tissue by RNA-seq analyses (mRNA n = 36; ncRNA n = 30) in HF patients (ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM)) and control subjects. We detected 28 altered genes in these patients, highlighting greater deregulation in ICM. Specifically, we found a general overexpression of complex V (ATP synthase) elements, among them, ATP5I (ICM, FC = 2.04; p < 0.01), ATP5MJ (ICM, FC = 1.33, p < 0.05), and ATP5IF1 (ICM, FC = 1.81; p < 0.001), which presented a significant correlation with established echocardiographic parameters of cardiac remodeling and ventricular function as follows: left ventricular end-systolic (p < 0.01) and end-diastolic (p < 0.01) diameters, and ejection fraction (p < 0.05). We also detected an increase in ATP5IF1 protein levels (ICM, FC = 1.75; p < 0.01) and alterations in the microRNA expression levels of miR-208b-3p (ICM, FC = -1.44, p < 0.001), miR-483-3p (ICM, FC = 1.37, p < 0.01), regulators of ATP5I. Therefore, we observed the deregulation of the OXPHOS transcriptome in ICM patients, highlighting the overexpression of complex V and its relationship with cardiac remodeling and function.

Characterizing the influence of cardiorespiratory fitness on left atrial size and function in the general population.

Increased left atrial (LA) size and reduced LA function have been associated with heart failure and atrial fibrillation (AF) in at-risk populations. However, atrial remodeling has also been associated with exercise training and the relationship between fitness, LA size, and function has not been defined across the fitness spectrum. In a cross-sectional study of 559 ostensibly healthy participants, comprising 304 males (mean age, 46 ± 20 yr) and 255 females (mean age, 47 ± 15 yr), we sought to define the relationship between cardiorespiratory fitness (CRF), LA size, and function. We also aimed to interrogate sex differences in atrial factors influencing CRF. Echocardiographic measures included biplane measures of LA volumes indexed to body surface area (LAVi) and atrial deformation using two-dimensional speckle tracking. CRF was measured as peak oxygen consumption (V̇o2peak) during cardiopulmonary exercise testing (CPET). Using multivariable regression, age, sex, weight, and LAVi (P < 0.001 for all) predicted V̇o2peak (P < 0.001, R2 = 0.66 for combined model). After accounting for these variables, heart rate reserve added strength to the model (P < 0.001, R2 = 0.74) but LA strain parameters did not predict V̇o2peak. These findings add important nuance to the perception that LA size is a marker of cardiac pathology. LA size should be considered in the context of fitness, and it is likely that the adverse prognostic associations of increased LA size may be confined to those with LA enlargement and low fitness.NEW & NOTEWORTHY Left atrial (LA) structure better predicts cardiorespiratory fitness (CRF) than LA function. LA function adds little statistical value to predictive models of peak oxygen uptake (V̇o2peak) in healthy individuals, suggesting limited discriminatory for CRF once LA size is factored. In the wider population of ostensibly healthy individuals, the association between increased LA volume and higher CRF provides an important counter to the association between atrial enlargement and heart failure symptoms in those with cardiac pathology.

Genetic ablation of Lmp2 increases the susceptibility for impaired cardiac function.

Proteasome degradation is an integral part of cellular growth and function. Proteasomal intervention may mitigate adverse myocardial remodeling, but is associated with the onset of heart failure. Previously, we have demonstrated that increasing abundance of cardiac Lmp2 and its incorporation into proteasome complexes is an endogenous mechanism for proteasome regulation during hypertrophic remodeling of the heart induced by chronic ß-adrenoreceptor stimulation. Here, we investigated whether Lmp2 is required for myocardial remodeling not driven by inflammation and show that Lmp2 is a tipping element for growth and function in the heart but not for proteasome insufficiency. While it has no apparent impact under unchallenged conditions, myocardial remodeling without Lmp2 exacerbates hypertrophy and restricts cardiac function. Under chronic ß-adrenoreceptor stimulation, as seen in the development of cardiovascular disease and the manifestation of heart failure, genetic ablation of Lmp2 in mice caused augmented concentric hypertrophy of the left ventricle. While the heart rate was similarly elevated as in wildtype, myocardial contractility was not maintained without Lmp2, and apparently uncoupled of the ß-adrenergic response. Normalized to the exacerbated myocardial mass, contractility was reduced by 41% of the pretreatment level, but would appear preserved at absolute level. The lack of Lmp2 interfered with elevated 26S proteasome activities during early cardiac remodeling reported previously, but did not cause bulk proteasome insufficiency, suggesting the Lmp2 containing proteasome subpopulation is required for a selected group of proteins to be degraded. In the myocardial interstitium, augmented collagen deposition suggested matrix stiffening in the absence of Lmp2. Indeed, echocardiography of left ventricular peak relaxation velocity (circumferential strain rate) was reduced in this treatment group. Overall, targeting Lmp2 in a condition mimicking chronic ß-adrenoreceptor stimulation exhibited the onset of heart failure. Anticancer therapy inhibiting proteasome activity, including Lmp2, is associated with adverse cardiac events, in particular heart failure. Sparing Lmp2 may be an avenue to reduce adverse cardiac events when chronic sympathetic nervous system activation cannot be excluded.

Implication of sleep apnea for cardiac remodeling in patients with hypertrophic cardiomyopathy.

OBJECTIVES: Cardiac remodeling is a life-long process in hypertrophic cardiomyopathy (HCM), and if uncontrolled, would cause substantial morbidity and mortality. Sleep apnea (SA) is a common comorbidity in HCM. This study aimed to investigate the relationship between SA and cardiac remodeling in a large series of patients with HCM. METHODS: A total of 606 patients with HCM who underwent sleep evaluations at Fuwai Hospital were included. Parameters of cardiac remodeling were evaluated by echocardiographic studies. RESULTS: SA was present in 363 (59.9%) patients. Left ventricular (LV) end-diastolic diameter (P < 0.001), left atrial (LA) diameter (P = 0.024), ascending aortic diameter (P < 0.001) all increased and maximal end-diastolic wall thickness (P < 0.001) decreased with the severity of SA. After adjustment for sex, age, body mass index, hypertension, hyperlipidemia, diabetes, coronary artery disease and cigarette use, log (apnea-hypopnea index+1) was independently correlated with increasing LV end-diastolic diameter (ß = 0.729, P = 0.003) and deceasing maximal end-diastolic wall thickness (ß = -0.503, P = 0.009). Log (percentage of total sleep time spent with oxygen saturation<90% + 1) was independently correlated with increasing LV end-diastolic diameter (ß = 0.609, P = 0.004) and LA diameter (ß = 0.695, P = 0.006). Severity of SA (severe SA with odds ratio, 2.38; 95% CI, 1.20-4.70; P = 0.013), log (apnea-hypopnea index+1) (OR, 1.28; 95% CI, 1.01-1.63; P = 0.045) and log (percentage of total sleep time spent with oxygen saturation<90% + 1) (OR, 1.31; 95% CI, 1.08-1.59; P = 0.006) were also independently associated with LV enlargement. CONCLUSIONS: Severity of SA is independently associated with cardiac remodeling indicating a trend toward enlarged chamber size and thinned wall. Clinical trials are required to determine whether treatment of SA improves cardiac remodeling and long-term outcomes in patients with HCM.

Extracellular vesicles in heart failure.

Physiologically, extracellular vesicles (EVs) have been implicated as crucial mediators of immune response, cell homeostasis, angiogenesis, cell differentiation and growth, and tissue repair. In heart failure (HF) they may act as regulators of cardiac remodeling, microvascular inflammation, micro environmental changes, tissue fibrosis, atherosclerosis, neovascularization of plaques, endothelial dysfunction, thrombosis, and reciprocal heart-remote organ interaction. The chapter summaries the nomenclature, isolation, detection of EVs, their biologic role and function physiologically as well as in the pathogenesis of HF. Current challenges to the utilization of EVs as diagnostic and predictive biomarkers in HF are also discussed.

Cardiac arrhythmogenesis: roles of ion channels and their functional modification.

Cardiac arrhythmias cause significant morbidity and mortality and pose a major public health problem. They arise from disruptions in the normally orderly propagation of cardiac electrophysiological activation and recovery through successive cardiomyocytes in the heart. They reflect abnormalities in automaticity, initiation, conduction, or recovery in cardiomyocyte excitation. The latter properties are dependent on surface membrane electrophysiological mechanisms underlying the cardiac action potential. Their disruption results from spatial or temporal instabilities and heterogeneities in the generation and propagation of cellular excitation. These arise from abnormal function in their underlying surface membrane, ion channels, and transporters, as well as the interactions between them. The latter, in turn, form common regulatory targets for the hierarchical network of diverse signaling mechanisms reviewed here. In addition to direct molecular-level pharmacological or physiological actions on these surface membrane biomolecules, accessory, adhesion, signal transduction, and cytoskeletal anchoring proteins modify both their properties and localization. At the cellular level of excitation-contraction coupling processes, Ca2+ homeostatic and phosphorylation processes affect channel activity and membrane excitability directly or through intermediate signaling. Systems-level autonomic cellular signaling exerts both acute channel and longer-term actions on channel expression. Further upstream intermediaries from metabolic changes modulate the channels both themselves and through modifying Ca2+ homeostasis. Finally, longer-term organ-level inflammatory and structural changes, such as fibrotic and hypertrophic remodeling, similarly can influence all these physiological processes with potential pro-arrhythmic consequences. These normal physiological processes may target either individual or groups of ionic channel species and alter with particular pathological conditions. They are also potentially alterable by direct pharmacological action, or effects on longer-term targets modifying protein or cofactor structure, expression, or localization. Their participating specific biomolecules, often clarified in experimental genetically modified models, thus constitute potential therapeutic targets. The insights clarified by the physiological and pharmacological framework outlined here provide a basis for a recent modernized drug classification. Together, they offer a translational framework for current drug understanding. This would facilitate future mechanistically directed therapeutic advances, for which a number of examples are considered here. The latter are potentially useful for treating cardiac, in particular arrhythmic, disease.

Cardiac Remodeling: Novel Pathophysiological Mechanisms and Therapeutic Strategies.

Morphological and structural remodeling of the heart, including cardiac hypertrophy and fibrosis, has been considered a therapeutic target for heart failure for approximately three decades. Groundbreaking heart failure medications demonstrating reverse remodeling effects have contributed significantly to medical advancements. However, nearly 50% of heart failure patients still exhibit drug resistance, posing a challenge to the healthcare system. Recently, characteristics of heart failure resistant to ARBs and ß-blockers have been defined, highlighting preserved systolic function despite impaired diastolic function, leading to the classification of heart failure with preserved ejection fraction (HFpEF). The pathogenesis and etiology of HFpEF may be related to metabolic abnormalities, as evidenced by its mimicry through endothelial dysfunction and excessive intake of high-fat diets. Our recent findings indicate a significant involvement of mitochondrial hyper-fission in the progression of heart failure. This mitochondrial pathological remodeling is associated with redox imbalance, especially hydrogen sulfide accumulation due to abnormal electron leak in myocardium. In this review, we also introduce a novel therapeutic strategy for heart failure from the current perspective of mitochondrial redox-metabolic remodeling.

Role and molecular mechanisms of SGLT2 inhibitors in pathological cardiac remodeling (Review).

Cardiovascular diseases are caused by pathological cardiac remodeling, which involves fibrosis, inflammation and cell dysfunction. This includes autophagy, apoptosis, oxidative stress, mitochondrial dysfunction, changes in energy metabolism, angiogenesis and dysregulation of signaling pathways. These changes in heart structure and/or function ultimately result in heart failure. In an effort to prevent this, multiple cardiovascular outcome trials have demonstrated the cardiac benefits of sodium­glucose cotransporter type 2 inhibitors (SGLT2is), hypoglycemic drugs initially designed to treat type 2 diabetes mellitus. SGLT2is include empagliflozin and dapagliflozin, which are listed as guideline drugs in the 2021 European Guidelines for Heart Failure and the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America Guidelines for Heart Failure Management. In recent years, multiple studies using animal models have explored the mechanisms by which SGLT2is prevent cardiac remodeling. This article reviews the role of SGLT2is in cardiac remodeling induced by different etiologies to provide a guideline for further evaluation of the mechanisms underlying the inhibition of pathological cardiac remodeling by SGLT2is, as well as the development of novel drug targets.

Ubiquitin specific protease 38 aggravates pathological cardiac remodeling by stabilizing phospho-TBK1.

Chronic pressure overload can cause pathological cardiac remodeling and eventually heart failure. The ubiquitin specific protease (USP) family proteins play a prominent role in regulating substrate protein degradation and cardiac structural and functional homeostasis. Although USP38 is expressed in the heart, uncertainty exists regarding the function of USP38 in pathological cardiac remodeling. We constructed and generated cardiac specific USP38 knockout mice and cardiac specific USP38 overexpression mice to assess the role of USP38 in pathological cardiac remodeling. Furthermore, we used co-immunoprecipitation (Co-IP) assays and western blot analysis to identify the molecular interaction events. Here, we reported that the expression of USP38 is significantly elevated under a hypertrophic condition in vivo and in vitro. USP38 deletion significantly mitigates cardiomyocyte enlargement in vitro and hypertrophic effect induced by pressure overload, while overexpression of USP38 markedly aggravates cardiac hypertrophy and remodeling. Mechanistically, USP38 interacts with TANK-binding kinase 1 (TBK1) and removes K48-linked polyubiquitination of TBK1, stabilizing p-TBK1 and promoting the activation of its downstream mediators. Overexpression of TBK1 in the heart of cardiac specific USP38 knockout mice partially counteracts the benefit of USP38 deletion on pathological cardiac remodeling. The TBK1 inhibitor Amlexanox significantly alleviates pressure overload induced-cardiac hypertrophy and myocardial fibrosis in mice with USP38 overexpression. Our results demonstrate that USP38 serves as a positive regulator of pathological cardiac remodeling and suggest that targeting the USP38-TBK1 axis is a promising treatment strategy for hypertrophic heart failure.