Risk Factor For Heart Failure Research Articles

A self-reinforcing cycle hypothesis in heart failure pathogenesis.

Heart failure is a progressive syndrome with high morbidity and mortality rates. Here, we suggest that chronic exposure of the heart to risk factors for heart failure damages heart mitochondria, thereby impairing energy production to levels that can suppress the heart's ability to pump blood and repair mitochondria (both energy-consuming processes). As damaged mitochondria accumulate, the heart becomes deprived of energy in a 'self-reinforcing cycle', which can persist after the heart is no longer chronically exposed to (or after antagonism of) the risk factors that initiated the cycle. Together with other previously described pathological mechanisms, this proposed cycle can help explain (1) why heart failure progresses, (2) why it can recur after cessation of treatment, and (3) why heart failure is often accompanied by dysfunction of multiple organs. Ideally, therapy of heart failure syndrome would be best attempted before the self-reinforcing cycle is triggered or designed to break the self-reinforcing cycle.

Identification and correction for collider bias in a genome-wide association study of diabetes-related heart failure

Type 2 diabetes (T2D) is a major risk factor for heart failure (HF) and has elevated incidence among individuals with HF. Since genetics and HF can independently influence T2D, collider bias may occur when T2D (i.e., collider) is controlled for by design or analysis. Thus, we conducted a genome-wide association study (GWAS) of diabetes-related HF with correction for collider bias. We first performed a GWAS of HF to identify genetic instrumental variables (GIVs) for HF and to enable bidirectional Mendelian randomization (MR) analysis between T2D and HF. We identified 61 genomic loci, significantly associated with all-cause HF in 114,275 individuals with HF and over 1.5 million controls of European ancestry. Using a two-sample bidirectional MR approach with 59 and 82 GIVs for HF and T2D, respectively, we estimated that T2D increased HF risk (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.04-1.10), while HF also increased T2D risk (OR 1.60, 95% CI 1.36-1.88). Then we performed a GWAS of diabetes-related HF corrected for collider bias due to the study design of index cases. After removing the spurious association of TCF7L2 locus due to collider bias, we identified two genome-wide significant loci close to PITX2 (chromosome 4) and CDKN2B-AS1 (chromosome 9) associated with diabetes-related HF in the Million Veteran Program and replicated the associations in the UK Biobank. Our MR findings provide strong evidence that HF increases T2D risk. As a result, collider bias leads to spurious genetic associations of diabetes-related HF, which can be effectively corrected to identify true positive loci.

Heart failure: From Definition to Prognosis - An Integrated Analysis of Epidemiological Data, Clinical and Paraclinical Findings, and Prognosis

Currently, heart failure (HF) represents a major challenge in the medical field, affecting a significant number of people globally. Although previous research has brought valuable contributions, recent discoveries and approaches bring new perspectives to this complex condition. Among the analyzed data, there is a notable increase in the incidence of HF, particularly among younger individuals, with a significant risk in hospitalizations in the future. Risk factors for HF are linked to unhealthy lifestyle and medical conditions such as atrial fibrillation, coronary artery disease, and hypertension. For diagnosis, paraclinical investigations, consisting of electrocardiography and echocardiography, are essential, while measuring plasma natriuretic peptides can provide valuable additional insights. The prognosis of HF patients varies depending on the type of HF, being influenced by factors such as age, gender, and comorbidities.

Non-cardiac comorbidities in heart failure: an update on diagnostic and management strategies.

Managing non-cardiac comorbidities in heart failure (HF) requires a tailored approach that addresses each patient's specific conditions and needs. Regular communication and coordination among healthcare providers is crucial to providing the best possible care for these patients. Poorly controlled hypertension contributes to left ventricular remodeling and diastolic dysfunction, emphasizing the importance of optimal blood pressure control while avoiding adverse effects. Among HF patients with diabetes, SGLT2 inhibitors and mineralocorticoid receptor antagonists have shown promise in reducing HF-related morbidity and mortality. Chronic kidney disease exacerbates HF and vice versa, forming the vicious cardiorenal syndrome, so disease-modifying therapies should be maintained in HF patients with comorbid CKD, even with transient changes in kidney function. Anemia in HF patients may be multifactorial, and there is growing evidence for the benefit of intravenous iron supplementation in HF patients with iron deficiency with or without anemia. Obesity, although a risk factor for HF, paradoxically offers a better prognosis once HF is established, though developing treatment strategies may improve symptoms and cardiac performance. In HF patients with stroke and atrial fibrillation, anticoagulation therapy is recommended. Among HF patients with sleep-disordered breathing, continuous positive airway pressure may improve sleep quality. Chronic obstructive pulmonary disease often coexists with HF, and many patients can tolerate cardioselective beta-blockers. Cancer patients with comorbid HF require careful consideration of cardiotoxicity risks associated with cancer therapies. Depression is underdiagnosed in HF patients and significantly impacts prognosis. Cognitive impairment is prevalent in HF patients and impacts their self-care and overall quality of life.

Potential molecular and cellular mechanisms of the effects of cuproptosis-related genes in the cardiomyocytes of patients with diabetic heart failure: a bioinformatics analysis.

Diabetes mellitus is an independent risk factor for heart failure, and diabetes-induced heart failure severely affects patients' health and quality of life. Cuproptosis is a newly defined type of programmed cell death that is thought to be involved in the pathogenesis and progression of cardiovascular disease, but the molecular mechanisms involved are not well understood. Therefore, we aimed to identify biomarkers associated with cuproptosis in diabetes mellitus-associated heart failure and the potential pathological mechanisms in cardiomyocytes. Cuproptosis-associated genes were identified from the previous publication. The GSE26887 dataset was downloaded from the GEO database. The consistency clustering was performed according to the cuproptosis gene expression. Differentially expressed genes were identified using the limma package, key genes were identified using the weighted gene co-expression network analysis(WGCNA) method, and these were subjected to immune infiltration analysis, enrichment analysis, and prediction of the key associated transcription factors. Consistency clustering identified three cuproptosis clusters. The differentially expressed genes for each were identified using limma and the most critical MEantiquewhite4 module was obtained using WGCNA. We then evaluated the intersection of the MEantiquewhite4 output with the three clusters, and obtained the key genes. There were four key genes: HSDL2, BCO2, CORIN, and SNORA80E. HSDL2, BCO2, and CORIN were negatively associated with multiple immune factors, while SNORA80E was positively associated, and T-cells accounted for a major proportion of this relationship with the immune system. Four enriched pathways were found to be associated: arachidonic acid metabolism, peroxisomes, fatty acid metabolism, and dorsoventral axis formation, which may be regulated by the transcription factor MECOM, through a change in protein structure. HSDL2, BCO2, CORIN, and SNORA80E may regulate cardiomyocyte cuproptosis in patients with diabetes mellitus-associated heart failure through effects on the immune system. The product of the cuproptosis-associated gene LOXL2 is probably involved in myocardial fibrosis in patients with diabetes, which leads to the development of cardiac insufficiency.

DNMT3A-mutant clonal haematopoiesis and the recovery of patients with acute ST-elevation myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart foundation Background Haematopoietic stem cells can acquire mutations and produce mutant blood cells. When this occurs in the absence of overt blood disease, it is clonal haematopoiesis of indeterminate potential (CHIP). CHIP is a novel, independent risk factor for ischaemic heart disease and heart failure (HF)(1). However, the molecular mechanisms are poorly understood. Myocardial infarction (MI) is a leading cause of HF due to ventricular remodelling and scar formation(2). We postulate CHIP mutations result in aberrant inflammation that contributes to maladaptive ventricular remodelling following MI. We investigated clinical outcomes and immune cell biology in CHIP and non-CHIP patients (pts) with acute ST-segment elevation MI (STEMI). Purpose Identify and quantify mutations with variant allele frequency (VAF)≥1% in STEMI pts. Assess leukocyte mutational burden. Investigate transcription profiles and leukocyte function in CHIP and non-CHIP STEMI pts. Methods 119 pts diagnosed with STEMI were prospectively recruited (REC19/SC/0362). We collected clinical data, including echocardiogram (echo) parameters and isolated plasma and peripheral blood mononucleated cells (PBMCs) from blood collected 48-96 hours post onset of chest pain. PBMCs were screened for mutations and analysed by flow cytometry. We assessed CHIP VAF with digital droplet PCR in flow-sorted monocytes (Mono), T and B-cells. We performed single-cell RNAseq (10x Genomics) on PBMCs. Luminex or ELISA kits were used to measure plasma proteins. Results 59/119 recruited pts had CHIP (VAF≥1%). CHIP pts were significantly older than non-CHIP pts. DNMT3A was the most commonly mutated gene (28%), followed by TET2 (17%) and ASXL1 (5.3%). 53 pts had impaired LV ejection fraction (LVEF) at admission and a follow-up Echo at median 4.6 months (2.5-8 IQR) post STEMI. They were classified as responder (R) n=24, Δ LVEF≥5% or non-responder (NR) n=29, ΔLVEF<5%. Pts with DNMT3A CHIP were 12 times more likely to be NR (p=0.02). Baseline LVEF was similar in CHIP and non-CHIP pts, but ΔLVEF was significantly reduced in DNMT3A vs non-CHIP pts (p<0.01). DNMT3A mutations were highest in Mono (mean VAF 6.3%), present in B cells (3%) but rare in T cells (1.7%). Within the Mono population, DNMT3A mutant pts had significantly higher proportions of classical Mono compared to non-CHIP (p=0.02). Using scRNAseq, we computed Mono trajectories and differential gene expression. Compared to non-CHIP, DNMT3A-mutant samples upregulated receptor for advanced glycation end-products (RAGE) and toll-like receptor signaling gene signatures. Despite this, we did not observe raised leukocyte count or detect increased levels of inflammatory cytokines in DNMT3A-mutant pts plasma samples. Conclusions DNMT3A CHIP is associated with poor LVEF recovery post-STEMI due to a dysregulated inflammatory response to acute myocardial injury. Furthermore, our data suggests that this may occur via different mechanisms than non-CHIP NR.

Development and validation of a nomogram model for all-cause mortality risk in patients with chronic heart failure and atrial fibrillation

BackgroundAs the global aging process continues to accelerate, heart failure (HF) has become an important cause of increased morbidity and mortality in elderly patients. Chronic atrial fibrillation (AF) is a major risk factor for HF. Patients with HF combined with AF are more difficult to treat and have a worse prognosis. The aim of this study was to explore the risk factors for 1-year mortality in patients with HF combined with AF and to develop a risk prediction assessment model.MethodsWe recruited hospitalized patients with HF and AF who received standardized care in the Department of Cardiology at Shengjing Hospital of China Medical University from January 2013 to December 2018. The patients were randomly divided into modeling and internal validation groups using a random number generator at a 1:1 ratio. Multivariate Cox regression analysis was used to identify risk factors for all-cause mortality during a one-year follow-up period. Then, a nomogram was constructed based on the weights of each index and validated. Receiver operating characteristic curve, the area under the curve (AUC), decision curve, and calibration curve analyses for survival were used to evaluate the model’s predictive and clinical validities and calibration.ResultsWe included 3,406 patients who met the eligibility criteria; 1,703 cases each were included in the modeling and internal validation groups. Eight statistically significant predictors were identified: age, sex, New York Heart Association cardiac function class III or IV, a history of myocardial infarction, and the albumin, triglycerides, N-terminal pro-b-type natriuretic peptide, and blood urea nitrogen levels. The AUCs were 0.793 (95% confidence interval: 0.763–0.823) and 0.794 (95% confidence interval: 0.763–0.823) in the modeling and validation cohorts, respectively.ConclusionsWe present a predictive model for all-cause mortality in patients with coexisting HF and AF comprising eight key factors. This model gives clinicians a simple assessment tool that may improve the clinical management of these patients.

Gender cardiology: clinical and pathophysiological features of the course the main diseases in women

Coronary heart disease is the leading cause of death for both women and men. Older women, when coronary heart disease first appears, have more comorbidities and usually complain of atypical symptoms. Mortality and hospitalization rates caused by acute myocardial infarction are higher for women. It should be noted that adherence to secondary prevention for women is lower.Female predominance has been noted in idiopathic pulmonary arterial hypertension (IPAH), hereditary pulmonary hypertension, and collagenosisassociated pulmonary arterial hypertension. However, according to the latest data of the European register COMPERA, gender differences disappear for elderly patients and for the patients having concomitant diseases. The more frequent occurrence of cardiomyopathies among women is considered. Peripartum cardiomyopathy associated with pregnancy and childbirth, and Takotsubo cardiomyopathy due to psychoemotional status, in particular a stressful situation, determines a woman's further prognosis. Arrythmias are explained by changes in hormonal status during pregnancy, menopause, or are associated with the onset of the underlying disease.Heart failure usually affects both sexes equally, with women more likely to suffer from HFpEF and men from HFrEF. The classic cardiovascular, gender, and social risk factors for cardiovascular disease and heart failure have a different meaning for women than for men. It is necessary to take into account the parameters for EchoCG diagnostics for women, since the size of the women heart is smaller.

Sodium-glucose cotransporter-2 inhibitors improve cardiovascular outcomes post-acute coronary syndrome complicated by acute heart failure.

Acute coronary syndrome (ACS) remains a risk factor for heart failure (HF). Therefore, we aimed to assess the cardioprotective role of sodium-glucose cotransporter-2 (SGLT2) inhibitors post-ACS in patients with acute HF (AHF) and diabetes. We conducted a retrospective observational cohort study employing propensity score matching. This study involved patients with diabetes admitted with ACS complicated by AHF, defined as either new clinical HF requiring diuretics during the index admission or having an ejection fraction (EF) of <40%. The study population was divided into two groups; (1) SGLT2 inhibitor users and (2) SGLT2 inhibitor non-users. The Cox proportional hazard regression analysis was used to evaluate the outcomes. A total of 465 patients (93% male; mean age, 55 ± 10 years) were included in this study. Using a 1 : 1 propensity score matching, 78 patients were included per arm with an absolute standardized difference of <0.1 for all baseline characteristics. The use of SGLT2 inhibitors resulted in lower composite outcomes of ACS, HF hospitalization, and all-cause mortality at 1 month and 12 months [1 month: 2.6% vs. 11.5%, HR = 0.20 (0.04-0.94), p = 0.041; 12 months: 14.1% vs. 23.1%, HR = 0.46 (0.22-0.99), p = 0.046]. The findings suggest that SGLT2 inhibitors may confer cardioprotective effects in ACS-induced AHF, thereby widening the spectrum for indications of SGLT2 inhibitors.

Cancer as an Individual Risk Factor for Heart Failure: A Review of Literature.

The intricate relationship between cancer and cardiovascular diseases (CVD), notably heart failure (HF), is gaining attention in the medical field. This literature review explores the intricate interplay between cancer and CVD, particularly HF, emphasizing their significant impact on global mortality and comorbidity. While preventive measures have contributed to reducing their incidence, challenges persist in predicting and managing cancer-related complications. This review article delves into various risk factors associated with both cancer and HF, including lifestyle factors, genetic predispositions, and immune system dysregulation. It highlights emerging evidence suggesting a direct interaction between cancer and HF, with studies indicating an elevated risk of mortality from cancer in patients with HF and vice versa. Pathological mechanisms such as inflammation, oxidative stress, and tissue hypoxia are implicated in cancer-induced cardiac dysfunction, underscoring the need for comprehensive clinical investigations and ethical considerations in patient care. The review also discusses the potential role of biomarkers in risk assessment, early detection of cardiotoxicity, and understanding common pathophysiological links between cancer and HF, paving the way for multifaceted preventive and therapeutic approaches.

Possible Role of Gut Microbiota Alterations in Myocardial Fibrosis and Burden of Heart Failure in Hypertensive Heart Disease.

Epidemiological studies have revealed that hypertensive heart disease is a major risk factor for heart failure, and its heart failure burden is growing rapidly. The need to act in the face of this threat requires first an understanding of the multifactorial origin of hypertensive heart disease and second an exploration of new mechanistic pathways involved in myocardial alterations critically involved in cardiac dysfunction and failure (eg, myocardial interstitial fibrosis). Increasing evidence shows that alterations of gut microbiota composition and function (ie, dysbiosis) leading to changes in microbiota-derived metabolites and impairment of the gut barrier and immune functions may be involved in blood pressure elevation and hypertensive organ damage. In this review, we highlight recent advances in the potential contribution of gut microbiota alterations to myocardial interstitial fibrosis in hypertensive heart disease through blood pressure-dependent and blood pressure-independent mechanisms. Achievements in this field should open a new path for more comprehensive treatment of myocardial interstitial fibrosis in hypertensive heart disease and, thus, for the prevention of heart failure.

Sodium-glucose exchanger 2 inhibitor canagliflozin promotes mitochondrial metabolism and alleviates salt-induced cardiac hypertrophy via preserving SIRT3 expression

IntroductionExcess salt intake is not only an independent risk factor for heart failure, but also one of the most important dietary factors associated with cardiovascular disease worldwide. Metabolic reprogramming in cardiomyocytes is an early event provoking cardiac hypertrophy that leads to subsequent cardiovascular events upon high salt loading. Although SGLT2 inhibitors, such as canagliflozin, displayed impressive cardiovascular health benefits, whether SGLT2 inhibitors protect against cardiac hypertrophy-related metabolic reprogramming upon salt loading remain elusive. ObjectivesTo investigate whether canagliflozin can improve salt-induced cardiac hypertrophy and the underlying mechanisms. MethodsDahl salt-sensitive rats developed cardiac hypertrophy by feeding them an 8% high-salt diet, and some rats were treated with canagliflozin. Cardiac function and structure as well as mitochondrial function were examined. Cardiac proteomics, targeted metabolomics and SIRT3 cardiac-specific knockout mice were used to uncover the underlying mechanisms. ResultsIn Dahl salt-sensitive rats, canagliflozin showed a potent therapeutic effect on salt-induced cardiac hypertrophy, accompanied by lowered glucose uptake, reduced accumulation of glycolytic end-products and improved cardiac mitochondrial function, which was associated with the recovery of cardiac expression of SIRT3, a key mitochondrial metabolic regulator. Cardiac-specific knockout of SIRT3 not only exacerbated salt-induced cardiac hypertrophy but also abolished the therapeutic effect of canagliflozin. Mechanistically, high salt intake repressed cardiac SIRT3 expression through a calcium-dependent epigenetic modifications, which could be blocked by canagliflozin by inhibiting SGLT1-mediated calcium uptake. SIRT3 improved myocardial metabolic reprogramming by deacetylating MPC1 in cardiomyocytes exposed to pro-hypertrophic stimuli. Similar to canagliflozin, the SIRT3 activator honokiol also exerted therapeutic effects on cardiac hypertrophy. ConclusionCardiac mitochondrial dysfunction caused by SIRT3 repression is a critical promotional determinant of metabolic pattern switching underlying salt-induced cardiac hypertrophy. Improving SIRT3-mediated mitochondrial function by SGLT2 inhibitors-mediated calcium handling would represent a therapeutic strategy against salt-related cardiovascular events.

Estrogen Regulation of PAD2 and Citrullination in the Aging Female Heart

Advanced age is the primary risk factor for heart failure, an enormous public health burden. With aging, men tend to develop systolic dysfunction whereas women are predisposed to develop diastolic dysfunction. Despite these known phenotype differences, underlying molecular mechanisms of sex differences in cardiac aging are unknown. Citrullination, a post-translational modification catalyzed by the peptidylarginine deiminases (PAD) enzyme family, is positively regulated by the sex hormone estrogen (E2) suggesting a potential novel mechanism of age-related cardiac functional changes in women. We hypothesized that PAD expression and citrullination are sexually dimorphic with aging such that as E2 levels decline, so too does citrullination, thus contributing to diastolic dysfunction. We quantified expression of PAD2, the primary cardiac isoform, in female young reproductively competent adult (3 months) and aged (21 months) C57Bl6 mice. Consistent with clinical reports, in our model of aging, female mice developed diastolic dysfunction, with a prolonged linear phase relaxation (54.0 ± 1.7 msec, adult and 66.0 ± 3.3 msec aged, p&lt;0.05). PAD2 expression decreased with age in the female heart, concomitant with decreases in myocardial protein citrullination. To identify potential mechanisms of differential citrullination by age, we performed cit-mass spectrometry. Adult female mice had higher overall citrullination patterns than aged females with enrichment of citrullinated proteins in metabolic, mitochondrial, and sarcomeric pathways. In reproductively competent adult females, cardiac PAD2 expression was higher during estrus compared to diestrus. To confirm direct regulation of PAD2 by E2, a cohort of adult mice underwent ovariectomy (OVX) with or without E2 replacement, provided orally in the water (0.5μM E2) for three weeks. Exogenous E2 supplementation post-OVX increased uterine weight and PAD2 expression, further confirming positive regulation by E2. Together, we suggest that hormonally regulated changes in PAD2 and citrullination with age contribute to sex-specific cardiac aging. Ongoing experiments will directly test the role of PAD2 in the heart by generation of a novel myocyte specific PAD2 deleted mouse across the female lifespan. This abstract was made possible by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under 2P20GM103432. This work was supported by the National Institutes of Health [K01 AG058810 DRB, [K01 AG066845 KCW]. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

EFFECTS OF DIFFERENT SEX HORMONES ON CARDIOVASCULAR DISEASE: A META-ANALYSIS AND SYSTEMATIC REVIEW

Objective: Sex hormones play different roles in cardiovascular risk of male and female patients. Especially for postmenopausal women, sex hormone disorder is the main reason for their increased risk of cardiovascular disease. This study mainly explores the effects of different sex hormone levels on cardiovascular diseases in men and postmenopausal women. Design and method: This study included 16 studies with 404,474 patients, including 387,361 male patients and 17,113 female patients. Hazard ratio (HR) and 95%CI results of studies on sex hormones and cardiovascular disease risk in the included literature were extracted as research data. The main outcome events are: cardiovascular disease (CVD), heart failure (HF), cardiovascular death, major cardiovascular adverse events (MACE) and all-cause death. This paper mainly researches the effects of sex hormones on cardiovascular risk and the differences of cardiovascular events between men and women. Results: 1. DHT is a protective factor of cardiovascular risk in male patients, HR = 0.83, 95% CI (0.72, 0.96). 2. For postmenopausal women, SHBG and cFT are the risk factors of CVD in postmenopausal women, with HR 95%CI of 1.06(1.01,1.11) and 1.11 (1.04, 1.19) respectively. 3. DHEA and TT is a risk factor for heart failure in postmenopausal women, which can increase the risk by 17% (HR = 1.17, 95% CI (1.09, 1.24)) and HR = 1.07, 95% CI (1.03, 1.12), while the SHBG and DHEA had no significant effect on the occurrence of chronic heart failure. Conclusions: DHT is a protective factor of cardiovascular disease risk in men, and the increase of androgen level is an important risk factor of cardiovascular disease risk in postmenopausal women.

Novel Role of YAP1 in Regulating Blood Pressure and Vascular Tone

Introduction: Hypertension is a major risk factor for occlusive vascular diseases, myocardial infarction, heart failure, stroke, and chronic kidney disease. In the U.S., ~30% of adults suffer from hypertension. Merely half of the individuals with hypertension have their blood pressure under control, despite the wide range of antihypertensive medications available, indicating an urgent need for a better understanding of the underlying causes of hypertension to identify novel therapeutic strategies for its treatment and prevention. Recent genome-wide association study (GWAS) has identified an unexpected association between a loss-of-function SNP in the YAP1 gene locus and decreased blood pressure (BP). Moreover, de novo analysis of publicly available RNAseq data revealed that the vascular tissues of hypertensive mice treated with Ang-II exhibit increased YAP1 expression. Suggesting a novel role of YAP1 in blood pressure regulation. However, whether Vascular smooth muscle cell (VSMC) expressed YAP1 has a specific role in VSMC contraction and BP regulation remains completely unknown. Therefore, we hypothesized that YAP1 could play a key role in regulating blood pressure. Methodology: We have generated a novel inducible SM-specific- Yap1 Knockout ( YAP1 iKO) mouse model and employed a pharmacological inhibitor of YAP1, Verteporfin, to delineate the functional role of VSMC-expressed YAP1 in hypertension in regulating vascular tone and BP. Vascular reactivity experiments were performed using wire myography. BP was measured in ambulant mice via radiotelemetry. In vitro gain- and loss-of-function studies utilizing human coronary artery SMCs were conducted to examine the impact of YAP1 on contractility signaling components using western blotting. Results: Consistent with GWAS and RNAseq data, we found that YAP1 is upregulated in vascular tissues of spontaneously hypertensive rats (SHRs). Using aortic rings from WT mice, we discovered that Verteporfin significantly reduced vasoconstrictive responses to Phenylephrine or Serotonin but did not alter endothelium-dependent vasorelaxant responses to Acetylcholine, suggesting a specific role of YAP1 in VSMCs. Consistently, YAP1 iKO exhibited attenuated responses to vasoconstrictors in isolated conduit and resistance vessels. Importantly, radiotelemetry studies demonstrated for the first time that YAP1 iKO mice exhibit a hypotensive phenotype. Mechanistically, YAP1 gain- and loss-of-function studies in human VSMCs showed that YAP1 activates multiple signaling pathways that play a key role in VSMC contractility including RhoA/ROCK1/actin polymerization and PKC/ERK signaling pathways. Summary/Conclusion: This is the first study to demonstrate that inhibition of SM-specific-Yap1 expression regulates BP and vascular tone, likely via the regulation of contractile machinery components. Together, our data suggest that YAP1 is a promising novel therapeutic target for ameliorating hypertension. This work is supported by a grant from National Heart, Lung, and Blood Institute (R00HL153896). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

RIGHT VENTRICLE IN PATIENTS WITH ARTERIAL HYPERTENSION AND B STAGE HEART FAILURE

Objective: According to ACC/AHA Heart failure (HF) classification the A stage of HF is a high risk for HF but without structural heart disease or symptoms; B stage is a structural heart disease but without signs or symptoms of HF. One of the most important risk factors of HF is Arterial Hypertension (AH). There is no information about Right Ventricular (RV) structure and function, in patients with stage A and B of HF. The aim of our research was to study RV structure and function in patients with AH and stage A or B HF. Design and method: We studied 163 patients with AH (female-76, male 87). 45 in stage A and 118 in stage B HF. All patients undergone standard EchoCG examination. RV outflow tract (RVout) was examined by M-mode from parasternal short axis and PW TDI from subcostal position (RVoutTDI). The shape of RWoutTDI was different from the Tricuspid anulus TDI. It consists from positive isometric contraction (ICTs), isotonic contraction (s), negative early diastolic (e) late (a) diastolic waves velocities, two negative (e1) positive (e2) isometric relaxation waves. We measured the pick velocities of these waves in cm/sec and isometric contraction (ICT), ejection (RVET) and isometric relaxation time (IRT) intervals in msec. On M-mode EcoCG of RVoutRV we measured Diastolic Diameter (Dd) systolic diameter (Ds), fractional shortening (RWoutFS) and RW wall systolic excursion (RWexc). Results: We did not find any significant differences between in RV EcoCG, RVout, RVoutTRI and Tricuspid annulus TDI parameters between the A and B Heart Failure groups in patients wit Arterial Hypertension. Conclusions: There is no difference in EchoCG parameters between A and B Heart Failure groups in patients with Arterial Hypertension.

High Variability of Body Mass Index Is Independently Associated With Incident Heart Failure.

Heart failure (HF) is a serious condition with increasing prevalence, high morbidity, and increased mortality. Obesity is an established risk factor for HF. Fluctuation in body mass index (BMI) has shown a higher risk of cardiovascular outcomes. We investigated the association between BMI variability and incident HF. In the UK Biobank, we established a prospective cohort after excluding participants with prevalent HF or cancer at enrollment. A total of 99 368 White participants with ≥3 BMI measures during >2 years preceding enrollment were included, with a median follow-up of 12.5 years. The within-participant variability of BMI was evaluated using standardized SD and coefficient of variation. The association of BMI variability with incident HF was assessed using Fine and Gray's competing risk model, adjusting for confounding factors and participant-specific rate of BMI change. Higher BMI variability measured in both SD and coefficient of variation was significantly associated with higher risk in HF incidence (SD: hazard ratio [HR], 1.05 [95% CI, 1.03-1.08], P<0.0001; coefficient of variation: HR, 1.07 [95% CI, 1.04-1.10], P<0.0001). Longitudinal health records capture BMI fluctuation, which independently predicts HF incidence.

Risk Factors of Postoperative Acute Heart Failure in Elderly Patients After Hip Fracture Surgery.

Background Postoperative acute heart failure (AHF) in elderly patients after hip fracture surgery is a common complication. Therefore, this study aimed to identify the risk factor of AHF after hip fracture surgery among the older population. Methods This retrospective cohort study was performed on 88 admitted patients whose hip fractures were fixed via internal fixation surgery in a tertiary care hospital in Rawalpindi, Pakistan, from January 2022 to March 2023. Recruitment of patients was made through established inclusion and exclusion criteria. Ethical approval and informed consent were also gained before the data collection. A self-designed form was used to collect data. Data analysis was carried out in the IBM SPSS Statistics for Windows, Version 25 (Released 2017; IBM Corp., Armonk, New York, United States). Both descriptive and inferential statistics were applied to compare the attributes of the patients with AHF and patients without AHF. Multivariate logistic regression was used to evaluate the association between the postoperative AHF and its potential risk factors. Results Out of 88 enrolled patients, 12 (13.64%) had developed postoperative AHF. Age ≥ 65 years (OR = 2.606, 95% CI = 1.035~4.160, p = 0.010), anemia (OR = 3.178, 95% CI = 1.847~5.990, p = 0.029), hypertension (OR = 2.019, 95% CI = 1.110~4.034, p = 0.012), diabetes mellitus (OR = 2.003, 95% CI = 1.115~4.012, p = 0.015), hypoalbuminemia (OR = 2.486, 95% CI = 1.218~4.619, p = 0.030), and operation time ≥ 120 minutes (OR = 1.702, 95% CI = 1.099~2.880, p = 0.018), were the risk factors of postoperative AHF in elderly patients after hip fracture surgery. Conclusions In the study population, the incidence of postoperative heart failure was significant and age ≥ 65 years, anemia, hypertension, diabetes mellitus, hypoalbuminemia, and operation time ≥ 120 were significantly involved in the development of it. Preoperative identification and management of AHF risk factors could lead to the prevention of postoperative complications.

Gut Microbiome and Its Role in Valvular Heart Disease: Not a "Gutted" Relationship.

The role of the gut microbiome (GM) and oral microbiome (OM) in cardiovascular disease (CVD) has been increasingly being understood in recent years. It is well known that GM is a risk factor for various CVD phenotypes, including hypertension, dyslipidemia, heart failure and atrial fibrillation. However, its role in valvular heart disease (VHD) is less well understood. Research shows that, direct, microbe-mediated and indirect, metabolite-mediated damage as a result of gut dysbiosis and environmental factors results in a subclinical, chronic, systemic inflammatory state, which promotes inflammatory cell infiltration in heart valves and subsequently, via pro-inflammatory molecules, initiates a cascade of reaction, resulting in valve calcification, fibrosis and dysfunction. This relationship between GM and VHD adds a pathophysiological link to the pathogenesis of VHD, which can be aimed therapeutically, in order to prevent or regress any risk for valvular pathologies. Therapeutic interventions include dietary modifications and lifestyle interventions, in order to influence environmental factors that can promote gut dysbiosis. Furthermore, the combination of probiotics and prebiotics, as well as fecal m transplantation and targeted treatment with inducers or inhibitors of microbial enzymes have showed promising results in animal and/or clinical studies, with the potential to reduce the inflammatory state and restore the normal gut flora in patients. This review, thus, is going to discuss the pathophysiological links behind the relationship of GM, CVD and VHD, as well as explore the recent data regarding the effect of GM-altering treatment in CVD, cardiac function and systemic inflammation.

The Role of Gut Microbiota and Its Metabolites in Patients with Heart Failure.

Heart failure (HF) is a significant health concern; early detection and prevention are crucial. Recent studies suggest that the gut microbiota and its metabolites may influence HF development and risk factors. We explored this relationship by examining changes in gut microbiota composition and metabolite levels in HF patients. HF patients often exhibit decreased alpha and beta diversity compared to controls, suggesting lower bacterial richness and community variation. Changes in specific bacterial phyla were observed, with decreases in Firmicutes (e.g., Ruminococcus) and Bacteroidetes (e.g., Prevotella) and increases in Proteobacteria (e.g., Escherichia, Shigella, and Klebsiella) and Actinobacteria. Gut-microbiota-related metabolites have been identified, potentially affecting various body systems, including the cardiovascular system. Among these are short-chain fatty acids (SCFAs), betaine, trimethylamine N-oxide (TMAO), phenylalanine, tryptophan-kynurenine, and phenylacetylgutamine (PAGIn). Although SCFAs positively affect our organisms, patients with HF have been observed to experience a decline in bacteria responsible for producing these chemical compounds. There have been indications of possible links between betaine, TMAO, phenylalanine, tryptophan-kynurenine, PAGIn, and heart failure. TMAO and phenylalanine, in particular, show promise as potential prognostic factors. However, their clinical significance has not yet been thoroughly evaluated and requires further investigation.