Cardiovascular Diseases Including Heart Failure Research Articles

Prognostic impact of left atrial reverse remodeling in patients with ADHF-HFpEF regardless of atrial fibrillation -PURSUIT-HFpEF Registry-

Abstract Background Left atrial (LA) dilatation is associated with increased mortality in patients with cardiovascular disease including heart failure (HF) and LA reverse remodeling (LARR) was reported to be associated with favorable outcomes in patients with HF. However, it remains to be clarified whether LARR could have prognostic value in patients with HF with preserved ejection fraction (HFpEF). Purpose The purpose of this study is to elucidate whether LARR is associated with clinical outcome in patients with HFpEF in relation to the presence of atrial fibrillation (AF). Methods We prospectively studied 492 patients with acute decompensated heart failure with preserved ejection fraction (ADHF-HFpEF) without the poor outcome during the first year postdischarge. Echocardiography was performed just before discharge and at 1 year after discharge. LARR was defined as the reduction of 15% or more in left atrial end-systolic volume (LAV). The primary outcome was rehospitalization for worsening heart failure. Results All study patients were divided into 2 groups according to the presence of AF at discharge (AF group, n=182 and non-AF group, n=310). During a mean follow-up period of 1.4±1.2 years, 78 patients were rehospitalized for worsening heart failure (37 patients in AF group and 41 in non-AF group). ΔLAV, the degree of reduction in LAV during the first year postdischarge, was significantly independently associated with primary outcome after multivariable adjustment both in AF group (p=0.033, HR 0.992 [0.984-0.999]) and non-AF group (p=0.021, HR 0.986 [0.974-0.998]). Kaplan-Meier analysis revealed that patients with LARR had significantly lower risk for primary outcome than those without LARR not only in the whole study patients (8% vs 20%, p=0.001) but also both in AF group (9% vs 24% p=0.013) and in non-AF group (8% vs 16% p=0.043). Among clinical characteristics during the index hospitalization, the presence of AF and prior HF hospitalization were significantly independently associated with LARR at multivariate Cox logistic regression analysis (p=0.006, OR 0.554 [0.364-0.843] and p=0.007, OR 0.491 [0.292-0.826], respectively). Conclusion(s) The left atrial reverse remodeling could have the prognostic impact in patients with ADHF-HFpEF regardless of the presence of atrial fibrillation.Kaplan-Meier curves in AF and non-AF

Po-Ge-Jiu-Xin decoction alleviate sepsis-induced cardiomyopathy via regulating phosphatase and tensin homolog-induced putative kinase 1 /parkin-mediated mitophagy

Ethnopharmacological relevanceSepsis is a life-threatening systemic syndrome usually accompanied by myocardial dysfunction. Po-Ge-Jiu-Xin decoction (PGJXD), a traditional Chinese prescription medicine, has been used clinically to treat cardiovascular disease including heart failure, sepsis-induced cardiomyopathy (SIC) and even septic shock. Previous clinical studies suggested PGJXD has shown promising results in improving cardiac function and treating heart failure in sepsis. However, more research is needed to elucidate the mechanisms underlying PGJXD's therapeutic effects in sepsis-induced cardiomyopathy. Materials and MethodsInitially, we identified the major compounds of PGJXD through ultra-performance liquid chromatography-mass spectrometry technology analysis. We established in a SIC rat model using cecal ligation and puncture(CLP) and treated by PGJXD and levosimendan. We evaluated pathological damage by hematoxylin and eosin staining and measured serum myocardial injury biomarkers. Myocardial apoptosis was detected by Tunel staining and quantifying specific biomarker protein levels. Subsequently, we evaluated myocardium mitochondrial quality using Transmission electron microscope (TEM), antioxidant stress indexes and tissue adenosine triphosphate(ATP) content. We detected the expression of phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), parkin, LC3, and p62 using Western blotting and Quantitative real time polymerase chain reaction(qRT-PCR). (Lipopolysaccharides, LPS)-induced H9c2 cell model was established to further explore the mechanism of PGJXD on SIC. In addition to measuring cell viability, we measured mitochondrial membrane potential using JC-1 staining. Additionally, Parkin-siRNA transfected into H9c2 cells to validate whether PGJXD conducted protective effects against SIC through PINK1/Parkin-mediated mitophagy. ResultsIt has been demonstrated that PGJXD reduced mortality in septic rat, contributed to ameliorating myocardium injury, suppressed inflammatory response and ameliorated the myocardial apoptosis. PGJXD could also alleviate mitochondrial structural abnormality, mitigated oxidative stress injury and promoted energy synthesis in CLP models. Western blotting and qRT-PCR have further confirmed that PGJXD can activate PINK1/parkin pathway-mediated mitophagy, resulting in preserving mitochondrial quality in the myocardium. Furthermore, Parkin siRNA partially reversed the beneficial effect of PGJXD on mitochondrial fission/fusion and mitophagy in vitro. Therefore, the cardioprotective effect of PGJXD is achieved by inducing PINK1/Parkin-mediated mitophagy in maintaining mitochondrial homeostasis. ConclusionsThese results suggest that the potential therapeutic effect of PGJXD on cardiac dysfunction during sepsis and support its mechanism of targeted induction of PINK1-Parkin-mediated mitophagy.

Hospital Utilization and Mortality Post-electrical Cardioversion in Patients With Atrial Fibrillation in a Community Hospital.

Background Electrical cardioversion (EC) is a procedure that restores normal sinus rhythm in patients with atrial fibrillation (AF). Data on post-EC outcomes relative to the success of inpatient EC is limited. Methods This is a retrospective study of patients admitted for AF who underwent inpatient EC from January 1, 2017, to January 1, 2021. We collected demographics and clinical, biochemical, and echocardiographic parameters that impact the success of EC. Outcome events were 30-day readmissions and mortality. Results Our study included 54 unique patients who either had EC in the emergency room or as part of their hospital admission course for atrial fibrillation. Most patients were men with an average age of 70 years with traditional risk factors for cardiovascular disease including heart failure, coronary artery disease, and chronic kidney disease. The group who had unsuccessful cardioversion was older than those in the ineffective EC. Mortality at 30 days (p < 0.01), 1 year (p < 0.01), and 30-day readmission rate (p < 0.01) were higher in patients with unsuccessful EC. Conclusion A predictive model for successful EC remains difficult to establish. Patients with unsuccessful in-hospital EC are at high risk for mortality and readmissionat 30 days and require a comprehensive pre-discharge multidisciplinary approach and prioritized and individualized post-discharge integrated care.

SNX5-Rab11a protects against cardiac hypertrophy through regulating LRP6 membrane translocation

BackgroundsPathological cardiac hypertrophy is considered one of the independent risk factors for heart failure, with a rather complex pathogenic machinery. Sorting nexins (SNXs), denoting a diverse family of cytoplasmic- and membrane-associated phosphoinositide-binding proteins, act as a pharmacological target against specific cardiovascular diseases including heart failure. Family member SNX5 was reported to play a pivotal role in a variety of biological processes. However, contribution of SNX5 to the development of cardiac hypertrophy, remains unclear. MethodsMice underwent transverse aortic constriction (TAC) to induce cardiac hypertrophy and simulate pathological conditions. TAC model was validated using echocardiography and histological staining. Expression of SNX5 was assessed by western blotting. Then, SNX5 was delivered through intravenous administration of an adeno-associated virus serotype 9 carrying cTnT promoter (AAV9-cTnT-SNX5) to achieve SNX5 cardiac-specific overexpression. To assess the impact of SNX5, morphological analysis, echocardiography, histological staining, hypertrophic biomarkers, and cardiomyocyte contraction were evaluated. To unravel potential molecular events associated with SNX5, interactome analysis, fluorescence co-localization, and membrane protein profile were evaluated. ResultsOur results revealed significant downregulated protein level of SNX5 in TAC-induced hypertrophic hearts in mice. Interestingly, cardiac-specific overexpression of SNX5 improved cardiac function, with enhanced left ventricular ejection fraction, fraction shortening, as well as reduced cardiac fibrosis. Mechanistically, SNX5 directly bound to Rab11a, increasing membrane accumulation of Rab11a (a Rab GTPase). Afterwards, this intricate molecular interaction upregulated the membrane content of low-density lipoprotein receptor-related protein 6 (LRP6), a key regulator against cardiac hypertrophy. Our comprehensive assessment of siRab11a expression in HL-1 cells revealed its role in antagonism of LRP6 membrane accumulation under SNX5 overexpression. ConclusionsThis study revealed that binding of SNX5 with LRP6 triggers their membrane translocation through Rab11a assisting, defending against cardiac remodeling and cardiac dysfunction under pressure overload. These findings provide new insights into the previously unrecognized role of SNX5 in the progression of cardiac hypertrophy.

Reinforcement learning for closed-loop regulation of cardiovascular system with vagus nerve stimulation: a computational study

Objective. Vagus nerve stimulation (VNS) is being investigated as a potential therapy for cardiovascular diseases including heart failure, cardiac arrhythmia, and hypertension. The lack of a systematic approach for controlling and tuning the VNS parameters poses a significant challenge. Closed-loop VNS strategies combined with artificial intelligence (AI) approaches offer a framework for systematically learning and adapting the optimal stimulation parameters. In this study, we presented an interactive AI framework using reinforcement learning (RL) for automated data-driven design of closed-loop VNS control systems in a computational study. Approach. Multiple simulation environments with a standard application programming interface were developed to facilitate the design and evaluation of the automated data-driven closed-loop VNS control systems. These environments simulate the hemodynamic response to multi-location VNS using biophysics-based computational models of healthy and hypertensive rat cardiovascular systems in resting and exercise states. We designed and implemented the RL-based closed-loop VNS control frameworks in the context of controlling the heart rate and the mean arterial pressure for a set point tracking task. Our experimental design included two approaches; a general policy using deep RL algorithms and a sample-efficient adaptive policy using probabilistic inference for learning and control. Main results. Our simulation results demonstrated the capabilities of the closed-loop RL-based approaches to learn optimal VNS control policies and to adapt to variations in the target set points and the underlying dynamics of the cardiovascular system. Our findings highlighted the trade-off between sample-efficiency and generalizability, providing insights for proper algorithm selection. Finally, we demonstrated that transfer learning improves the sample efficiency of deep RL algorithms allowing the development of more efficient and personalized closed-loop VNS systems. Significance. We demonstrated the capability of RL-based closed-loop VNS systems. Our approach provided a systematic adaptable framework for learning control strategies without requiring prior knowledge about the underlying dynamics.

Low serum irisin levels predicted newly atrial fibrillation in patients with any phenotypes of chronic heart failure

Abstract Background Atrial fibrillation (AF) continues to be a major health problem among patients with known cardiovascular disease including heart failure (HF). AF is not only powerful risk factor for newly HF, but also it contributes to untoward clinical course of the condition. Although, natriuretic peptides are well-validated biomarkers to predict poor clinical outcomes of HF, their accuracy for AF in patients with different phenotypes of HF is not optimal. Recent studies showed that adipocytokines including irisin affect the risk of AF occurrence. We hypothesized that serum irisin can have additional discriminative potency for AF among HF in patients. Methods The study group comprised 541 consecutive patients with chronic HF aged 41 to 76 years recruited for the study from October 2020 to December 2022. We included 153 patients with any phenotypes of HF who were hospitalized due to paroxysmal or persistent AF and a control group of 388 age- and sex-matched individuals admitted to hospitals due to exacerbation of HF. All patients included in the study were examined by conventional general clinical and physical investigations, B-mode echocardiography and Doppler. The plasma levels N-terminal-natriuretic pro-peptide (NT-proBNP), high sensitivity (hs) C-reactive protein, tumor necrosis factor-alpha (TNF-alpha), hs-troponin T, adropin, apelin, leptin, adiponectin, and irisin were measured using ELISA. Results Compared with patients from control groups, patients with AF had greater left atrial volume index (LAVI), higher serum levels of NT-proBNP, hs-CRP, TNF-alpha, and lower left ventricular ejection fraction (LVEF), irisin and apelin levels. There were no significant difference between groups in left ventricular mass index, the serum levels of hs-troponin T, adropin, leptin, and adiponectin. Multivariate linear regression adjusted to LVEF and LAVI revealed that irisin and NT-proBNP were the predictors for AF. We found that the well-balanced cut-off point for serum concentration of irisin (AF versus non-AF) were 10.5 ng/mL (area under curve [AUC] = 0.96, sensitivity = 81.0%, specificity = 88.0%; P = 0.0001). Cutoff point of NT-proBNP that distinguished patients with AF and without AF was 750 pmol/L (AUC = 0.96; sensitivity = 72.7%, specificity 76.5%, р = 0.0001). Multivariate Cox regression model yielded that the serum levels of irisin &amp;lt; 10.5 ng/mL (odds ratio [OR] = 1.40; P = 0.001) and NT-proBNP &amp;gt; 750 pmol/mL (OR = 1.22; P = 0.012), LAVI &amp;gt; 34 mL/m2 (OR = 1.06; P = 0.010) remained to be strong predictors for newly AF. Add-on of irisin &amp;lt; 10.5 ng/mL to the predictive model constructed from NT-proBNP (&amp;gt; 750 pg/mL) significantly improved discriminatory potency of the whole model for HF. Conclusion We found that decreased serum levels of irisin significantly predicted newly AF in patients with any phenotypes of HF.

Pooled prevalences of obstructive sleep apnea and heart failure: a systematic review andmeta-analysis.

Obstructive sleep apnea (OSA) is a disease with intermittent hypoxemia during sleep. It has been shown that OSA is related to several cardiovascular diseases including heart failure. Both OSA and heart failure have a close association bidirectionally. This study aimed to estimatethe pooled prevalence of OSA in patients with heart failure as well as pooled prevalence of heart failure in patients with OSA. This was a systematic review with a meta-analysis. The inclusion criteria were observational or epidemiological studies conducted in adult patients with heart failure to evaluate the prevalence of OSA and patients with OSA to evaluate the prevalence of heart failure. The outcomes of this study were prevalence of OSA in patients with heart failure and prevalence of heart failure in patients with OSA. Four databases were used for systematic searching including PubMed, Science Direct, Scopus, and CINAHL Plus. Manual searches for related studies were also conducted. Proportion meta-analyses using a random-effects model were conducted to identify pooled proportion (prevalence) of heart failure in patients with OSA and vice versa. Among 3,941 articles from the four databases met the study criteria. Thirty-three studies showed the prevalence of OSA in patients with heart failure, while thirteen studies presented the prevalence of heart failure in patients with OSA. The prevalence of OSA in patients with heart failure was 38.4% (95% CI 31.9 to 45.2; I2 of 96.1%). Using a diagnostic criterion of OSA of more than 10 events/hr had the highest prevalence of OSA in patients with heart failure at 53.4% (95% CI 42.0 to 64.5). The highest prevalence of OSA in patients with heart failure was 60.1% (95% CI 51.4 to 68.3) in a report from India. The pooled prevalence of heart failure in patients with OSA was 12.8% (95% CI 8.1 to 19.5; I2 of 94.6%). The prevalence in Romania was highest at 22.6% (95% CI 20.4 to 24.9). The pooled prevalence of OSA in patients with heart failure was higher than the pooled prevalence of heart failure in patients with OSA. The pooled prevalence rates of these associations varied among the diagnostic criteria of OSA and countries.

Nrf2-Keap1 in Cardiovascular Disease: Which Is the Cart and Which the Horse?

High levels of oxidant stress in the form of reactive oxidant species are prevalent in the circulation and tissues in various types of cardiovascular disease including heart failure, hypertension, peripheral arterial disease, and stroke. Here we review the role of nuclear factor erythroid 2-related factor 2 (Nrf2), an important and widespread antioxidant and anti-inflammatory transcription factor that may contribute to the pathogenesis and maintenance of cardiovascular diseases. We review studies showing that downregulation of Nrf2 exacerbates heart failure, hypertension, and autonomic function. Finally, we discuss the potential for using Nrf2 modulation as a therapeutic strategy for cardiovascular diseases and autonomic dysfunction.

Focus on the Role of Inflammation as a Bridge between Ferroptosis and Atrial Fibrillation: A Narrative Review and Novel Perspective.

In this comprehensive review, we examine the intricate interplay between inflammation, ferroptosis, and atrial fibrillation (AF), highlighting their significant roles in AF pathophysiology and pathogenesis. Augmented inflammatory responses are pivotal to AF, potentially leading to atrial remodeling and reentry phenomena by impacting calcium channels and atrial tissue fibrosis. A strong correlation exists between inflammatory cytokines and AF, underscoring the importance of inflammatory signaling pathways, such as NOD-like receptor thermal protien domain associated protein 3 (NLRP3) inflammasome, Nuclear Factor kappa B (NF- B) signaling, and Tumor necrosis factor- (TNF- ) signaling in AF development. Ferroptosis, a non-apoptotic regulated mode of cell death, has been widely studied in relation to cardiovascular diseases including heart failure, myocardial infarction, cardiomyopathy, and reperfusion injury. The interaction between ferroptosis and inflammation is complex and mutually influential. While significant progress has been made in understanding the inflammation-AF relationship, the role of inflammation as a conduit linking ferroptosis and AF remains underexplored. The specific pathogenesis and key molecules of atrial fibrosis caused by ferroptosis are still not fully understood. Here we review the role of inflammatory signaling in ferroptosis and AF. We elucidated the association between ferroptosis and AF, aiming to unveil mechanisms for targeted inhibition of atrial cell fibrosis and to propose novel therapeutic strategies for AF. This exploration is vital for advancing our knowledge and developing more effective interventions for AF, a condition deeply intertwined with inflammatory processes and ferroptotic pathways.

The Role of Circular RNA for Early Diagnosis and Improved Management of Patients with Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are responsible for approximately 17.9 million deaths every year. There is growing evidence that circular RNAs (circRNAs) may play a significant role in the early diagnosis and treatment of cardiovascular diseases. As regulatory molecules, circular RNAs regulate gene expression, interact with proteins and miRNAs, and are translated into proteins that play a key role in a wide variety of biological processes, including the division and proliferation of cells, as well as the growth and development of individuals. An overview of the properties, expression profiles, classification, and functions of circRNAs is presented here, along with an explanation of their implications in cardiovascular diseases including heart failure, hypertension, ischemia/reperfusion injury, myocardial infarction, cardiomyopathies, atherosclerosis, and arrhythmia.

New Insights into Endothelial Dysfunction in Cardiometabolic Diseases: Potential Mechanisms and Clinical Implications.

The endothelium is a monocellular layer covering the inner surface of blood vessels. It maintains vascular homeostasis regulating vascular tone and permeability and exerts anti-inflammatory, antioxidant, anti-proliferative, and anti-thrombotic functions. When the endothelium is exposed to detrimental stimuli including hyperglycemia, hyperlipidemia, and neurohormonal imbalance, different biological pathways are activated leading to oxidative stress, endothelial dysfunction, increased secretion of adipokines, cytokines, endothelin-1, and fibroblast growth factor, and reduced nitric oxide production, leading eventually to a loss of integrity. Endothelial dysfunction has emerged as a hallmark of dysmetabolic vascular impairment and contributes to detrimental effects on cardiac metabolism and diastolic dysfunction, and to the development of cardiovascular diseases including heart failure. Different biomarkers of endothelial dysfunction have been proposed to predict cardiovascular diseases in order to identify microvascular and macrovascular damage and the development of atherosclerosis, particularly in metabolic disorders. Endothelial dysfunction also plays an important role in the development of severe COVID-19 and cardiovascular complications in dysmetabolic patients after SARS-CoV-2 infection. In this review, we will discuss the biological mechanisms involved in endothelial dysregulation in the context of cardiometabolic diseases as well as the available and promising biomarkers of endothelial dysfunction in clinical practice.

Cardiovascular aging: spotlight on mitochondria.

Mitochondria are cellular organelles critical for ATP production and are particularly relevant to cardiovascular diseases including heart failure, atherosclerosis, ischemia-reperfusion injury, and cardiomyopathies. With advancing age, even in the absence of clinical disease, mitochondrial homeostasis becomes disrupted (e.g., redox balance, mitochondrial DNA damage, oxidative metabolism, and mitochondrial quality control). Mitochondrial dysregulation leads to the accumulation of damaged and dysfunctional mitochondria, producing excessive reactive oxygen species and perpetuating mitochondrial dysfunction. In addition, mitochondrial DNA, cardiolipin, and N-formyl peptides are potent activators of cell-intrinsic and -extrinsic inflammatory pathways. These age-related mitochondrial changes contribute to the development of cardiovascular diseases. This review covers the impact of aging on mitochondria and links these mechanisms to therapeutic implications for age-associated cardiovascular diseases.

Prognostic significance of growth differentiation factor-15 across the BMI spectrum in patients with chronic heart failure: Insights from the SUPPORT trial

Abstract Background Obesity is a risk factor for cardiovascular diseases including heart failure (HF), yet patients with obesity have better outcomes than their leaner counterparts in HF (i.e. the obesity paradox). We sought to investigate whether growth differentiation factor-15 (GDF15), an emerging biomarker in HF reflecting inflammation and oxidative stress, is a prognostic indicator across the body mass index (BMI) spectrum in chronic heart failure (CHF). Methods Serum levels of GDF15 and its prognostic significance across BMI were examined in a total of 1,040 Japanese patients with CHF enrolled in a randomized clinical trial of the SUPPORT trial (supplemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan) (mean age 66.0±9.9 years, 26% female). Patients were categorized into four groups: underweight (BMI &amp;lt;18.5 kg/m2; n = 56), normal (BMI 18.5-22.9; n = 304), overweight (BMI 23-24.9; n = 257), and obese (BMI ≥25; n = 423) defined based on the WHO recommendation for Asian-Pacific population. Results The underweight group consisted of older patients with a higher prevalence of NYHA class III and reduced left ventricular ejection fraction (LVEF) compared to obese patients (mean age 69.0 vs 64.7 years, NYHA class III 17.9 vs 5.9%, and mean LVEF 49.3 vs 55.5%; all p&amp;lt;0.05). Median GDF15 level in the underweight group was higher (1,864 pg/mL [IQR 1,070-2,626]) but was similar in overweight and obese groups (1,285 [953, 1772] and 1,220 [888-1,789], respectively) compared to normal BMI group (1,276 [879-2,018]). During follow-up (median 10.3 years), 540 composite events of HF hospitalization or all-cause death occurred. The risk was higher in the underweight group (adjusted HR 1.8, 95%CI [1.3-2.5]) and lower in the obesity group (adjusted HR 0.8 [95% CI 0.6-0.9]) compared to the normal BMI group. An increased GDF15 incurred a consistently higher risk from underweight to obese groups; per unit increase in logGDF15 (pg/mL) was associated with 4.1, 2.4, 1.7 and 2.4 times higher risk, respectively. The optimal cut-off point for discriminating those with and without the composite events was 1,343 pg/mL in overall patients. This cut-off value performed well as a prognostic indicator across the continuous BMI spectrum including those with higher BMI (Figure). Conclusions The prognostic significance of GDF15 persisted across the BMI spectrum in patients with CHF. GDF15 may be useful for providing prognostic information across patients with a diverse range of BMI even in those with modest outcomes.HF events in high GDF15 across BMI

Change in hbA1c following treatment with and the short-term risk of major adverse cardiovascular outcomes

Abstract Background Post-hoc analyses from glucagon-like peptide-1 receptor agonist (GLP1-RA) trial populations have shown a benefit on cardiovascular outcomes from reduction in glycated hemoglobin (HbA1c). It is of interest to see if this finding translates into a cohort of real-world GLP1-RA users. Purpose To study among new GLP1-RA users, how reaching a Hba1c below 53 mmol/mol six months after initiation affects the risk of major adverse cardiovascular outcomes (MACE), compared with a HbA1c above 53 mmol/mol. Methods We included new GLP1-RA users six months after initiation of treatment, with an available HbA1c value 0-6 months before and 0-6 months after GLP1-RA initiation, from the Danish registries between 2010-2022. HbA1c levels pre- and post-treatment were categorized as above 53 mmol/mol or below 53mmol/mol. The primary outcome was defined as a composite of myocardial infarction, stroke, and all-cause death. Patients were followed from index (6 months after GLP1-RA initiation) until the outcome, a total of 1 years, or end-of-study (31.12.21), whichever comes first. Crude 1-year risks were compared using the Kaplan Meier estimator, or the Aalen Johansen estimator if competing risk was present. The effect of HbA1c below 53 mmol/mol versus a HbA1c above 53 mmol/mol on MACE was estimated using a Cox regression model adjusted for age, sex, educational level, baseline comorbidities, type 2 diabetes duration, and baseline cardiovascular disease including heart failure. Hospitalization for hyperglycemia was also evaluated using a Cox regression. Results A total of 4,081 new GLP1-RA users (median age: 58y [IQR:50;66], 52% males) were included, 3,090 had a post-treatment HbA1c below 53 mmol/mol and 991 had a post-treatment Hba1c above 53 mmol/mol. During a median follow-up of 1 year (IQR:1.0,1.0), the crude 1-year risk of MACE in persons with a HbA1c below 53 mmol/mol was 6.4% (95% confidence interval [CI]: 5.5;7.2) and 9.5% (7.7;11.3) in persons with HbA1c above 53 mmol/mol, yielding a hazard rate of 0.69 (0.54;0.88). No interaction between pre-and post HbA1c was found (p=0.59). The hazard rate of hospitalization for hypoglycemia was 0.76 (0.45:1.23) for persons reaching HbA1c level below 53 mmol/mol compared to patients with a HbA1c above 53 mmol/mol, with no interaction between pre- and post HbA1c observed (p =0.052). Conclusion A HbA1c level below 53 mmol/mol, among GLP1-RA users reduced the 1-year rate of MACE and did not significantly increase the 1-year rate of hospitalization for hypoglycemia.

Accelerated decline in lung function is associated with cardiac structure and function and independently predicts incident heart failure

Abstract Background The association between impaired lung function and cardiovascular disease is well known. However, it is not fully understood how a decline in lung function affects the development of cardiovascular disease including heart failure (HF). Purpose We aimed to investigate the association between declining lung function and changes in cardiac structure and function. Furthermore, we investigated the association between a decline in lung function and the risk of HF. Methods The study included 2,995 participants from a general population study. All participants had two examinations with spirometry performed 10 years apart. Participants were free of valvular heart disease and HF. A subsample (n=1,164) was also examined with echocardiography at both timepoints. The decline in the forced expiratory volume in one second (dFEV1) from the first visit to the second visit, was calculated. The change in cardiac structure and function between the two visits, was calculated as the decline in left ventricular ejection fraction (dLVEF), global longitudinal strain (dGLS), left ventricular mass index (dLVMi) and the ratio of early diastolic mitral inflow velocity to early diastolic mitral annulus velocity (dE/e’). Linear regression models were adjusted for the baseline FEV1 and echocardiographic value to account for regression to the mean. Outcome was incident HF. Results The entire sample consisted of 57% women, and the mean age was 62 ± 14 years. A total of 59% had hypertension, 8% had ischemic heart disease (IHD), 6% had diabetes, and 18% were active smokers. Mean FEV1 at baseline was 2.8 ± 0.95 liters (95 ± 19% as percentage of the predicted value). The mean decline in FEV1 between visits (median 10.8 years, IQR: 10.3-11.2) was 309 ± 362 mL. In the subsample examined with echocardiography, decreasing dLVEF was significantly associated with decreasing dFEV1 (p=0.030) in multivariable linear regression analysis, whereas dGLS, dLVMi, and dE/e’ were not. In the total study sample, 105 participants developed incident heart failure following the second visit during a median follow-up of 5.4 years (IQR: 4.5-6.3). Participants in the lowest quartile of dFEV1 (no change or increase) had an incidence rate of 2.48 per 1,000 person years (95%CI 1.33-4.60) versus participants in the highest quartile of dFEV1 (largest decline) with an incidence rate of 13.9 per 1,000 person years (95%CI 10.6-18.3), p&amp;lt;0.001. In multivariable Cox regression analysis, dFEV1 was an independent predictor of HF with a hazard ratio of 3.37 per 1 liter decline (95%CI 1.53-7.43, p=0.003). Conclusion We found a strong association between a decline in FEV1 and a decline in LVEF over a decade. Decreasing FEV1 was independently associated with incident HF. The incidence was highest for those with the largest decline in FEV1.A) Linear association B) Hist. of dLVEFA) Incidence rate B) Cumulative inc.

Abstract 16389: Inflammatory Chronic Kidney Disease is Associated With Incident Heart Failure: A Pooled Cohort Analysis

Introduction: High sensitivity C-reactive protein (hsCRP), a biomarker of inflammation, can risk stratify patients for cardiovascular disease including heart failure (HF). It is not well established if inflammation increases the risk of HF in patients with chronic kidney disease (CKD) and if hsCRP can be utilized to risk stratify patients with CKD for their risk of incident HF. Aims: We assessed the role of hsCRP in risk stratifying patients with CKD for incident HF. Methods: We studied participants of 3 major epidemiologic cohorts: Atherosclerosis Risk in Communities Study, Multi-Ethnic Study of Atherosclerosis, and Jackson Heart Study. High inflammation was classified as hsCRP &gt;3 mg/L and CKD was classified as estimated glomerular filtration rate &lt;60 mL/min/1.73m2. Participants were stratified into 3 groups: neither CKD nor high inflammation, CKD without high inflammation, or CKD with high inflammation. Cox hazards models adjusted for age, sex, race, body mass index, smoking, alcohol use, diabetes, hypertension, and coronary disease were utilized for analysis. Results: 8,692 participants with 460 incident HF events followed over a median 8.32 years were included in our analysis. Participants with CKD without high inflammation (HR = 1.45; 95% CI 1.14 to 1.85) and CKD with high inflammation (2.05; 1.61 to 2.61) were associated with an increased risk of incident HF compared with participants without CKD or high inflammation (referent, Figure). Furthermore, participants with CKD and a hsCRP &gt;3 mg/L had an increased risk of incident HF (1.41; 1.06 to 1.88) compared with participants with CKD but hsCRP ≤3 mg/L (referent). Conclusions: Patients with CKD and high levels of inflammation carry a 2-fold increased risk of incident HF. In patients with CKD, hsCRP levels &gt;3mg/L may be useful to risk stratify patients with increased risk of developing HF.

Abstract 15653: Heart Failure Medications Have a Direct Inhibitory Effect on Endothelial-to-Mesenchymal Transition in an in vitro Model

Introduction: Endothelial-to-Mesenchymal Transition (EndoMT) is a process where endothelial cells can transform into mesenchymal cells. This mechanism, while well established in embryogenesis and cancer, has been accumulating evidence as a contributor to cardiovascular diseases including heart failure (HF). While current guideline-directed medications (GDMT) for HF have postulated benefits to help cardiomyocytes and the heart, further investigation on the specific impact of HF drugs on this pro-fibrotic mechanism of EndoMT is required. Hypothesis: We hypothesize that HF drugs can inhibit EndoMT in an in vitro model Methods: Human umbilical vascular endothelial cells (HUVECs) were incubated for 24 h with the drugs - metoprolol, losartan, lisinopril, dapagliflozin, and valsartan/sacubitril, at concentrations ranging from 1 mg to 1 ng per mL, to evaluate cell viability using alamarBlue TM assay. In vitro EndoMT is induced with Nω-Nitro-L-arginine methyl ester hydrochloride and angiotensin II in HUVECs. During EndoMT, HUVECs were co-incubated with the drugs to determine their effect on EndoMT. Immunofluorescence for Endothelial (VE-Cadherin) and Mesenchymal (Transgelin) markers was used to characterize EndoMT. Results: All the HF drugs tested had a dose-dependent effect on HUVEC viability. The highest drug concentration (1 mg/mL) resulted in cell death while lower concentrations (1 μg to 1 ng per mL) did not affect cell viability. A concentration of 1 μg/mL was used to investigate the drugs’ effect on EndoMT. Immunofluorescence staining revealed reduced levels of expression for Transgelin in HUVCEs induced to undergo EndoMT in the presence of the treated drugs compared to the untreated and vehicle-treated cells after 4 days of incubation. Conclusion All the HF medications inhibited EndoMT in an in vitro model. Our results show that some of the beneficial effects of the HF GDMT medications used in clinical practice could be through an inhibitory effect on EndoMT.

Abstract 14547: Genetically Predicted Inhibition of HMG-CoA Reductase Reduces Risk of DNMT3A Clonal Hematopoiesis

Introduction: Clonal hematopoiesis (CH) is associated with increased morbidity and mortality from cancer and cardiovascular diseases including heart failure and ischemic heart disease. At present no medications are known to protect from CH. However, leukemia cells with equivalent mutations show sensitivity to statin-induced cell death. Aims: To evaluate the association of LDL-C lowering genetic variants at HMGCR (the target of statins) with CH risk using two-sample Mendelian randomization. Methods: We investigated whether lower LDL-C genetically predicted by 6 variants at HMGCR associates with CH risk. Secondary exposures included a polygenic instrument of 74 LDL-C-lowering genome-wide variants. Genetic associations for LDL-C derived from a genome-wide association study (GWAS) meta-analysis of circulating LDL-C levels by the Global Lipid Genetics Consortium (N≤188,578 individuals of European ancestry). Outcome associations for CH were from a GWAS in 368,526 European individuals in UK Biobank. Results: Genetically predicted reduction in HMG-CoA reductase activity equivalent to a 38.7mg/dL lower circulating LDL-C level was associated with reduced odds of overall CH (OR 0.75, 95% CI 0.58-0.97, P = 0.027) or DNMT3A CH (OR 0.64, 95% CI 0.48-0.86, P = 0.003) but not TET2 CH (OR 1.12, 95% CI 0.63-2.00, P = 0.70). Associations were consistent across all 6 HMGCR variants in sensitivity analyses. Co-localization plots showed evidence of co-localization of LDL-C with DNMT3A CH and overall CH at the HMGCR locus. Associations were stronger for CH with variant allele fraction ≥10%, and, statins suppressed colony formation of mutant DNMT3A cells in vitro , suggesting statins may limit clonal expansion. In a secondary analysis to explore LDL-C dependence, LDL-C lowering predicted by the polygenic instrument did not associate with overall or DNMT3A CH but associated with increased odds of TET2 CH (OR 1.13, 95% CI 1.01-1.27, P = 0.03). Findings were replicated in a non-European cohort. Conclusions: Genetically predicted lifelong reduction of HMG-CoA reductase activity was associated with reduced risk of overall and DNMT3A -mutant CH, likely by LDL-C-independent mechanisms. This provides a strong rationale for clinical trials testing the effects of statins in CH.

Fatty acid metabolism disorders and potential therapeutic traditional Chinese medicines in cardiovascular diseases.

Cardiovascular diseases are currently the primary cause of mortality in the whole world. Growing evidence indicated that the disturbances in cardiac fatty acid metabolism are crucial contributors in the development of cardiovascular diseases. The abnormal cardiac fatty acid metabolism usually leads to energy deficit, oxidative stress, excessive apoptosis, and inflammation. Targeting fatty acid metabolism has been regarded as a novel approach to the treatment of cardiovascular diseases. However, there are currently no specific drugs that regulate fatty acid metabolism to treat cardiovascular diseases. Many traditional Chinese medicines have been widely used to treat cardiovascular diseases in clinics. And modern studies have shown that they exert a cardioprotective effect by regulating the expression of key proteins involved in fatty acid metabolism, such as peroxisome proliferator-activated receptor α and carnitine palmitoyl transferase 1. Hence, we systematically reviewed the relationship between fatty acid metabolism disorders and four types of cardiovascular diseases including heart failure, coronary artery disease, cardiac hypertrophy, and diabetic cardiomyopathy. In addition, 18 extracts and eight monomer components from traditional Chinese medicines showed cardioprotective effects by restoring cardiac fatty acid metabolism. This work aims to provide a reference for the finding of novel cardioprotective agents targeting fatty acid metabolism.

Non-contact heart vibration measurement using computer vision-based seismocardiography

Seismocardiography (SCG) is the noninvasive measurement of local vibrations of the chest wall produced by the mechanical activity of the heart and has shown promise in providing clinical information for certain cardiovascular diseases including heart failure and ischemia. Conventionally, SCG signals are recorded by placing an accelerometer on the chest. In this paper, we propose a novel contactless SCG measurement method to extract them from chest videos recorded by a smartphone. Our pipeline consists of computer vision methods including the Lucas–Kanade template tracking to track an artificial target attached to the chest, and then estimate the SCG signals from the tracked displacements. We evaluated our pipeline on 14 healthy subjects by comparing the vision-based SCG^mathrm{{v}} estimations with the gold-standard SCG^mathrm{{g}} measured simultaneously using accelerometers attached to the chest. The similarity between SCG^mathrm{{g}} and SCG^mathrm{{v}} was measured in the time and frequency domains using the Pearson correlation coefficient, a similarity index based on dynamic time warping (DTW), and wavelet coherence. The average DTW-based similarity index between the signals was 0.94 and 0.95 in the right-to-left and head-to-foot directions, respectively. Furthermore, SCG^mathrm{{v}} signals were utilized to estimate the heart rate, and these results were compared to the gold-standard heart rate obtained from ECG signals. The findings indicated a good agreement between the estimated heart rate values and the gold-standard measurements (bias = 0.649 beats/min). In conclusion, this work shows promise in developing a low-cost and widely available method for remote monitoring of cardiovascular activity using smartphone videos.