Major Cause Of Cardiovascular Morbidity Research Articles

Development of a polygenic risk score to improve detection of peripheral artery disease.

Peripheral artery disease (PAD) is a major cause of cardiovascular morbidity and mortality, yet timely diagnosis is elusive. Larger genome-wide association studies (GWAS) have now provided the ability to evaluate whether genetic data, in the form of genome-wide polygenic risk scores (PRS), can help improve our ability to identify patients at high risk of having PAD. Using summary statistic data from the largest PAD GWAS from the Million Veteran Program, we developed PRSs with genome data from UK Biobank. We then evaluated the clinical utility of adding the best-performing PRS to a PAD clinical risk score. A total of 487,320 participants (5759 PAD cases) were included in our final genetic analysis. Compared to participants in the lowest 10% of PRS, those in the highest decile had 3.1 higher odds of having PAD (95% CI, 3.06-3.21). Additionally, a PAD PRS was associated with increased risk of having coronary artery disease, congestive heart failure, and cerebrovascular disease. The PRS significantly improved a clinical risk model (Net Reclassification Index = 0.07, p < 0.001), with most of the performance seen in downgrading risk of controls. Combining clinical and genetic data to detect risk of PAD resulted in a model with an area under the curve of 0.76 (95% CI, 0.75-0.77). We demonstrate that a genome-wide PRS can discriminate risk of PAD and other cardiovascular diseases. Adding a PAD PRS to clinical risk models may help improve detection of prevalent, but undiagnosed disease.

Exercise capacity assessed with the one-minute sit-to-stand test (1-min STST) is associated with echocardiographic findings in patients with heart failure with preserved ejection fraction (HFpEF)

Abstract Funding Acknowledgements Type of funding sources: None. Background Heart failure with preserved ejection fraction (HFpEF) is a major cause of cardiovascular morbidity and mortality (1). Non-invasive imaging, particularly echocardiography, plays a central role in the evaluation of HFpEF patients. Numerous prognostic markers for mortality have been identified in patients with HFpEF, including right ventricular tricuspid annular plane systolic excursion (TAPSE) and estimated systolic pulmonary artery pressure (ePASP) [(2) (3) (4)]. ePASP is calculated with Doppler measurement of peak tricuspid regurgitation velocity (TRV). Despite those markers, precise risk stratification remains challenging. Recently the one-minute sit-to-stand-test (1-min STST), a quick and objective test of functional capacity that can be potentially used for risk stratification, has attracted the interest of researchers. In this test, participants are encouraged to stand up and sit down from a chair as quickly and as many times as possible within one minute. The 1-min STST provides valuable information on the ability to perform daily life activities in HFpEF patients and adds to our options of diagnostic tests in HFpEF. Purpose The aim of this investigation was to prospectively examine whether 1-min STST results correlate with transthoracic echocardiographic parameters in a group of HFpEF patients. Patient and methods 32 HFpEF patients [59% New York Heart Association (NYHA) Class III, 63% female, age (mean ± standard deviation) 70 ± 11 years and 66% atrial fibrillation] were prospectively studied. Functional performance was examined with the 1-min STST. Echocardiographic estimations of pulmonary artery pressure and additional parameters (TRV and systolic function measured by echocardiography) as well as clinical characteristics were obtained. Results Mean 1-min STST repetitions were 16.41 ± 6.7. Twelve (38%) of the 32 HFpEF patients had moderate to severe mitral regurgitation and 29 (91%) had moderate or more tricuspid regurgitation. Mean left ventricular ejection fraction (LVEF) was 52.57 ± 1.74 % and mean ePASP was 65.81 ± 23.17 mmHg. 10 (32%) patients were in NYHA class I or II, 22 (69%) in NYHA class III or IV. There was a significant inverse association between higher NYHA class and the 1-min STST (t = 2.6, p = 0.012). The following additional parameters correlated significantly with the 1-min STST: ePASP (r = -0.545, p = 0.001), TRV (r = -0.598, p &amp;lt; 0.001) and the ratio of TAPSE/ePASP (r = 0.767, p = 0.001) (see table 1). Interestingly, the decline in oxygen saturation during the 1-min STST showed significant correlation with ePASP (r = -0.559, p &amp;lt; 0.001) and TRV (r = 0.540, p = 0.002). Conclusion Our investigation shows a direct linear correlation between ePASP, TRV and TAPSE/ePASP measured by echocardiography and measurements of functional capacity derived by the 1-min STST. Thus, the current results emphasize the role of the 1-min STST as an additional diagnostic tool in patients with HFpEF. Abstract Figure.

The pathophysiology of RHD and outstanding gaps

Rheumatic heart disease (RHD) is the major cause of cardiovascular morbidity and mortality in children and young adults in low- and middle-income countries. Acute rheumatic fever (ARF) is characterised by multiorgan inflammatory symptoms initiated through cross reaction of immune responses (IRs) to group A streptococcus (GAS) proteins to host proteins. Recurrence of these IRs targeting the heart valves may lead to permanent damage, a sequela which is termed RHD. Preliminary studies suggested genetic associations in RF reactions, but that other host factors are also involved, leaving the determinants of RHD progression incompletely understood. Previous clinical and recent epidemiological studies support differential clinical phenotypes, with varying history from different settings. This review summarises the protein-centric biomolecular changes in RHD and highlights outstanding molecular gaps where urgent focus is required to improve our understanding RHD pathophysiology. Numerous studies have confirmed alterations in the expression of structural and immune response proteins, but the modifications giving rise to neo-epitopes and their involvement in RHD have not been established. As RHD is associated with poor living conditions, identification of other factors driving inflammation to enhance RHD progression is necessary to advance our knowledge and improve patient management. Furthermore, biomarkers for early identification, disease stratification, and alternative therapeutic strategies are necessary to improve treatment and prevention strategies in order to reduce the burden of RHD. Relevance: Despite the explosion of scientific innovation over the last few decades, fundamental scientific studies to understand the pathophysiological mechanisms of RHD remain in their infancy and the determinants of RHD progression thus remain uncertain. Moreover, inconsistency in natural history and phenotypic presentations are seen between Africans and other cohorts in which preliminary studies were conducted, implying that differences in genetic complexity and environmental factors may be responsible for the differential disease progression rates.

Mid and long-term follow-up of 50 pediatric cardiac Chadians operated in France from 2003 to 2012.

Introductioncardiac valvular diseases (CVDs) are the major cause of cardiovascular morbidity and mortality globally, with predominance of rheumatic heart disease (RHD) in developing countries. Congenital heart defects (CHD) diagnoses are delayed due to socioeconomic factors. This study aims to evaluate the post-operative surgical outcomes of CHD and valvular RHD.Methodsthis study is conducted with 50 patients from Chad, operated on between 2003 and 2012. Post-operative outcomes are evaluated from 2010 to 2012.Resultswith the follow-up of 19 RHD patients who underwent plasty, 8 (42.1%) had no complications, 4 (21%) presented with mild regurgitation, 7 (36.8%) required re-operation due to 6 mitral stenosis (MS) cases (mitral surface range from 0.7 to 1.2 cm2) and 1 severe mitral regurgitation (MR) case. While those patients with valve replacement, 2 (50%) had no complications, 1 (25%) had mild regurgitation and 1 (25%) patient died. Two patients with aortic regurgitation (AR) that underwent annuloplasty presented with severe regurgitation. Regarding AR with valve replacement, 3 (60%) had no complications, and 2 (40%) had mild regurgitation. Among the tricuspid regurgitation (TR) patients who had plasty, 6 (85.7%) had no complications, and 1 (14.3%) had severe regurgitation. The surgical repair was curative in all CHD patients. The loss to follow-up rate was 13/50 (26%).Conclusionthe annuloplasty on rheumatic valve disease (MR and AR) has proven to be disappointing. Plasty is debated without justified indication for AR. The outcomes of CHD, mitral and aortic valve replacement are successful.

Single-pill fixed-dose drug combinations to reduce blood pressure: the right pill for the right patient.

Arterial hypertension is one of the major causes of cardiovascular morbidity and mortality worldwide. Effective and sustained reduction in blood pressure is essential to reduce individual cardiovascular risk. In daily clinical practice, single-pill fixed-dose combinations of different drug classes are important therapeutic resources that could improve both treatment adherence and cardiovascular risk management by targeting distinct pathophysiological mechanisms. The aim of this practical narrative review is to help physicians choosing the right single-pill fixed-dose combination for the right patient in the daily clinical practice, based on the individual clinical phenotype and cardiovascular risk profile.

Real-world data-driven risk prediction of hospitalization for heart failure in non-diabetic CKD

Abstract Background Heart failure (HF) is a major cause of cardiovascular morbidity and mortality. Despite recent advances in diagnosis and management of HF, the prognosis remains poor. HF and chronic kidney disease (CKD) are interlinked chronic health conditions. The availability of large volume of patient data and modern analytic techniques opens new opportunities for identification of individuals at elevated risk of HF. Purpose Develop risk prediction model for HF hospitalizations (HHF) in patients with non-diabetic CKD by applying data-driven computational intelligence techniques to a US population-based administrative claims database. Methods Individual-level data from the US Optum Clinformatics Data Mart for years 2008–2018 were analysed. To be eligible for inclusion, adult individuals were required to have non-diabetic CKD stage 3 or 4 (index event) and one year continuous insurance coverage prior to the index date (baseline period). Selection criteria and the main clinical outcome, hospitalisation for heart failure (HHF), were identified by using laboratory tests results and/or specific codes from common clinical coding systems. Risk prediction model for HHF was built on patient data in the baseline period composed to more than 6,000 variables. Computational intelligence method based on ant colony optimization was used to develop a time-to-first-event risk prediction model for HHF. Results Of the 64 million individuals in the database, 504,924 satisfied the selection criteria. Median age was 75 years, 60% were female. Among most common baseline comorbidities were hypertension (85%) and hyperlipidaemia (68%). Coronary artery disease, HF, atrial fibrillation and peripheral artery disease were recorded in 24%, 16%, 15% and 14% of individuals. Over a median follow-up of 744 days, 53,282 (11%) patients had recorded HHF, the corresponding incidence rate was 3.95 events/100 patient-years. The developed risk prediction model for HHF in non-diabetic CKD contained 20 risk factors. The five strongest risk factors were history of HF, intake of loop diuretics, severely increased albuminuria, atrial fibrillation or flutter and CKD 4 as observed “yes/no” in the baseline period. Fig. 1 depicts the final risk prediction model. To assess model performance, all patients in the cohort were stratified into five HHF risk groups. For each group, a Kaplan-Meier curve was built based on the HHF outcome data in the database. Fig. 2 shows clear separation between the curves, demonstrating high performance of the developed risk prediction model. Conclusion Despite many existing scores to predict HHF, their use is limited. Some scores rely on availability of rarely collected information, some are applicable for specific patient populations only. Risk prediction model for HHF in non-diabetic CKD is presented, which contains risk factors routinely collected by healthcare providers. Therefore, it might be applicable for HHF risk estimation in various settings. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Bayer AG Forest plot of HHF risk prediction modelKaplan-Meier plot of risk strata

Real-world data-driven risk prediction of hospitalization for heart failure in non-diabetic CKD

Abstract Background Heart failure (HF) is a major cause of cardiovascular morbidity and mortality. Despite recent advances in diagnosis and management of HF, the prognosis remains poor. HF and chronic kidney disease (CKD) are interlinked chronic health conditions. The availability of large volume of patient data and modern analytic techniques opens new opportunities for identification of individuals at elevated risk of HF. Purpose Develop risk prediction model for HF hospitalizations (HHF) in patients with non-diabetic CKD by applying data-driven computational intelligence techniques to a US population-based administrative claims database. Methods Individual-level data from the US Optum Clinformatics Data Mart for years 2008–2018 were analysed. To be eligible for inclusion, adult individuals were required to have non-diabetic CKD stage 3 or 4 (index event) and one year continuous insurance coverage prior to the index date (baseline period). Selection criteria and the main clinical outcome, hospitalisation for heart failure (HHF), were identified by using laboratory tests results and/or specific codes from common clinical coding systems. Risk prediction model for HHF was built on patient data in the baseline period composed to more than 6,000 variables. Computational intelligence method based on ant colony optimization was used to develop a time-to-first-event risk prediction model for HHF. Results Of the 64 million individuals in the database, 504,924 satisfied the selection criteria. Median age was 75 years, 60% were female. Among most common baseline comorbidities were hypertension (85%) and hyperlipidaemia (68%). Coronary artery disease, HF, atrial fibrillation and peripheral artery disease were recorded in 24%, 16%, 15% and 14% of individuals. Over a median follow-up of 744 days, 53,282 (11%) patients had recorded HHF, the corresponding incidence rate was 3.95 events/100 patient-years. The developed risk prediction model for HHF in non-diabetic CKD contained 20 risk factors. The five strongest risk factors were history of HF, intake of loop diuretics, severely increased albuminuria, atrial fibrillation or flutter and CKD 4 as observed “yes/no” in the baseline period. Fig. 1 depicts the final risk prediction model. To assess model performance, all patients in the cohort were stratified into five HHF risk groups. For each group, a Kaplan-Meier curve was built based on the HHF outcome data in the database. Fig. 2 shows clear separation between the curves, demonstrating high performance of the developed risk prediction model. Conclusion Despite many existing scores to predict HHF, their use is limited. Some scores rely on availability of rarely collected information, some are applicable for specific patient populations only. Risk prediction model for HHF in non-diabetic CKD is presented, which contains risk factors routinely collected by healthcare providers. Therefore, it might be applicable for HHF risk estimation in various settings. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Bayer AG Forest plot of HHF risk prediction modelKaplan-Meier plot of risk strata

HYPERTENSION: AN AYURVEDIC PERSPECTIVE

Hypertension (HTN) is a major public health issue worldwide, because of its high prevalence and concomitant increase in the risk of disease. In the contemporary situation Hypertension is the most critical disease in the world. If we focus on the present situation then we can see that due to rapid globalization we are facing Hypertension. Due to rapid modernization, people are leading more stressful lives. As a result, hypertension is one of the wide- spread disorders which came across in practice. Ab. India is labelled as the global capital of hypertension. Nowa- days, not only lifestyle disorders are becoming more common, but they are also affecting younger populations. Hence, the population at risk shifts from 40+ to maybe 30+ or even younger. Hypertension results from a variety of reasons like stress, obesity, genetic factors, overuse of the salts in the diet and ageing etc. As we all know, Hy- pertension is called a silent killer because it rarely exhibits symptoms before it damages the heart, brain or kidney. Though a lot of potent antihypertensive drugs are available today in modern medicine, none of them is free from untoward effects. The principal focus of Ayurveda is on maintaining good health and adopting a healthy way of life. In Ayurveda, there is no description of such a single disease that can resemble hypertension. As per Ayurve- dic principles, in case of an unknown disease, the physician should try to understand the nature of the disease through Dosha, Dushya and Samprapti; then should initiate the treatment. So, it becomes our prime concern to understand hypertension thoroughly with an Ayurvedic perspective. Hypertension (HTN or HT), also known as High blood pressure or arterial hypertension, is a chronic medical condition in which the blood pressure in the arteries is persistently elevated. Hypertension is one of the major causes of cardiovascular morbidity and mortalityworldwide. It is a global health problem affecting people of different ethnicity and ages around the world. It is an asymptomatic medical condition in which systemic arterial blood pressure is elevated beyond the normal value. Keywords: High Blood Pressure, Lifestyle disorders, Silent killer.

MANAGEMENT OF ESSENTIAL HYPERTENSION USING HERBAL FORMULATION WITH AND WITHOUT GOKSHURA KWATHA – A COMPARATIVE STUDY

Hypertension is one of the major causes of cardiovascular morbidity and mortality worldwide. It is a global health problem affecting the people of different ethnicity and ages around the world. An estimated 1.13 billion people worldwide have hypertension, most (two-thirds) living in low- and middle-income countries. According to WHO (2015) the overall prevalence of hypertension in India was 24.2% and 22% among the men and women respectively. Hypertension is called a silent killer, non-communicable chronic disease because it rarely exhibits symptoms before it damages vital organs like kidney, brain or heart. In Ayurveda there is not a single disease which resemble with hypertension, but physician should understand the disease through Dosha, Dushya, Samprapti and initiate the treatment. A lot of potent modern antihypertensive drugs are available but none of them are free from untoward side-effects. So, a clinical study was done using herbal formulation containing Sarpaghandha, Sankhpushpi, Arjuna, Jatamansi and Ashwagandha in the form of Ghanvati. A comparative study was done as this Ghanvati was given with and without Gokshur kwath. For clinical study 52 (Group A- 25 and Group B- 27) clinically diagnosed patients of essential hypertension who fulfil inclusion criteria were selected irrespective of their age, sex, religion, occupation etc. and simple random sampling technique was followed for grouping the patients into 2 groups. All the patients selected for the clinical trial were divided in two groups ‘A’ and ‘B’. Patients of Group A were given 250 mg of Ghanvati two times a day with water as Anupan and patients of Group B were given 250 mg of Ghanvati with water as Anupan and Gokshur kwath both two times a day. Duration of the study for each group was 30 days. The present study showed that herbal formulation is also effective in the management of essential hypertension. Keywords: Essential hypertension, Ghanvati

An investment case for the prevention and management of rheumatic heart disease in the African Union 2021–30: a modelling study

SummaryBackgroundDespite declines in deaths from rheumatic heart disease (RHD) in Africa over the past 30 years, it remains a major cause of cardiovascular morbidity and mortality on the continent. We present an investment case for interventions to prevent and manage RHD in the African Union (AU).MethodsWe created a cohort state-transition model to estimate key outcomes in the disease process, including cases of pharyngitis from group A streptococcus, episodes of acute rheumatic fever (ARF), cases of RHD, heart failure, and deaths. With this model, we estimated the impact of scaling up interventions using estimates of effect sizes from published studies. We estimated the cost to scale up coverage of interventions and summarised the benefits by monetising health gains estimated in the model using a full income approach. Costs and benefits were compared using the benefit–cost ratio and the net benefits with discounted costs and benefits.FindingsOperationally achievable levels of scale-up of interventions along the disease spectrum, including primary prevention, secondary prevention, platforms for management of heart failure, and heart valve surgery could avert 74 000 (UI 50 000–104 000) deaths from RHD and ARF from 2021 to 2030 in the AU, reaching a 30·7% (21·6–39·0) reduction in the age-standardised death rate from RHD in 2030, compared with no increase in coverage of interventions. The estimated benefit–cost ratio for plausible scale-up of secondary prevention and secondary and tertiary care interventions was 4·7 (2·9–6·3) with a net benefit of $2·8 billion (1·6–3·9; 2019 US$) through 2030. The estimated benefit–cost ratio for primary prevention scale-up was low to 2030 (0·2, <0·1–0·4), increasing with delayed benefits accrued to 2090. The benefit–cost dynamics of primary prevention were sensitive to the costs of different delivery approaches, uncertain epidemiological parameters regarding group A streptococcal pharyngitis and ARF, assumptions about long-term demographic and economic trends, and discounting.InterpretationIncreased coverage of interventions to control and manage RHD could accelerate progress towards eradication in AU member states. Gaps in local epidemiological data and particular components of the disease process create uncertainty around the level of benefits. In the short term, costs of secondary prevention and secondary and tertiary care for RHD are lower than for primary prevention, and benefits accrue earlier.FundingWorld Heart Federation, Leona M and Harry B Helmsley Charitable Trust, and American Heart Association.

Short-term Effect of LDL-Apheresis on Lipid Profile of Patients with Nephrotic and Non-Nephrotic Hyperlipidemia: A Comparative Study

Background: Persistent hyperlipidemia is a major cause of cardiovascular morbidity in patients with nephrotic and non-nephrotic patients. Low-density lipoprotein-apheresis (LDL-apheresis) was shown to rapidly remove lipid structures. The current study aimed to compare the initial lipid profiles in patients with nephrotic syndrome and non-nephrotic hyperlipidemia as well as to evaluate the lipid profile of each group following a single treatment with LDL-apheresis. Methods: This is an open-label observational cross-sectional study of patients treated with LDL-apheresis including ten patients with nephrotic syndrome and thirteen patients with non-nephrotic hyperlipidemia who were either resistant and/or intolerant of lipid lowering therapy, with normal kidney function. Routine blood tests with full traditional lipid profile (Total cholesterol-(TC), Low-density lipoprotein (LDL), High-density lipoprotein (HDL), Triglycerides-(TG)) were determined before and after 12-hours following a single LDL-apheresis procedure. Results: Both groups were comparable by sex and age with more males than female in both groups. Baseline lipid profile was different between the two groups with nephrotic syndrome patients having significantly higher TC (p=0.05), LDL (p<0.001) and HDL (p<0.02) than those with non-nephrotic hyperlipidemia. A single treatment with LDL-apheresis resulted in significant improvements in the lipid profile of both groups including TC, HDL, LDL and TG, however HDL not significantly reduced in patients with nephrotic syndrome. Conclusion: Resistant nephrotic syndrome patients have a more severe and persistent hyperlipidemia than patients with non-nephrotic hyperlipidemia. The current study shows that LDL-apheresis is a safe and effective alternative to those who cannot tolerate or resistant to conventional treatments.

Association between Adherence to SSRI Treatment and Mortality among Individuals with Metabolic Syndrome Components.

Depression and anxiety have been associated with type 2 diabetes mellitus and metabolic syndrome, major causes of cardiovascular morbidity and mortality. The effect of antidepressants in this association is unknown. This study aimed to examine the association between adherence to selective serotonin receptor inhibitors (SSRIs) and all-cause mortality among individuals with metabolic syndrome components (hypertension, obesity, and diabetes mellitus). Data on 201 777 patients who were prescribed SSRIs during the years 2008-2011 were analyzed retrospectively. Adherence was measured using prescription purchase records. The moderating effect of SSRI and statin adherence on the association between metabolic syndrome load and mortality hazard risk (HR) during the study period were analyzed. The Cox-proportional hazard model adjusted to background variables was used to this end. During the study period, the maximal metabolic load was associated with mortality HR=1.89 (95% CI: 1.79-2) compared to participants without metabolic risk factors. A slight reduction in mortality HR was demonstrated among those with low and moderate SSRI adherence rates. Adherence to statins was negatively associated with the risk of mortality across all levels of adherence. A significant association (r=0.214, p<0.01) was found between adherence to statins and adherence to SSRIs, with higher rates of adherence to statins across all metabolic load categories. While a high metabolic load is associated with a higher risk of mortality, adherence to SSRIs only partially moderated the risk of mortality, in contrast to the protective effect of statins. Adherence differences to statins and SSRIs among individuals prescribed both medications merit further investigation.

Vascular Calcification in Chronic Kidney Disease: Diversity in the Vessel Wall.

Vascular calcification (VC) is one of the major causes of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). VC is a complex process expressing similarity to bone metabolism in onset and progression. VC in CKD is promoted by various factors not limited to hyperphosphatemia, Ca/Pi imbalance, uremic toxins, chronic inflammation, oxidative stress, and activation of multiple signaling pathways in different cell types, including vascular smooth muscle cells (VSMCs), macrophages, and endothelial cells. In the current review, we provide an in-depth analysis of the various kinds of VC, the clinical significance and available therapies, significant contributions from multiple cell types, and the associated cellular and molecular mechanisms for the VC process in the setting of CKD. Thus, we seek to highlight the key factors and cell types driving the pathology of VC in CKD in order to assist in the identification of preventative, diagnostic, and therapeutic strategies for patients burdened with this disease.

Tumor necrosis factor alpha and interleukin 1 beta suppress myofibroblast activation via nuclear factor kappa B signaling in 3D-cultured mitral valve interstitial cells

Mitral valve disease is a major cause of cardiovascular morbidity throughout the world. Many different mitral valve pathologies feature fibrotic remodeling, often accompanied by an inflammatory state. Mitral valve fibrosis is mediated by valvular interstitial cells (VICs), which reside in the valve leaflets and often differentiate into myofibroblast-like cells during disease conditions. In this study, we investigated the effects of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) on mitral VICs, since these pro-inflammatory cytokines have been shown to exert pleiotropic effects on various cell types in other fibrotic disorders. Using biomimetic three-dimensional culture systems, we demonstrated that TNF-α and IL-1β suppress myofibroblast differentiation in mitral VICs, as evidenced by gene and protein expression of alpha smooth muscle actin and smooth muscle 22 alpha. Addition of TNF-α and IL-1β also inhibited mitral VIC-mediated contraction of collagen gels. Furthermore, inhibition of NF-κB, which is downstream of TNF-α and IL-1β, reversed these effects. These results reveal targetable pathways for potential development of pharmaceutical treatments for alleviating fibrosis during mitral valve disease. Statement of significanceMitral valve disease is a common cardiovascular condition that is often accompanied by fibrotic tissue remodeling. Valvular interstitial cells (VICs), the fibroblast-like cells that reside in heart valve leaflets, are thought to drive fibrosis during valve disease by differentiating into activated myofibroblasts. However, the signaling pathways that regulate this process in the mitral valve are not fully understood. In the present study, we cultured mitral VICs in collagen and poly(ethylene glycol) scaffolds designed to mimic the heart valve microenvironment and treated the cell-seeded scaffolds with cytokines. Using these 3D culture models, we found that the pro-inflammatory cytokines TNF-α and IL-1β downregulate myofibroblast and fibrosis markers in mitral VICs via the canonical NF-κB signaling pathway.

A small molecule inhibitor of the chloride channel TMEM16A blocks vascular smooth muscle contraction and lowers blood pressure in spontaneously hypertensive rats

Hypertension is a major cause of cardiovascular morbidity and mortality, despite the availability of antihypertensive drugs with different targets and mechanisms of action. Here, we provide evidence that pharmacological inhibition of TMEM16A (ANO1), a calcium-activated chloride channel expressed in vascular smooth muscle cells, blocks calcium-activated chloride currents and contraction in vascular smooth muscle invitro and decreases blood pressure in spontaneously hypertensive rats. The acylaminocycloalkylthiophene TMinh-23 fully inhibited calcium-activated TMEM16A chloride current with nanomolar potency in Fischer rat thyroid cells expressing TMEM16A, and in primary cultures of rat vascular smooth muscle cells. TMinh-23 reduced vasoconstriction caused by the thromboxane mimetic U46619 in mesenteric resistance arteries of wild-type and spontaneously hypertensive rats, with a greater inhibition in spontaneously hypertensive rats. Blood pressure measurements by tail-cuff and telemetry showed up to a 45-mmHg reduction in systolic blood pressure lasting for four-six hours in spontaneously hypertensive rats after a single dose of TMinh-23. A minimal effect on blood pressure was seen in wild-type rats or mice treated with TMinh-23. Five-day twice daily treatment of spontaneously hypertensive rats with TMinh-23 produced sustained reductions of 20-25 mmHg in daily mean systolic and diastolic blood pressure. TMinh-23 action was reversible, with blood pressure returning to baseline in spontaneously hypertensive rats by three days after treatment discontinuation. Thus, our studies provide validation for TMEM16A as a target for antihypertensive therapy and demonstrate the efficacy of TMinh-23 as an antihypertensive with a novel mechanism of action.

Outcomes of patients hospitalized for acute pulmonary embolism by obstructive sleep apnea status.

Pulmonary embolism (PE) is a major cause of cardiovascular morbidity and mortality. Obstructive sleep apnea (OSA) is increasingly recognized in the aging population, especially with the rising obesity epidemic. The impact of OSA on inpatient mortality in PE is not well understood. We used the Nationwide Inpatient Sample databases from 2005 to 2016 to identify 755,532 acute PE patients (age≥18 years). Among these, 61,050 (8.1%) were OSA+. Temporal trends in length of stay, inpatient mortality, and its association with OSA in PE patients were analyzed. The proportion of PE patients who were OSA+ increased from 2005 to 2016. OSA+ PE patients were younger and predominantly men. Despite a higher prevalence of traditional risk factors for inpatient mortality in OSA+ patients, OSA was associated with a lower risk of mortality in PE patients (odds ratio, 95% confidence interval; p: unadjusted 0.56, 0.53–0.58; p < 0.0001 and adjusted 0.55, 0.52–0.58; p < 0.0001). Overall mortality and length of stay in PE patients decreased over time. Relative to OSA– patients, there was a slight increase in mortality among OSA+ PE patients over time, although the length of stay remained unchanged between the two groups. In conclusion, OSA+ PE patients had a lower inpatient mortality compared to OSA– patients despite a higher prevalence of traditional mortality risk factors. Secondary pulmonary hypertension related to OSA with preconditioning of the right ventricle to elevated afterload may potentially explain the protective effect of OSA on mortality in PE. However, mechanistic studies need to further elucidate the links behind this association.

Genetic Risk Score to Identify Risk of Venous Thromboembolism in Patients With Cardiometabolic Disease.

Venous thromboembolism (VTE) is a major cause of cardiovascular morbidity and mortality and has a known genetic contribution. We tested the performance of a genetic risk score for its ability to predict VTE in 3 cohorts of patients with cardiometabolic disease. We included patients from the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) trials (history of a major atherosclerotic cardiovascular event, myocardial infarction, and diabetes, respectively) who consented for genetic testing and were not on baseline anticoagulation. We calculated a VTE genetic risk score based on 297 single nucleotide polymorphisms with established genome-wide significance. Patients were divided into tertiles of genetic risk. Cox proportional hazards models were used to calculate hazard ratios for VTE across genetic risk groups. The polygenic risk score was compared with available clinical risk factors (age, obesity, smoking, history of heart failure, and diabetes) and common monogenic mutations. A total of 29 663 patients were included in the analysis with a median follow-up of 2.4 years, of whom 174 had a VTE event. There was a significantly increased gradient of risk across VTE genetic risk tertiles (P-trend <0.0001). After adjustment for clinical risk factors, patients in the intermediate and high genetic risk groups had a 1.88-fold (95% CI, 1.23-2.89; P=0.004) and 2.70-fold (95% CI, 1.81-4.06; P<0.0001) higher risk of VTE compared with patients with low genetic risk. In a continuous model adjusted for clinical risk factors, each standard deviation increase in the genetic risk score was associated with a 47% (95% CI, 29-68) increased risk of VTE (P<0.0001). In a broad spectrum of patients with cardiometabolic disease, a polygenic risk score is a strong, independent predictor of VTE after accounting for available clinical risk factors, identifying 1/3 of patients who have a risk of VTE comparable to that seen with established monogenic thrombophilia.

Acute pulmonary embolism following recent hospitalization or surgery.

Pulmonary embolism (PE) is a major cause of cardiovascular morbidity and mortality. Recent hospitalization or surgery is a leading risk factor for PE, yet there are minimal data examining its effect on treatment and outcomes. We conducted a retrospective review of institutional billing codes for hospitalized patients with acute PE from August 2012 to August 2018. Patients were stratified based on whether they had a recent major medical encounter (MME), defined as surgery or hospitalization within 90days. Primary outcomes included in-hospital mortality and 30- and 90-day readmission rates. Secondary outcomes included length of stay (LOS), use of advanced therapies, major bleeding, discharge anticoagulation and recurrent venous thromboembolism (VTE) at 90days. Outcomes were adjusted for confounders using multivariable regression modeling. 2063 patients were hospitalized for an acute PE; 633 (30.7%) had a recent MME. Patients with a recent MME had a higher average Charlson Comorbidity Index (4.6 vs. 4.0, p < 0.01). Both 30- and 90-day readmission rates were higher in patients with a recent MME (21.7% vs. 14.4%; adjusted OR 1.06 [1.00, 1.12], p = 0.037; 30.8% vs 18.7%; adjusted OR 1.11 [1.11, 1.62], p = 0.003, respectively). After adjustment, there were no between-group differences in in-hospital mortality, LOS, use of advanced therapies, major bleeding, or recurrent VTE at 90days. In-hospital mortality was higher for patients with a recent medical hospitalization compared to those with a recent surgery (10.2% vs. 5.6%, adjusted OR 1.08 [1.01, 1.15] p = 0.032). Despite recent hospitalization and/or surgery and greater number of comorbidities, patients admitted with a PE and recent MME had similar in-hospital outcomes, but experienced higher readmission rates. In-hospital mortality was higher in those with a recent medical compared to surgical encounter. Clinicians should optimize post-discharge transitional care in this subset of patients.

Tumor Necrosis Factor Alpha and Interleukin 1 Beta Suppress Myofibroblast Activation Via Nuclear Factor Kappa B Signaling in 3D-Cultured Mitral Valve Interstitial Cells

Mitral valve disease is a major cause of cardiovascular morbidity throughout the world. Many different mitral valve pathologies demonstrate a pronounced degree of fibrotic remodeling, often accompanied by an inflammatory state. Mitral valve fibrosis is mediated by valvular interstitial cells (VICs), which reside in the valve leaflets and show a tendency to differentiate into myofibroblast-like cells during disease conditions. In this study, we investigated the effects of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) on mitral VICs, since these pro-inflammatory cytokines have been shown to exert pleiotropic effects on various cell types in other fibrotic disorders. Using biomimetic three-dimensional culture systems, we demonstrated that TNF-α and IL-1β suppress myofibroblast differentiation in mitral VICs, as evidenced by gene and protein expression of alpha smooth muscle actin and smooth muscle 22 alpha. Addition of TNF-α and IL-1β also inhibited mitral VIC-mediated contraction of collagen gels. Furthermore, inhibition of NF-κB, which is downstream of TNF-α and IL-1β, reversed these effects. These results reveal targetable pathways that could enable the development of pharmaceutical treatments for alleviating fibrosis during mitral valve disease.

Abstract MP30: Small Molecule Inhibitor Of Chloride Channel Tmem16a Blocks Vascular Smooth Muscle Contraction And Lowers Blood Pressure In Spontaneously Hypertensive Rats

Hypertension is a major cause of cardiovascular morbidity and mortality, despite the availability of antihypertensive drugs with different targets and mechanisms of action. There is an unmet need for antihypertensive drugs with novel mechanisms of action to better control hypertension and reduce cardiovascular morbidity and mortality. Here, we provide evidence that pharmacological inhibition of TMEM16A (transmembrane member 16A or anoctamin-1), a Ca 2+ -activated Cl - channel expressed in vascular smooth muscle cells, reduces in vitro vascular smooth muscle contraction and decreases blood pressure in spontaneously hypertensive rats (SHR). We recently identified by high-throughput screening and subsequent medicinal chemistry, small molecule TMEM16A inhibitor TM inh -23 (2-bromodifluoroacetylamino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid o-tolylamide) that inhibits TMEM16A current fully, with IC 50 ~ 30 nM. TM inh -23 pretreatment blocked maximum in vitro vascular smooth muscle contractions induced by a thromboxane mimetic (U46619) in rat mesenteric arteries by 90%. Intraperitoneal (ip) administration of TM inh -23 to rodents at 10 mg/kg produced sustained serum concentrations of &gt;10 μM for &gt;4 hours. BP measurements by tail-cuff and telemetry showed a maximum ~45 mmHg reduction in SBP in spontaneously hypertensive rats (SHR) after a single dose (10 mg/kg, ip) TM inh -23 administration compared to vehicle treatment, with BP gradually returning to baseline values within 6-8 hours after TM inh -23 treatment. Minimal effect on BP (less than 10 mmHg decrease in SBP) was seen in wild-type rats and mice with TM inh -23 treatment (10 mg/kg, ip). Chronic 5-day treatment of SHR with TM inh -23 (10 mg/kg, ip, twice daily) caused sustained decreases (~20-25 mmHg) in daily average SBP, DBP and MAP during the treatment period. TM inh -23 action was reversible, with BP returning to baseline (~170/115 mmHg) by 3 days after discontinuation of treatment. These studies provide validation for TMEM16A as a target for antihypertensive therapy, and demonstrate the proof-of-concept for efficacy of TM inh -23 as an antihypertensive with a novel mechanism of action.