Forms Of Heart Disease Research Articles

In Case You Haven't Heard…

Keeping your brain sharp as you age has a lot to do with your heart — and the younger you start taking better care of it, the better — according to a new scientific statement published by the American Heart Association (AHA), CNN Health reported Oct. 10. “Dementia is commonly seen as an incurable and relentless disease that cannot be prevented,” said Fernando Testai, M.D., Ph.D., a professor of neurology and rehabilitation at the University of Illinois College of Medicine in Chicago, in a statement. “Evidence shows, however, that adopting a healthy lifestyle and identifying and treating vascular risk factors early may help preserve normal brain function and reduce the burden of Alzheimer's disease and other related dementias,” said Testai, who chaired the statement writing group. Nearly 130 million adults in the United States have some form of heart disease, according to the AHA. The disease also takes a toll on the brain. The narrowing of arteries that occurs with coronary heart disease and high blood pressure can reduce blood flow and cause damage to the small blood vessels in the brain, resulting in cognitive impairment, the AHA said. High blood pressure and Type 2 diabetes can also reduce blood flow to the brain and increase inflammation, leading to cognitive decline and dementia. Having coronary heart disease raises the risk of future dementia by 27% compared with people without heart disease, the AHA statement said.

Experimental studies of spiral wave teleportation in a light sensitive Belousov-Zhabotinsky system.

Cardiac arrythmias are a form of heart disease that contributes toward making heart disease a significant cause of death globally. Irregular rhythms associated with cardiac arrythmias are thought to arise due to singularities in the heart tissue that generate reentrant waves in the underlying excitable medium. A normal approach to removing such singularities is to apply a high voltage electric shock, which effectively resets the phase of the cardiac cells. A concern with the use of this defibrillation technique is that the high-energy shock can cause lasting damage to the heart tissue. Various theoretical works have investigated lower-energy alternatives to defibrillation. In this work, we demonstrate the effectiveness of a low-energy defibrillation method in an experimental 2D Belousov-Zhabotinsky (BZ) system. When implemented as a 2D spatial reaction, the BZ reaction serves as an effective analog of general excitable media and supports regular and reentrant wave activity. The defibrillation technique employed involves targeted low-energy perturbations that can be used to "teleport" and/or annihilate singularities present in the excitable BZ medium.

Comparative proteomics reveals that fatty acid metabolism is involved in myocardial adaptation to chronic hypoxic injury.

Congenital heart disease (CHD) is the most serious form of heart disease, and chronic hypoxia is the basic physiological process underlying CHD. Some patients with CHD do not undergo surgery, and thus, they remain susceptible to chronic hypoxia, suggesting that some protective mechanism might exist in CHD patients. However, the mechanism underlying myocardial adaptation to chronic hypoxia remains unclear. Proteomics was used to identify the differentially expressed proteins in cardiomyocytes cultured under hypoxia for different durations. Western blotting assays were used to verify protein expression. A Real-Time Cell Analyzer (RTCA) was used to analyze cell growth. In this study, 3881 proteins were identified by proteomics. Subsequent bioinformatics analysis revealed that proteins were enriched in regulating oxidoreductase activity. Functional similarity cluster analyses showed that chronic hypoxia resulted in proteins enrichment in the mitochondrial metabolic pathway. Further KEGG analyses found that the proteins involved in fatty acid metabolism, the TCA cycle and oxidative phosphorylation were markedly upregulated. Moreover, knockdown of CPT1A or ECI1, which is critical for fatty acid degradation, suppressed the growth of cardiomyocytes under chronic hypoxia. The results of our study revealed that chronic hypoxia activates fatty acid metabolism to maintain the growth of cardiomyocytes.

Prevalence and 3-year incidence of physical illnesses after schizophrenia diagnosis: Comparison with general population

AimPeople with schizophrenia are at a greater risk of poor physical health than the general population. This study investigated the annual incidence of physical illnesses after a new schizophrenia diagnosis, which has rarely been investigated in the literature. MethodsThe authors collected data from Taiwan's National Health Insurance Research Database from January 1, 1996, to December 31, 2013, and enrolled 1910 patients with newly diagnosed schizophrenia cases aged 10–40 years and 7640 age- and sex-matched controls from the general population. They estimated the 1-year prevalence and annual incidence rate ratio (IRR) of specified physical diseases across 3 years in the schizophrenia group compared with the controls. ResultsSeveral physical illnesses were prevalent within 1 year of schizophrenia diagnosis. Regarding incident physical illnesses, patients had a moderate to strong risk of numerous physical illnesses (IRR > 3.0: ischemic heart disease, cerebrovascular disease, diabetes mellitus, and cancer; IRR 1.8–3.0: other forms of heart disease, vein and lymphatic diseases, pneumonia, chronic hepatic disease, and ulcer disease) within the first year after schizophrenia diagnosis. The IRRs of most physical illnesses declined over 3 years, except for that of cerebrovascular disease, which significantly increased (IRR > 3.0) over the 3 years after schizophrenia diagnosis. Cerebrovascular disease had a significant incidence risk (IRR > 3) persistently across the 3 years. ConclusionVarious comorbid physical illnesses can occur in the early stages of schizophrenia. Clinicians should consider these vulnerabilities to physical illnesses during the evaluation of patients with newly diagnosed schizophrenia by attempting to prevent, screen for, and manage them.

Cross Validation of the Post Event-Cardiovascular Risk Perception Survey Instrument among Cardiac Rehabilitation Patients

Background: By 2035, nearly half of U.S. adults will have some form of heart disease. COVID-19 altered the delivery of care for cardiac rehabilitation patients who experienced a cardiac event.Objective: To cross-validate the Post Event-Cardiovascular Risk Perception Survey (PE-CRPS).Methods: A cross-sectional and descriptive study was conducted to validate CVD risk perception survey. Explorative factor analysis (EFA) was utilized to explore the factors, validate the scale, and measure variance in the data.Results: Of the 261 individuals, majority were males (71%, mean age: 65.77 years), Caucasian-Non-Hispanic origin (94%) with co morbidities (hypertension, hyper-lipidemia and diabetes). EFA identified 16 latent (eigenvalues >1) with 45 observed variables to measure CVD risk perception. Factors explained 68% of the variance. Bartlett’s test of sphericity was significant (p=.001), indicating variances not significant and the factors correlated.Conclusions: PE-CRPS was valid and can be used to assess cardiac risk perceptions among cardiac rehabilitation individuals.

Attention-Deficit/Hyperactivity Disorder Medications and Long-Term Risk of Cardiovascular Diseases

Use of attention-deficit/hyperactivity disorder (ADHD) medications has increased substantially over the past decades. However, the potential risk of cardiovascular disease (CVD) associated with long-term ADHD medication use remains unclear. To assess the association between long-term use of ADHD medication and the risk of CVD. This case-control study included individuals in Sweden aged 6 to 64 years who received an incident diagnosis of ADHD or ADHD medication dispensation between January 1, 2007, and December 31, 2020. Data on ADHD and CVD diagnoses and ADHD medication dispensation were obtained from the Swedish National Inpatient Register and the Swedish Prescribed Drug Register, respectively. Cases included individuals with ADHD and an incident CVD diagnosis (ischemic heart diseases, cerebrovascular diseases, hypertension, heart failure, arrhythmias, thromboembolic disease, arterial disease, and other forms of heart disease). Incidence density sampling was used to match cases with up to 5 controls without CVD based on age, sex, and calendar time. Cases and controls had the same duration of follow-up. Cumulative duration of ADHD medication use up to 14 years. The primary outcome was incident CVD. The association between CVD and cumulative duration of ADHD medication use was measured using adjusted odds ratios (AORs) with 95% CIs. Of 278 027 individuals with ADHD aged 6 to 64 years, 10 388 with CVD were identified (median [IQR] age, 34.6 [20.0-45.7] years; 6154 males [59.2%]) and matched with 51 672 control participants without CVD (median [IQR] age, 34.6 [19.8-45.6] years; 30 601 males [59.2%]). Median (IQR) follow-up time in both groups was 4.1 (1.9-6.8) years. Longer cumulative duration of ADHD medication use was associated with an increased risk of CVD compared with nonuse (0 to ≤1 year: AOR, 0.99 [95% CI, 0.93-1.06]; 1 to ≤2 years: AOR, 1.09 [95% CI, 1.01-1.18]; 2 to ≤3 years: AOR, 1.15 [95% CI, 1.05-1.25]; 3 to ≤5 years: AOR, 1.27 [95% CI, 1.17-1.39]; and >5 years: AOR, 1.23 [95% CI, 1.12-1.36]). Longer cumulative ADHD medication use was associated with an increased risk of hypertension (eg, 3 to ≤5 years: AOR, 1.72 [95% CI, 1.51-1.97] and >5 years: AOR, 1.80 [95% CI, 1.55-2.08]) and arterial disease (eg, 3 to ≤5 years: AOR, 1.65 [95% CI, 1.11-2.45] and >5 years: AOR, 1.49 [95% CI, 0.96-2.32]). Across the 14-year follow-up, each 1-year increase of ADHD medication use was associated with a 4% increased risk of CVD (AOR, 1.04 [95% CI, 1.03-1.05]), with a larger increase in risk in the first 3 years of cumulative use (AOR, 1.08 [95% CI, 1.04-1.11]) and stable risk over the remaining follow-up. Similar patterns were observed in children and youth (aged <25 years) and adults (aged ≥25 years). This case-control study found that long-term exposure to ADHD medications was associated with an increased risk of CVDs, especially hypertension and arterial disease. These findings highlight the importance of carefully weighing potential benefits and risks when making treatment decisions about long-term ADHD medication use. Clinicians should regularly and consistently monitor cardiovascular signs and symptoms throughout the course of treatment.

Evidence-informed development of women-focused cardiac rehabilitation education

BackgroundDespite their differential risk factor burden, context and often different forms of heart disease, cardiac rehabilitation (CR) programs generally do not provide women with needed secondary prevention information specific to them. Objectiveto co-design evidence-informed, theory-based comprehensive women-focused education, building from Health e-University's Cardiac College for CR. MethodsA multi-disciplinary, multi-stakeholder steering committee (N = 18) oversaw the four-phase development of the women-focused curriculum. Phase 1 involved a literature review on women's CR information needs and preferences, phase 2 a CR program needs assessment, phase 3 content development (including determining content and mode, assigning experts to create the content, plain language review and translation), and phase 4 will comprise evaluation and implementation. In phase 2, a focus group was conducted with Canadian CR providers; it was analyzed using Braun and Clarke's iterative approach. ResultsNineteen providers participated in the focus group, with four themes emerging: current status of education, challenges to delivering women-focused education, delivery modes and topical resources. Results were consistent with those from our related global survey, supporting saturation of themes. Co-designed educational materials included 19 videos. These were organized across 5 webpages in English and French, specific to tests and treatments, exercise, diet, psychosocial well-being, and self-management. Twelve corresponding session slide decks with notes for clinicians were created, to support program delivery in CR flexibly. ConclusionWhile further evaluation is underway, these open-access CR education resources will be disseminated for implementation, to support women in reducing their risk of cardiovascular sequelae.

Reduced Mitochondrial Protein Translation Promotes Cardiomyocyte Proliferation and Heart Regeneration.

The importance of mitochondria in normal heart function are well recognized and recent studies have implicated changes in mitochondrial metabolism with some forms of heart disease. Previous studies demonstrated that knockdown of the mitochondrial ribosomal protein S5 (MRPS5) by small interfering RNA (siRNA) inhibits mitochondrial translation and thereby causes a mitonuclear protein imbalance. Therefore, we decided to examine the effects of MRPS5 loss and the role of these processes on cardiomyocyte proliferation. We deleted a single allele of MRPS5 in mice and used left anterior descending coronary artery ligation surgery to induce myocardial damage in these animals. We examined cardiomyocyte proliferation and cardiac regeneration both in vivo and in vitro. Doxycycline treatment was used to inhibit protein translation. Heart function in mice was assessed by echocardiography. Quantitative real-time polymerase chain reaction and RNA sequencing were used to assess changes in transcription and chromatin immunoprecipitation (ChIP) and BioChIP were used to assess chromatin effects. Protein levels were assessed by Western blotting and cell proliferation or death by histology and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays. Adeno-associated virus was used to overexpress genes. The luciferase reporter assay was used to assess promoter activity. Mitochondrial oxygen consumption rate, ATP levels, and reactive oxygen species were also analyzed. We determined that deletion of a single allele of MRPS5 in mice results in elevated cardiomyocyte proliferation and cardiac regeneration; this observation correlates with improved cardiac function after induction of myocardial infarction. We identified ATF4 (activating transcription factor 4) as a key regulator of the mitochondrial stress response in cardiomyocytes from Mrps5+/- mice; furthermore, ATF4 regulates Knl1 (kinetochore scaffold 1) leading to an increase in cytokinesis during cardiomyocyte proliferation. The increased cardiomyocyte proliferation observed in Mrps5+/- mice was attenuated when one allele of Atf4 was deleted genetically (Mrps5+/-/Atf4+/-), resulting in the loss in the capacity for cardiac regeneration. Either MRPS5 inhibition (or as we also demonstrate, doxycycline treatment) activate a conserved regulatory mechanism that increases the proliferation of human induced pluripotent stem cell-derived cardiomyocytes. These data highlight a critical role for MRPS5/ATF4 in cardiomyocytes and an exciting new avenue of study for therapies to treat myocardial injury.

SAT118 The "Intelligent" Chatbot: Can It Answer Questions About Health And Health Disparities?

Abstract Disclosure: G. Wu: None. W. Zhao: None. E. Cheng: None. A. Wong: None. H. Gim: None. Y. Zhang: None. P. Dorado: None. N. Mansubi: None. Introduction: In 2022, &amp;gt;130 million adults have diabetes or prediabetes and ∼122 million have a form of heart disease. Of those with diabetes; non-Hispanic blacks 12.1%, Hispanics 11.8%, Native Americans 14.5%, Asian Americans 9.5%, and non-Hispanic whites 7.4%. ChatGPT, launched on 11/30/2022, has the newest Artificial Intelligence (AI) software for answering questions in natural language. Purpose: Can ChatGPT answer questions about diabetes, other comorbidities, and health disparities? Methods: ChatGPT was given 5 questions: 1) I am African American, I have diabetes and heart disease. What are my risks of dying? 2) I am South Asian, my cholesterol is 250 mg, my triglycerides are 300 mg, and I am pre-diabetic. What is my risk of dying? 3) I am Native American, I have diabetes and heart disease, drink alcohol, and I smoke. What are my chances of dying versus my blonde American wife? 4) I am Chinese American, and my hemoglobin/A1C is 9. My fasting blood sugar is 200. I cannot read my newspaper anymore. Why? 5) I am Mexican American and my fasting blood glucose is 300, and I was just diagnosed with diabetes but for the past 6 months, I cannot feel my toes. Why? The questions were evaluated with the keywords below: (each keyword was given one point, maximum of 11 pts per question) healthcare team, stroke, heart attack, ADA/Endocrine Society, ACC/AHA, high blood sugar, high blood pressure, complications (eye, kidney, neuropathy, feet), statistics relating to ethnicity, metabolic syndrome. Keyword Scores: Qn1=4/11; Qn2=5/11; Qn3=1/11; Qn4=3/11; Qn5=3/11 Results: All answers mention “healthcare team,” 4/5 mention heart disease, 4/5 mention high blood sugar, 2/5 mention stroke, 1/5 mention diabetic retinopathy, and 1/5 mention neuropathy. None of the responses list ADA/Endocrine Society, ACC/AHA, statistics, or metabolic syndrome. None of the answers mention eye MD/ophthalmologist, endocrinologist, nephrologist, or podiatrist. None mention health disparities. Qn 1 answers: stroke, heart attack, high blood sugar, and health care team. Qn 2 answers: increased cholesterol as a risk factor and the same answers as Qn1. The answer to Qn 3, involving Native Americans, does not mention “stroke” in the setting of diabetes, heart disease, smoking, and alcohol consumption. Despite the words of "South Asian" and "Chinese American", Qn 2 and 4, respectively, do not mention metabolic syndrome. Qn 4 does not mention the risks of kidney disease and stroke. Only two answers (Qn 1, 2) mention stroke as a risk factor. Conclusions: ChatGPT is not perfect but it provides baseline information for diabetic patients and is a great start to furthering health education for the public. Presentation: Saturday, June 17, 2023

Association between migraine and cardiovascular disease mortality: A prospective population-based cohort study.

The study assessed the association between migraine and cardiovascular disease (CVD) mortality in the US population. Previous studies have drawn different conclusions about the association between migraine and CVD mortality based on different populations; therefore, it is important to explore the relationship between migraine and CVD mortality in the US population. This prospective cohort study included 10,644 participants from the National Health and Nutrition Examination Survey (NHANES) 1999-2004. Participants who reported having severe headache or migraine were classified as having migraine. Mortality data were obtained by linkage of the cohort database to the National Death Index as of December 31, 2019. Based on the International Classification of Diseases, Tenth Revision, CVD mortality includes the following disease codes: I00-I09 (acute rheumatic fever and chronic rheumatic heart diseases), I11 (hypertensive heart disease), I13 (hypertensive heart and renal disease), I20-I25 (ischemic heart diseases), I26-I28 (pulmonary embolism and other acute pulmonary heart diseases), I29 (various cardiovascular diseases caused by different reasons), I30-I51 (other forms of heart disease), and I60-I69 (cerebrovascular diseases). Data were analyzed from October to November 2022. Among 10,644 adults included in the study (mean age, 46.4 [0.3] years, 5430 men [47.4%]), 2106 (20.4%) had migraine. During a median follow-up period of 201 months, there were 3078 all-cause deaths and 997 CVD deaths. Compared to individuals without migraine, those with migraine had an adjusted hazard ratio (HR) of 1.30 (95% confidence interval [CI], 1.04-1.62; p = 0.019) for CVD mortality and 1.23 (95% CI, 1.13-1.35; p < 0.001) for all-cause mortality. In subgroup analyses, migraine was associated with CVD mortality in participants who were women (HR, 1.43; 95% CI, 1.06-1.93), aged < 45 years (HR, 1.69; 95% CI, 1.04-2.76), non-Hispanic White (HR, 1.42; 95% CI, 1.09-1.86), those with a body mass index < 30 kg/m2 (HR, 1.36; 95% CI, 1.03-1.78), former or current smokers (HR, 1.36; 95% CI, 1.00-1.85), former or current alcohol drinkers (HR, 1.33; 95% CI, 1.03-1.72), and those without metabolic syndrome (HR, 1.31; 95% CI, 1.01-1.71). The association between migraine and CVD mortality was robust in sensitivity analyses, after excluding participants who died within 2 years of follow-up (HR, 1.31; 95% CI, 1.05-1.65) or those with a history of cancer at baseline (HR, 1.28; 95% CI, 1.01-1.62). Migraine was associated with a higher CVD mortality rate in the US population.

Impact of Diabetes Duration and Control on the Extent and Severity of Coronary Artery Disease in Egyptian Patients: Evaluation by Coronary CT Angiography

Abstract Background Diabetes mellitus (DM) has reached epidemic proportions worldwide and approximately 40% of diabetics die due to ischemic heart disease, 15% from other forms of heart disease, principally congestive heart failure, and about 10% from stroke. The role of DM in CAD progression is now universally accepted. Aim of the Work To explore the association between diabetes duration and control on the extent of coronary artery disease (CAD) using coronary computed tomography angiography (CCTA). Patients and Methods This study is a cross sectional observational study that included 100 diabetic patients who were eligible for CT coronary angiography. They were evaluated in the diabetic outpatient clinic of the internal affairs ministry Hospitals for symptoms suggestive of CAD or for preoperative cardiovascular system risk stratification. CT coronary angiography was performed in all patients, and CACS was calculated using Agatston score. CCTA was analyzed for the site and severity of stenosis. For each patient, the number of diseased vessels was calculated through the assignment of one, two, and three or left main (LM) coronary artery vessels. Results The prevalence of atherosclerotic coronary artery disease among diabetics in the studied population was 78%, moderate to severe degree of obstructive lesions was found in 81% of them as detected by CTCA. Coronary calcification was found in 65% of diabetic patients. Coronary calcium score showed a significant positive correlation with age (p-value =0.002), HB1c level and the Triglycerides, cholesterol and LDL levels. The severity of atherosclerotic coronary artery disease was significantly associated with dyslipidemia. On the other hand, the extent of coronary affection was associated with the duration of diabetes. Among the studied subjects, the LAD was the most frequently affected artery (60% of patients). Low risk diabetics (zero calcium and no atherosclerotic plaques) had a mean duration of DM &amp;lt; 10 years with controlled lipid profile. Conclusion Based on the results of the current study, we can draw several conclusions. Diabetic patients are at risk for significant CAD with or without calcium burden. Extensive significant CAD is associated with long standing diabetes. Uncontrolled diabetes mellitus and the presence of dyslipidemia augment the process of atherosclerosis and the severity of the disease. Younger patients with controlled diabetes and lipid profile have a more favorable coronary anatomy profile and a favorable outcome. The LAD is the artery of predilection in diabetics. Abbreviations ASCVD: Atherosclerotic cardiovascular disease; BP: Blood pressure; CABG: Coronary artery bypass graft; CAD: Coronary artery disease; CCTA: Coronary computed tomography angiography; CVD: Cardiovascular disease; DM: Diabetes mellitus; HDL-c: High density lipoprotein cholesterol; HS: Highly significant; IQR: Inter-quartile range; LAD: Left anterior descending; LCX: Left circumflex; LDL-c: Low density lipoprotein cholesterol; LM: Left main; MDCT: Multidetector coronary CT angiography; MSCT: Multi-slice computed tomography; NS: Non significant; PCI: Percutaneous coronary intervention; RCA: Right coronary artery; S: Significant; TC: Total cholesterol; TG: Triglycerides

Cardiac myosin velocity and force are dramatically improved with an alternative triphosphate substrate.

Cardiac myosin is the molecular motor that drives the pumping action of the heart; therefore, there is strong interest in gaining control over its function in an effort to develop more effective treatments for various forms of heart disease. We sought to determine if the force and motion generating capacity of β-cardiac myosin could be altered in vitro by replacing ATP with different isomers of an alternative energy source, azobenzene triphosphate (AzoTP). Using the ortho-isomer of AzoTP, cardiac myosin moved actin filaments 62% faster than ATP in a motility assay (p<0.001). Subsequent experiments suggested that the increased velocity may be the result of an accelerated rate of ortho-AzoDP-release from myosin. Cardiac myosin also generated 10% more force when using ortho-AzoTP compared to ATP in a laser trap assay (p<0.001), which was likely due to an increased rate of attachment to actin because the frequency of single actomyosin binding events observed in a three-bead laser trap assay was double that observed for ortho-AzoTP vs. ATP (p<0.001). In contrast to ortho-AzoTP, with the meta isomer of AzoTP cardiac myosin translocated actin filaments 90% slower than with ATP (p<0.001). This finding is likely do to a slowed rate of detachment from actin, based on preliminary single molecule findings. With the para-isomer of AzoTP no movement was detected in the motility assay, suggesting it may not bind to the nucleotide-binding site. Thus, these findings demonstrate that the function of beta-cardiac myosin can be manipulated using structural isomers of an alternative energy substrate (AzoTP). These findings therefore may provide important new insights into how to alter the function of cardiac myosin in vivo, which could help in the development of novel therapies to different forms of heart disease.

High throughput image processing software for analyzing hiPSC-CM sarcomere physiology and cardiac fibroblast activation.

Heart disease is the leading cause of death worldwide and discovering therapies that treat its underlying cause is paramount to improving survivability and patient health. Since heart disease often results in detrimental remodeling of heart tissue, high-throughput screening (HTS) using cardiomyocytes and cardiac fibroblasts is frequently used for drug discovery. A major challenge in analyzing HTS data is ensuring that analysis is both fast and minimally biased. In many forms of heart disease and remodeling, cardiomyocytes will suffer from loss of sarcomeres and sarcomere disarray, while fibroblasts will often express increased α-smooth muscle actin (α-SMA) stress fibers when activated into myofibroblasts. Two custom MATLAB HTS image processing scripts named ‘Tamarack’ and ‘Porcupine’ were developed for quantifying human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) sarcomere morphology and cardiac fibroblast activation, respectively. Both scripts use wavelet transforms to detect subcellular structures that are of interest for analyzing phenotypes at the cellular level. Tamarack enables quantification of sarcomere metrics, including sarcomere count, length, orientation, and α-actinin rich areas. Porcupine enables quantification of fibroblast activation metrics, including α-SMA stress fiber count, length, orientation, nuclei and α-SMA overlap, and F-actin and α-SMA overlap. Both scripts enable analysis of other cellular features, such as nuclei count and stain intensity/protein expression. Tamarack obtained statistically significant results when comparing control hiPSC-CMs with hiPSC-CMs subjected to siRNA knockdowns of genes of interest. Porcupine was validated by analyzing fibroblasts with increasing concentrations of TGF-β which induced increasing activation. By developing technology for analyzing cardiomyocyte and fibroblast imaged-based screens, drug candidates can be efficiently evaluated without bias on cell types that are relevant to human heart disease. This research may help expand drug candidate portfolios and improve the number of treatments available to patients worldwide.

Proteomic Insights into Cardiac Fibrosis: From Pathophysiological Mechanisms to Therapeutic Opportunities.

Cardiac fibrosis is a common pathophysiologic process in nearly all forms of heart disease which refers to excessive deposition of extracellular matrix proteins by cardiac fibroblasts. Activated fibroblasts are the central cellular effectors in cardiac fibrosis, and fibrotic remodelling can cause several cardiac dysfunctions either by reducing the ejection fraction due to a stiffened myocardial matrix, or by impairing electric conductance. Recently, there is a rising focus on the proteomic studies of cardiac fibrosis for pathogenesis elucidation and potential biomarker mining. This paper summarizes the current knowledge of molecular mechanisms underlying cardiac fibrosis, discusses the potential of imaging and circulating biomarkers available to recognize different phenotypes of this lesion, reviews the currently available and potential future therapies that allow individualized management in reversing progressive fibrosis, as well as the recent progress on proteomic studies of cardiac fibrosis. Proteomic approaches using clinical specimens and animal models can provide the ability to track pathological changes and new insights into the mechanisms underlining cardiac fibrosis. Furthermore, spatial and cell-type resolved quantitative proteomic analysis may also serve as a minimally invasive method for diagnosing cardiac fibrosis and allowing for the initiation of prophylactic treatment.

MgADP Promotes Myosin Head Movement toward Actin at Low [Ca2+] to Increase Force Production and Ca2+-Sensitivity of Contraction in Permeabilized Porcine Myocardial Strips.

Myosin cross-bridges dissociate from actin following Mg2+-adenosine triphosphate (MgATP) binding. Myosin hydrolyses MgATP into inorganic phosphate (Pi) and Mg2+-adenosine diphosphate (ADP), and release of these hydrolysis products drives chemo-mechanical energy transitions within the cross-bridge cycle to power muscle contraction. Some forms of heart disease are associated with metabolic or enzymatic dysregulation of the MgATP-MgADP nucleotide pool, resulting in elevated cytosolic [MgADP] and impaired muscle relaxation. We investigated the mechanical and structural effects of increasing [MgADP] in permeabilized myocardial strips from porcine left ventricle samples. Sarcomere length was set to 2.0 µm at 28 °C, and all solutions contained 3% dextran T-500 to compress myofilament lattice spacing to near-physiological values. Under relaxing low [Ca2+] conditions (pCa 8.0, where pCa = -log10[Ca2+]), tension increased as [MgADP] increased from 0-5 mM. Complementary small-angle X-ray diffraction measurements show that the equatorial intensity ratio, I1,1/I1,0, also increased as [MgADP] increased from 0 to 5 mM, indicating myosin head movement away from the thick-filament backbone towards the thin-filament. Ca2+-activated force-pCa measurements show that Ca2+-sensitivity of contraction increased with 5 mM MgADP, compared to 0 mM MgADP. These data show that MgADP augments tension at low [Ca2+] and Ca2+-sensitivity of contraction, suggesting that MgADP destabilizes the quasi-helically ordered myosin OFF state, thereby shifting the cross-bridge population towards the disordered myosin ON state. Together, these results indicate that MgADP enhances the probability of cross-bridge binding to actin due to enhancement of both thick and thin filament-based activation mechanisms.

Clusterin is increased in morphologically normal cardiomyocytes in lymphocytic myocarditis.

Clusterin is increased in morphologically normal cardiomyocytes in lymphocytic myocarditis.

Abstract 11750: Disparities Among Covid-19 Mortality in Patients With Concurrent Cancer and Cardiovascular Disease in 2020: A Nationwide Analysis

Introduction: The COVID-19 pandemic has highlighted important socioeconomic health disparities in the United States. Both cardiovascular disease (CVD) and cancer are associated with worse COVID-19 outcomes. We describe racial or ethnic, sex, and rural disparities in mortality rates from COVID-19 in the US cardio-oncology (C-O) population with concurrent cancer and CVD. Methods: Using the multiple causes of death data files within CDC WONDER, we assessed survival outcomes from March to December 2020 (most intense for COVID-19 deaths) by race or ethnicity, sex, and rural status. C-O populations were defined as having ICD 10 codes C00-C97 for “malignant neoplasms” and ICD 10 codes I10-I15 for “hypertensive heart disease”, I20-I25 for “ischemic heart disease” I30-I51 for “other forms of heart disease” encompassing valvular disorders, cardiac arrythmias, myocarditis, and heart failure &amp; cardiomyopathies, or I70 for peripheral atherosclerosis listed as contributing causes of death. In this population, those with ICD 10 code U07.1 for “COVID-19” listed as an underlying cause of death were included. Age-adjusted mortality rates (AAMR) were calculated based on contemporary US population standards. Results: Overall, there were 6,311 deaths from COVID-19 among 16,282 all-cause deaths in the C-O population (AAMR 5.17 deaths/1,000,000 person-years; 95% CI 5.04-5.29). These deaths comprised 1.80% of all COVID-19 deaths (total 350,831) in the study period. Mortality rates were higher in men than women (AAMR 7.35 vs 3.44 deaths/1,000,000; HR 2.13, p&lt;0.0001). Among racial or ethnic groups, mortality rates were highest among African Americans (AAMR 9.31 deaths/1,000,000; 95% CI 8.75-9.88), and higher among Hispanic than non-Hispanic Americans (AAMR 7.10 vs 4.86 deaths/1,000,000; HR 1.46, p&lt;0.0001). Mortality rates were higher in rural areas than metropolitan areas (crude mortality rate 9.15 vs 6.20 deaths/1,000,000; HR 1.48, p &lt;0.001). Conclusion: Among cancer patients with concurrent CVD, COVID-19 deaths were disproportionately higher in male, African American, Hispanic, and rural patients. Further research is needed to understand socioeconomic factors underpinning these disparities and design interventions to improve patient outcomes.

Gestational diabetes, preeclampsia and the maternal heart

Abstract Background Gestational diabetes mellitus (GDM) and preeclampsia (pE) are both associated with an increased risk of cardiovascular mortality and morbidity, including an increased risk of developing heart failure in later life. Both conditions are increasing in prevalence; GDM affects up to 12% and pE affects 3–5% of pregnancies worldwide. Compromised cardiac energy production is an important contributor to most forms of heart disease. The changes in myocardial energetics in GDM and pE have not been characterised previously. Purpose We sought to assess if women with GDM and women with pE in the third trimester of pregnancy exhibit adverse cardiac alterations in myocardial energetics, function or tissue characteristics. Methods Thirty-eight healthy pregnant (HP) women, thirty women with GDM and fifteen women with pE were recruited, matched for age and ethnicity. Participants underwent phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance for assessment of myocardial energetics (phosphocreatine to ATP ratio (PCr/ATP)), tissue characteristics, biventricular volumes and ejection fractions, left ventricular (LV) mass, global longitudinal strain (GLS) and mitral in-flow E/A ratio. Results The biochemical characteristics and multiparametric MR results are given in Table 1. The women in the GDM and the pE groups had higher body-mass index. There was a stepwise increase in the systolic and diastolic BP from the HP to the GDM to the pE group. There was no difference in NTproBNP concentrations between the groups. The gestational weight gain was higher in women with GDM and pE compared to the HP group. The women in the GDM and the pE groups showed similar reductions in myocardial PCr/ATP ratios compared to HP group (Figure 1a), accompanied by lower LV end-diastolic volumes and higher LV mass (Figure 1b) and enhanced LV concentricity in both groups (Figure 1c). While LV ejection fractions were similar across the groups, the GLS was reduced in women with GDM and in women with pE (Figure 1d). Conclusions We show here for the first time that despite no prior diagnosis of diabetes or hypertension, women with GDM or pE manifest impaired myocardial contractility and higher LV mass, associated with reductions in myocardial energetics. These findings may aid our understanding of the long-term cardiovascular risks associated with these conditions. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Wellcome Trust

Sphingosine-1-phosphate Attenuates Endoplasmic Reticulum Stress-induced Cardiomyocyte Apoptosis Through Sphingosine-1-phosphate Receptor 1

Endoplasmic reticulum stress (ER stress) is involved in the development and progression of various forms of heart disease and may lead to myocardial apoptosis. Sphingosine-1-phosphate (S1P) possesses cardioprotective properties, including anti-apoptosis. However, little is known about the link between S1P and ER stress-induced myocardial apoptosis. This study investigated the regulatory role of S1P in ER stress-induced apoptosis in cardiomyocytes. ER stress and myocardial apoptosis were induced by transverse aortic constriction (TAC) or tunicamycin in mice, which were then treated with 2-acetyl-5-tetrahydroxybutyl imidazole (THI) or S1P. AC16 cells were treated with tunicamycin or thapsigargin, or pretreated with S1P, sphingosine-1-phosphate receptor (S1PR) subtype antagonists, S1PR1 agonist, and PI3K and MEK inhibitors. Cardiac function, the level of S1P in plasma and heart, ER stress markers, cell viability, and apoptosis were detected. S1P reduced the expression of ER stress-related molecules and ER stress-induced myocardial apoptosis in mice subjected to TAC or an injection of tunicamycin. Furthermore, in AC16 cells exposed to thapsigargin or tunicamycin, S1P decreased the expression of ER stress-related molecules, promoting cell viability and survival. Nevertheless, the S1PR1 antagonist abrogated the protection of S1P. Subsequently, in TAC S1PR1 heterozygous (S1PR1^+/-) mice, S1P had no effect on ER stress and apoptosis in cardiomyocytes. Notably, in vitro, the impact of anti-ER stress-induced myocardial apoptosis by the S1PR1 agonist was reversed by PI3K and MEK inhibitors. This study is the first to demonstrate that S1P relieves ER stress-induced myocardial apoptosis via S1PR1/AKT and S1PR1/ERK1/2, which are potential therapeutic targets for heart disease.

Healthcare utilization and comorbidity shortly before suicide mortality in patients with attention-deficit/hyperactivity disorder: a nested case-control study.

Few studies have analyzed healthcare utilization before suicide among individuals with attention-deficit/hyperactivity disorder (ADHD). This study examined the pattern of healthcare utilization and comorbidities shortly before death among patients with ADHD who died by suicide and compared these data with those of living controls. This study used Taiwan's National Health Insurance Research Database to identify patients with ADHD (N = 379,440) between January 1, 2001, and December 31, 2016. Subsequently, the researchers identified 159 suicide decedents by linking each patient with the National Mortality Database. By conducting a nested case-control study with risk-set sampling from the ADHD cohort, the researchers selected 20 age- and sex-matched controls (n = 3180) for each patient who died by suicide (cases). The researchers then applied conditional logistic regression to investigate differences in healthcare utilization as well as psychiatric and physical comorbidities between case patients and controls. Case patients had higher healthcare utilization within 3months before suicide, particularly in the psychiatry, emergency, internal medicine, neurosurgery, and plastic surgery departments. These patients also had higher risks of psychiatric comorbidities, including schizophrenia, bipolar disorder, depressive disorder, and sleep disorder, as well as physical comorbidities such as hypertension and other forms of heart disease. Among patients with ADHD, suicide decedents had increased healthcare utilization and higher risks of specific psychiatric and physical comorbidities than living controls. Thus, for suicide prevention among individuals with ADHD, suicide risk must be detected early and comorbidities should be adequately managed.