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Background Reduced uterine artery compliance is associated with adverse pregnancy outcomes (APOs) and may indicate underlying maternal cardiovascular pathology. We investigated associations between second trimester uterine artery Doppler (UAD) parameters and incident maternal hypertension 2–7 years after delivery. Methods A cohort of 10,038 nulliparous US participants was recruited early in pregnancy. A subgroup of 3739, without baseline hypertension and with complete follow-up visits 2–7 years after delivery, were included in this analysis. We investigated UAD indicators of compliance including: 1) early diastolic notch; 2) resistance index (RI); and 3) pulsatility index (PI). We defined hypertension as systolic blood pressure ≥130 mmHg, diastolic ≥80 mmHg, or antihypertensive medication use. We calculated odds ratios (OR) and 95 % confidence intervals (95%CI) for associations between UAD parameters and hypertension, adjusting for age, obesity, race/ethnicity, insurance, smoking, and APOs. Results A total of 187 (5 %) participants developed hypertension after the index pregnancy. Presence of early diastolic notch on UAD was not associated with incident hypertension. Increased RI and PI correlated with higher odds of hypertension (RI: adjusted OR 1.15 [95 % CI 1.03–1.30]; PI: adjusted OR 1.03 [95%CI 1.01–1.05] for each 0.1 unit increase). Maximum RI above 0.84 or maximum PI above 2.3 more than doubled the odds of incident hypertension (RI: adjusted OR 2.49, 95%CI 1.45–4.26; PI: adjusted OR 2.36, 95%CI 1.45–3.86). Conclusion Higher resistance and pulsatility indices measured on second trimester UAD were associated with increased odds of incident hypertension 2–7 years later, and may be biomarkers of higher maternal cardiovascular risk., Graphical abstract Image 1

Background eHealth interventions are developed to support and facilitate patients with lifestyle changes and self-care tasks after being diagnosed with a cardiovascular disease (CVD). Creating long-lasting effects on lifestyle change and health outcomes with eHealth interventions is challenging and requires good understanding of patient values. Objective The aim of the study was to identify values of importance to patients with CVD to aid in designing a technological lifestyle platform. Methods A mixed method design was applied, combining data from usability testing with an additional online survey study, to validate the outcomes of the usability tests. Results A total of 11 relevant patient values were identified, including the need for security, support, not wanting to feel anxious, tailoring of treatment, and personalized, accessible care. The validation survey shows that all values but one (value 9: To have extrinsic motivation to accomplish goals or activities [related to health/lifestyle]) were regarded as important/very important. A rating of very unimportant or unimportant was given by less than 2% of the respondents (value 1: 4/641, 0.6%; value 2: 10/641, 1.6%; value 3: 9/641, 1.4%; value 4: 5/641, 0.8%; value 5: 10/641, 1.6%; value 6: 4/641, 0.6%; value 7: 10/639, 1.6%; value 8: 4/639, 0.6%; value 10: 3/636, 0.5%; value 11: 4/636, 0.6%) to all values except but one (value 9: 56/636, 8.8%). Conclusions There is a high consensus among patients regarding the identified values reflecting goals and themes central to their lives, while living with or managing their CVD. The identified values can serve as a foundation for future research to translate and integrate these values into the design of the eHealth technology. This may call for prioritization of values, as not all values can be met equally.

Background Patients with heart failure (HF) in skilled nursing facilities (SNFs) have 30-day hospital readmission rates as high as 43%. A virtual cardiovascular care program, consisting of patient selection, initial televisit, postconsultation care planning, and follow-up televisits, was developed and delivered by Heartbeat Health, Inc., a cardiovascular digital health company, to 11 SNFs (3510 beds) in New York. The impact of this program on the expected SNF 30-day HF readmission rate is unknown, particularly in the COVID-19 era. Objective The aim of the study was to assess whether a virtual cardiovascular care program could reduce the 30-day hospital readmission rate for patients with HF discharged to SNF relative to the expected rate for this population. Methods We performed a retrospective case review of SNF patients who received a virtual cardiology consultation between August 2020 and February 2021. Virtual cardiologists conducted 1 or more telemedicine visit via smartphone, tablet, or laptop for cardiac patients identified by a SNF care team. Postconsult care plans were communicated to SNF clinical staff. Patients included in this analysis had a preceding index admission for HF. Results We observed lower hospital readmission among patients who received 1 or more virtual consultations compared with the expected readmission rate for both cardiac (3% vs 10%, respectively) and all-cause etiologies (18% vs 27%, respectively) in a population of 3510 patients admitted to SNF. A total of 185/3510 patients (5.27%) received virtual cardiovascular care via the Heartbeat Health program, and 40 patients met study inclusion criteria and were analyzed, with 26 (65%) requiring 1 televisit and 14 (35%) requiring more than 1. Cost savings associated with this reduction in readmissions are estimated to be as high as US $860 per patient. Conclusions The investigation provides initial evidence for the potential effectiveness and efficiency of virtual and digitally enabled virtual cardiovascular care on 30-day hospital readmissions. Further research is warranted to optimize the use of novel virtual care programs to transform delivery of cardiovascular care to high-risk populations.

Highlights • Senicapoc was successfully administered intravenously. • Senicapoc did not reduce cerebral edema 4 h after cardiac arrest. • Senicapoc did not increase mean arterial pressure within 4 h from resuscitation., Aim Formation of cerebral edema and cardiovascular dysfunction may worsen brain injury following cardiac arrest. We hypothesized that administration of the intermediate calcium-activated potassium (KCa3.1) channel blocker, senicapoc, would reduce cerebral edema and augment mean arterial pressure in the early post-resuscitation period. Method Male Sprague-Dawley rats, aged 11–15 weeks, were utilized in the study. Rats were exposed to 8 min of asphyxial cardiac arrest. Shortly after resuscitation, rats were randomized to receive either vehicle or senicapoc (10 mg/kg) intravenously. The primary outcome was cerebral wet to dry weight ratio 4 h after resuscitation. Secondary outcomes included mean arterial pressure, cardiac output, norepinephrine dose, inflammatory cytokines and neuron specific enolase levels. Additionally, a sub-study was conducted to validate intravenous administration of senicapoc. Results The sub-study revealed that senicapoc-treated rats maintained a significantly higher mean arterial pressure during administration of SKA-31 (a KCa3.1 channel opener). The plasma concentration of senicapoc was 1060 ± 303 ng/ml 4 h after administration. Senicapoc did not reduce cerebral edema or augment mean arterial pressure 4 h after resuscitation. Likewise, cardiac function and norepinephrine dose did not vary between groups. Inflammatory cytokines and neuron specific enolase levels increased in both groups after resuscitation with no difference between groups. Senicapoc enhanced the PaO2/FiO2 ratio significantly 4 h after resuscitation. Conclusion Senicapoc was successfully administered intravenously after resuscitation, but did not reduce cerebral edema or increase mean arterial pressure in the early post-resuscitation period.

Air pollution might affect atherosclerosis through DNA methylation changes in cells crucial to atherosclerosis, such as monocytes. We conducted an epigenome-wide study of DNA methylation in CD14+ monocytes and long-term ambient air pollution exposure in adults participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We also assessed the association between differentially methylated signals and cis-gene expression. Using spatiotemporal models, one-year average concentrations of outdoor fine particulate matter (PM2.5) and oxides of nitrogen (NOX) were estimated at participants��� homes. We assessed DNA methylation and gene expression using Illumina 450k and HumanHT-12 v4 Expression BeadChips, respectively (n = 1,207). We used bump hunting and site-specific approaches to identify differentially methylated signals (false discovery rate of 0.05) and used linear models to assess associations between differentially methylated signals and cis-gene expression. Four differentially methylated regions (DMRs) located on chromosomes 5, 6, 7, and 16 (within or near SDHAP3, ZFP57, HOXA5, and PRM1, respectively) were associated with PM2.5. The DMRs on chromosomes 5 and 6 also associated with NOX. The DMR on chromosome 5 had the smallest p-value for both PM2.5 (p = 1.4��10���6) and NOX (p = 7.7��10���6). Three differentially methylated CpGs were identified for PM2.5, and cg05926640 (near TOMM20) had the smallest p-value (p = 5.6��10���8). NOX significantly associated with cg11756214 within ZNF347 (p = 5.6��10���8). Several differentially methylated signals were also associated with cis-gene expression. The DMR located on chromosome 7 was associated with the expression of HOXA5, HOXA9, and HOXA10. The DMRs located on chromosomes 5 and 16 were associated with expression of MRPL36 and DEXI, respectively. The CpG cg05926640 was associated with expression of ARID4B, IRF2BP2, and TOMM20. We identified differential DNA methylation in monocytes associated with long-term air pollution exposure. Methylation signals associated with gene expression might help explain how air pollution contributes to cardiovascular disease.

Background Cardiovascular disease is the leading cause of death worldwide. Early recognition, diagnosis, and reperfusion are the key elements of treatment for ST-segment elevation myocardial infarction. The absence of a prehospital 12-lead electrocardiogram (P12ECG) can cause definitive treatment delay and repeated transfer. Although guidelines highly recommend the measurement and transmission of P12ECG data, P12ECG use has not been widely established. Objective The aim of this study was to verify the time-efficiency and feasibility of the use of a patchy-type 12-lead ECG measuring and transmitting device (P-ECG) by an emergency medical technician (EMT) in an ambulance during patient transport. Methods This was a simulation-based prospective randomized crossover-controlled study that included EMTs. The participants were randomly assigned to one of two groups. Group A began the experiment with a conventional 12-lead ECG (C-ECG) device and then switched to the intervention device (P-ECG), whereas group B began the experiment with the P-ECG and then switched to the C-ECG. All simulations were performed inside an ambulance driving at 30 km/h. The time interval was measured from the beginning of ECG application to completion of sending the results. After the simulation, participants were administered the System Usability Scale questionnaire about usability of the P-ECG. Results A total of 18 EMTs were recruited for this study with a median age of 35 years. The overall interval time for the C-ECG was 254 seconds (IQR 247-270), whereas the overall interval time for the P-ECG was 130 seconds (IQR 112-150), with a significant difference (P Conclusions Performance of 12-lead ECG examination and transmission of the results using P-ECG are faster than those of C-ECG during ambulance transport. With the additional time afforded, EMTs can provide more care to patients and transport patients more rapidly, which may help reduce the symptoms-to-balloon time for patients with acute coronary syndrome. Trial Registration ClinicalTrials.gov NCT04114760; https://www.clinicaltrials.gov/ct2/show/NCT04114760

Despite major efforts to reduce atherosclerotic cardiovascular disease (ASCVD) burden with conventional risk factor control, significant residual risk remains. Recent evidence on non-traditional determinants of cardiometabolic health has advanced our understanding of lifestyle–disease interactions. Chronic exposure to environmental stressors like poor diet quality, sedentarism, ambient air pollution and noise, sleep deprivation and psychosocial stress affect numerous traditional and non-traditional intermediary pathways related to ASCVD. These include body composition, cardiorespiratory fitness, muscle strength and functionality and the intestinal microbiome, which are increasingly recognized as major determinants of cardiovascular health. Evidence points to partially overlapping mechanisms, including effects on inflammatory and nutrient sensing pathways, endocrine signalling, autonomic function and autophagy. Of particular relevance is the potential of low-risk lifestyle factors to impact on plaque vulnerability through altered adipose tissue and skeletal muscle phenotype and secretome. Collectively, low-risk lifestyle factors cause a set of phenotypic adaptations shifting tissue cross-talk from a proinflammatory milieu conducive for high-risk atherosclerosis to an anti-atherogenic milieu. The ketone body ß-hydroxybutyrate, through inhibition of the NLRP-3 inflammasome, is likely to be an intermediary for many of these observed benefits. Adhering to low-risk lifestyle factors adds to the prognostic value of optimal risk factor management, and benefit occurs even when the impact on conventional risk markers is discouragingly minimal or not present. The aims of this review are (a) to discuss novel lifestyle risk factors and their underlying biochemical principles and (b) to provide new perspectives on potentially more feasible recommendations to improve long-term adherence to low-risk lifestyle factors.

Telomere length is considered to be a biomarker of biological aging and age-related disease. There are few studies that have evaluated the association between telomere length and diet, and none of them have evaluated the impact of a vegetarian diet on telomere length and its correlation with cardiovascular biomarkers in apparently healthy subjects. Therefore, our objectives were to evaluate leukocyte telomere length (LTL) in vegetarians and omnivorous subjects and its association with classical cardiovascular risk biomarkers. From the total of 745 participants initially recruited, 44 omnivorous and 44 vegetarian men apparently healthy were selected for this study and LTL was measured in 39 omnivorous and 41 vegetarians by Real-Time Quantitative PCR reaction. Although telomere length was not different between omnivorous and vegetarians, we found a strong negative correlation between LTL and IMT (intima-media thickness) in omnivorous, but not in vegetarian group. In addition, omnivorous who were classified with short telomere length had higher carotid IMT compared to vegetarians. Our data suggest that telomere length can be a marker of subclinical atherosclerosis in the omnivorous group.

Key points As reactivation of the fetal gene program has been implicated in pathological remodelling during heart failure (HF), we examined whether cardiomyocyte subcellular structure and function revert to an immature phenotype during this disease.Surface and internal membrane structures appeared gradually during development, and returned to a juvenile state during HF. Similarly, dyadic junctions between the cell membrane and sarcoplasmic reticulum were progressively ‘packed’ with L‐type Ca2+ channels and ryanodine receptors during development, and ‘unpacked’ during HF.Despite similarities in subcellular structure, dyads were observed to be functional from early developmental stages, but exhibited an impaired ability to release Ca2+ in failing cardiomyocytes.Thus, while immature and failing cardiomyocytes share similarities in subcellular structure, these do not fully account for the marked impairment of Ca2+ homeostasis observed in HF. Abstract Reactivation of the fetal gene programme has been implicated as a driver of pathological cardiac remodelling. Here we examined whether pathological remodelling of cardiomyocyte substructure and function during heart failure (HF) reflects a reversion to an immature phenotype. Using scanning electron microscopy, we observed that Z‐grooves and t‐tubule openings at the cell surface appeared gradually during cardiac development, and disappeared during HF. Confocal and super‐resolution imaging within the cell interior revealed similar structural parallels; disorganization of t‐tubules in failing cells was strikingly reminiscent of the late stages of postnatal development, with fewer transverse elements and a high proportion of longitudinal tubules. Ryanodine receptors (RyRs) were observed to be laid down in advance of developing t‐tubules and similarly ‘orphaned’ in HF, although RyR distribution along Z‐lines was relatively sparse. Indeed, nanoscale imaging revealed coordinated packing of L‐type Ca2+ channels and RyRs into dyadic junctions during development, and orderly unpacking during HF. These findings support a ‘last in, first out’ paradigm, as the latest stages of dyadic structural development are reversed during disease. Paired imaging of t‐tubules and Ca2+ showed that the disorganized arrangement of dyads in immature and failing cells promoted desynchronized and slowed Ca2+ release in these two states. However, while developing cells exhibited efficient triggering of Ca2+ release at newly formed dyads, dyadic function was impaired in failing cells despite similar organization of Ca2+ handling proteins. Thus, pathologically deficient Ca2+ homeostasis during HF is only partly linked to the re‐emergence of immature subcellular structure, and additionally reflects lost dyadic functionality., Key points As reactivation of the fetal gene program has been implicated in pathological remodelling during heart failure (HF), we examined whether cardiomyocyte subcellular structure and function revert to an immature phenotype during this disease.Surface and internal membrane structures appeared gradually during development, and returned to a juvenile state during HF. Similarly, dyadic junctions between the cell membrane and sarcoplasmic reticulum were progressively ‘packed’ with L‐type Ca2+ channels and ryanodine receptors during development, and ‘unpacked’ during HF.Despite similarities in subcellular structure, dyads were observed to be functional from early developmental stages, but exhibited an impaired ability to release Ca2+ in failing cardiomyocytes.Thus, while immature and failing cardiomyocytes share similarities in subcellular structure, these do not fully account for the marked impairment of Ca2+ homeostasis observed in HF.

Key points Prevailing dogma holds that activation of the β‐adrenergic receptor/cAMP/protein kinase A signalling pathway leads to enhanced L‐type CaV1.2 channel activity, resulting in increased Ca2+ influx into ventricular myocytes and a positive inotropic response. However, the full mechanistic and molecular details underlying this phenomenon are incompletely understood.CaV1.2 channel clusters decorate T‐tubule sarcolemmas of ventricular myocytes. Within clusters, nanometer proximity between channels permits Ca2+‐dependent co‐operative gating behaviour mediated by physical interactions between adjacent channel C‐terminal tails.We report that stimulation of cardiomyocytes with isoproterenol, evokes dynamic, protein kinase A‐dependent augmentation of CaV1.2 channel abundance along cardiomyocyte T‐tubules, resulting in the appearance of channel ‘super‐clusters’, and enhanced channel co‐operativity that amplifies Ca2+ influx.On the basis of these data, we suggest a new model in which a sub‐sarcolemmal pool of pre‐synthesized CaV1.2 channels resides in cardiomyocytes and can be mobilized to the membrane in times of high haemodynamic or metabolic demand, to tune excitation–contraction coupling. Abstract Voltage‐dependent L‐type CaV1.2 channels play an indispensable role in cardiac excitation–contraction coupling. Activation of the β‐adrenergic receptor (βAR)/cAMP/protein kinase A (PKA) signalling pathway leads to enhanced CaV1.2 activity, resulting in increased Ca2+ influx into ventricular myocytes and a positive inotropic response. CaV1.2 channels exhibit a clustered distribution along the T‐tubule sarcolemma of ventricular myocytes where nanometer proximity between channels permits Ca2+‐dependent co‐operative gating behaviour mediated by dynamic, physical, allosteric interactions between adjacent channel C‐terminal tails. This amplifies Ca2+ influx and augments myocyte Ca2+ transient and contraction amplitudes. We investigated whether βAR signalling could alter CaV1.2 channel clustering to facilitate co‐operative channel interactions and elevate Ca2+ influx in ventricular myocytes. Bimolecular fluorescence complementation experiments reveal that the βAR agonist, isoproterenol (ISO), promotes enhanced CaV1.2–CaV1.2 physical interactions. Super‐resolution nanoscopy and dynamic channel tracking indicate that these interactions are expedited by enhanced spatial proximity between channels, resulting in the appearance of CaV1.2 ‘super‐clusters’ along the z‐lines of ISO‐stimulated cardiomyocytes. The mechanism that leads to super‐cluster formation involves rapid, dynamic augmentation of sarcolemmal CaV1.2 channel abundance after ISO application. Optical and electrophysiological single channel recordings confirm that these newly inserted channels are functional and contribute to overt co‐operative gating behaviour of CaV1.2 channels in ISO stimulated myocytes. The results of the present study reveal a new facet of βAR‐mediated regulation of CaV1.2 channels in the heart and support the novel concept that a pre‐synthesized pool of sub‐sarcolemmal CaV1.2 channel‐containing vesicles/endosomes resides in cardiomyocytes and can be mobilized to the sarcolemma to tune excitation–contraction coupling to meet metabolic and/or haemodynamic demands., Key points Prevailing dogma holds that activation of the β‐adrenergic receptor/cAMP/protein kinase A signalling pathway leads to enhanced L‐type CaV1.2 channel activity, resulting in increased Ca2+ influx into ventricular myocytes and a positive inotropic response. However, the full mechanistic and molecular details underlying this phenomenon are incompletely understood.CaV1.2 channel clusters decorate T‐tubule sarcolemmas of ventricular myocytes. Within clusters, nanometer proximity between channels permits Ca2+‐dependent co‐operative gating behaviour mediated by physical interactions between adjacent channel C‐terminal tails.We report that stimulation of cardiomyocytes with isoproterenol, evokes dynamic, protein kinase A‐dependent augmentation of CaV1.2 channel abundance along cardiomyocyte T‐tubules, resulting in the appearance of channel ‘super‐clusters’, and enhanced channel co‐operativity that amplifies Ca2+ influx.On the basis of these data, we suggest a new model in which a sub‐sarcolemmal pool of pre‐synthesized CaV1.2 channels resides in cardiomyocytes and can be mobilized to the membrane in times of high haemodynamic or metabolic demand, to tune excitation–contraction coupling.

Rheumatoid arthritis (RA) is an independent risk factor for the development of a variety of cardiovascular diseases, with a 1.5-factor increase in risk. This literature review aims to provide a global overview of the pathogenesis, effects of anti-rheumatoid treatment on cardiovascular risk, a description of the cardiovascular complications associated with RA, and current opinion on cardiovascular risk assessment and management in patients with RA. Author conducted a literature search in PubMed, Scopus, Web of Science and Embase regarding RA and associated cardiovascular complications. The mechanism of increased risk of cardiovascular disease in patients with RA is complex. There are specific genetic factors associated with both diseases, and traditional cardiovascular risk factors may be more prevalent in patients with RA. Most anti-rheumatic drugs decrease cardiovascular risk, and general recommendations focus on reduction of disease activity and strict management of cardiovascular risk as per the general population.

Introduction Behcet’s disease (BD) is a chronic inflammatory and multisystem vasculitis. Cardiac involvement is one of the major complications of BD. Cardiac involvement is sporadic in terms of its specific relationship to mortality. How to identify and follow up on cardiac-related complications in BD patients has yet to be determined. Aim The aim of our study is to assess cardiovascular diseases in BD patients by measuring metabolic function and copeptin levels and comparing these to a healthy control group. Knowing the specific metabolic functions that are negatively affected by BD will help doctors determine which functions need to be more closely monitored in BD patients. Our study is the first study in the available literature that evaluates copeptin in BD patients. Material and methods A control group of 58 healthy volunteers, including 32 females and 26 males (average age: 39.8 ±10.3 years, range: 18–50 years), was formed to compare with 84 BD patients (average age: 40.5 ±11 years, range: 21–63 years), including 39 females and 45 males. Diastolic and systolic blood pressure, height, weight, body mass index (BMI), and waistline were measured for both groups. All study patients were also given hemograms, and fasting blood sugar (FBS), uric acid, lipid profile, insulin, C-reactive protein (CRP), and copeptin levels were measured. An ELISA Kit was used to measure copeptin. Results FBS, CRP, and insulin levels were significantly higher in the patient group (p < 0.001, p = 0.004, and p = 0.038, respectively). Patients who had had the disease for more than 10 years had higher BMIs, total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels (p = 0.034, p = 0.004, p = 0.016, and p = 0.045, respectively). Additionally, CRP levels were found to be higher in long-term patients and patients with active lesions. Diastolic blood pressure and waist circumference were also higher in the BD group. Patients who had active lesions had significantly higher diastolic blood pressure (p = 0.047). There were no statistically significant differences in copeptin levels between BD and control groups. Conclusions Cardiovascular involvement rarely contributes to the high mortality rate of BD patients. There were meaningful elevations in metabolic markers identified when BD and cardiovascular disease risk was assessed with metabolic parameters. The cardiac disease risk should be closely followed using metabolic functions, particularly in long-term BD patients with vascular involvement.

Rationale: The incidence of gestational diabetes mellitus (GDM) is increasing worldwide. However, whether and how GDM exposure induces fetal programming of adult cardiac dysfunctional phenotype, especially the underlying epigenetic molecular mechanisms and theranostics remain unclear. To address this problem, we developed a late GDM rat model. Methods: Pregnant rats were made diabetic on day 12 of gestation by streptozotocin (STZ). Experiments were conducted in 6 weeks old offspring. Results: There were significant increases in ischemia-induced cardiac infarction and gender-dependent left ventricular (LV) dysfunction in male offspring in GDM group as compared to controls. Exposure to GDM enhanced ROS level and caused a global DNA methylation in offspring cardiomyocytes. GDM attenuated cardiac Sirt 1 protein and p-Akt/Akt levels, but enhanced autophagy-related proteins expression (Atg 5 and LC3 II/LC3 I) as compared to controls. Ex-vivo treatment of DNA methylation inhibitor, 5-Aza directly inhibited Dnmt3A and enhanced Sirt 1 protein expression in fetal hearts. Furthermore, treatment with antioxidant, N-acetyl-cysteine (NAC) in offspring reversed GDM-mediated DNA hypermethylation, Sirt1 repression and autophagy-related gene protein overexpression in the hearts, and rescued GDM-induced deterioration in heart ischemic injury and LV dysfunction. Conclusion: Our data indicated that exposure to GDM induced offspring cardiac oxidative stress and DNA hypermethylation, resulting in an epigenetic down-regulation of Sirt1 gene and aberrant development of heart ischemia-sensitive phenotype, which suggests that Sirt 1-mediated signaling is the potential therapeutic target for the heart ischemic disease in offspring.

Stem cell-based cardiogenesis has become a powerful tool to enhance our understanding of cardiac development and test novel therapeutics for cardiovascular diseases. However, transcriptional and epigenetic regulation of multiple transitional stages from pluripotent cells to committed cardiomyocytes has not yet been fully characterized. To characterize how transcription factors, lincRNAs and DNA methylation change at temporal developmental stages, and identify potential novel regulators during cardiogenesis. We utilized a previously reported protocol that yields human cardiomyocytes (hCM) with more than 90% purity from human Embryonic Stem Cells (hESC). Leveraging the purity of cells resulting from this protocol, we systematically examined how gene expression and DNA methylation programs change at temporal developmental stages during cardiogenesis. Our results provide a comprehensive view of expression changes during cardiogenesis that extend previous studies, allowing us to identify key transcription factors as well as lincRNAs that are strongly associated with cardiac differentiation. Moreover, we incorporated a simple but powerful method to screen for novel regulators of cardiogenesis solely based on expression changes and found four novel cardiac-related transcription factors, i.e., SORBS2, MITF, DPF3, and ZNF436, which have no or few prior literature reports and we were able to validate using siRNA. Our strategy of identifying novel regulators of cardiogenesis can also be easily implemented in other stem cell-based systems. Our results provide a valuable resource for understanding cardiogenesis that extends previous findings by leveraging the purity of our cell lines, which allowed us to identify four novel cardiac-related regulators.

BackgroundCardiovascular disease is the leading cause of mortality and disability worldwide. A noninvasive test that can detect underlying cardiovascular disease has the potential to identify patients at risk prior to the occurrence of adverse cardiovascular events. We sought to determine whether an easily observed imaging finding indicative of retinal ischemia, which we term 'retinal ischemic perivascular lesions' (RIPLs), could serve as a biomarker for cardiovascular disease.MethodsWe reviewed optical coherence tomography (OCT) scans of individuals, with no underlying retinal pathology, obtained at UC San Diego Health from July 2014 to July 2019. We identified 84 patients with documented cardiovascular disease and 76 healthy controls. OCT scans were assessed for evidence of RIPLs. In addition, the 10-year atherosclerotic cardiovascular disease (ASCVD) risk calculator was used to risk-stratify the subjects into four different categories.FindingsPatients with documented cardiovascular disease had higher number of RIPLs compared to healthy controls (2.8vs 0.8, p37). The number of RIPLs in individuals with intermediate and high 10-year ASCVD risk scores was higher than in those with low ASCVD risk scores (1.7vs 0.64, p=0.02 and 2.9vs 0.64, p 0.002, respectively).InterpretationThe presence of RIPLs, which are anatomical markers of prior retinal ischemic infarcts, is suggestive of coexisting cardiovascular disease. RIPLs detection, obtained from routine retinal scans, may thus provide an additional biomarker to identify patients at risk of developing adverse cardiovascular events.FundingNone.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency in the enzyme α-galactosidase A due to mutations in the GLA gene. This leads to an accumulation of globotriaosylceramide (GL-3) in many tissues, which results in progressive damage to the kidneys, heart, and nervous system. We present the molecular and clinical characteristics and long-term outcomes of FD patients from a multidisciplinary clinic at the University of California, Irvine treated with agalsidase beta enzyme replacement therapy (ERT) for 2-20years. This cohort comprised 24 adults (11 males, 13 females) and two male children (median age 45; range 10-68years). Of the 26 patients in this cohort, 20 were on ERT (12 males, 8 females). We describe one novel variant not previously reported in the literature in a patient with features of 'classic' FD. The vast majority of patients in this cohort presented with symptoms of 'classic' FD including peripheral neuropathic pain, some form of cardiac involvement, angiokeratomas, corneal verticillata, hypohidrosis, tinnitus, and gastrointestinal symptoms, primarily abdominal pain. The majority of males had clinically evident renal involvement. An annual eGFR reduction of -1.88mL/min/1.73m2/yr during the course of ERT was seen in this cohort. The most common renal presentation was proteinuria, and one individual required a renal transplant. Other common findings were pulmonary involvement, lymphedema, hearing loss, and significantly, three patients had strokes. Notably, there was a high prevalence of endocrine dysfunction and low bone mineral density, including several with osteoporosis. While enzyme replacement therapy (ERT) cleared plasma GL-3 in this cohort, there was limited improvement in renal function or health-related quality of life based on the patient-reported SF-36 Health Survey. Physical functioning significantly declined over the course of ERT treatment, which may be, in part, due to the late initiation of ERT in several patients. Further delineation of the phenotypic and genotypic spectrum in patients with FD and the long-term outcome of ERT will help improve management and treatment options for this disease.

Background Heart failure (HF) together with type 2 diabetes (T2D) and chronic kidney disease (CKD) are major pandemics of the twenty first century. It is not known in people with new onset HF, what the distinct and combined associations are between T2D and CKD comorbidities and cause-specific hospital admissions and death, over the past 20 years. Methods An observational study using the UK Clinical Practice Research Datalink linked to the Hospital Episode Statistics in England (1998–2017). Participants were people aged ≥30 years with new onset HF. Exposure groups were HF with: (i) no T2D and no CKD (reference group); (ii) CKD-only (estimated glomerular filtration rate (eGFR)

Few studies have addressed how reduced water salinity affects cardiovascular and metabolic function in marine euryhaline fishes, despite its relevance for predicting impacts of natural salinity variations and ongoing climate change on marine fish populations. Here, shorthorn sculpin (Myoxocephalus scorpius) were subjected to different durations of reduced water salinity from 33 to 15 ppt. Routine metabolic rate decreased after short-term acclimation (4–9 days) to 15 ppt, which corresponded with similar reductions in cardiac output. Likewise, standard metabolic rate decreased after acute transition (3 h) from 33 to 15 ppt, suggesting a reduced energetic cost of osmoregulation at 15 ppt. Interestingly, gut blood flow remained unchanged across salinities, which contrasts with previous findings in freshwater euryhaline teleosts (e.g., rainbow trout) exposed to different salinities. Although plasma osmolality, [Na+], [Cl−] and [Ca2+] decreased in 15 ppt, there were no signs of cellular osmotic stress as plasma [K+], [hemoglobin] and hematocrit remained unchanged. Taken together, our data suggest that shorthorn sculpin are relatively weak plasma osmoregulators that apply a strategy whereby epithelial ion transport mechanisms are partially maintained across salinities, while plasma composition is allowed to fluctuate within certain ranges. This may have energetic benefits in environments where salinity naturally fluctuates, and could provide shorthorn sculpin with competitive advantages if salinity fluctuations intensify with climate change in the future.

Background Cardiovascular disease (CVD) is the greatest health problem in Australia, which kills more people than any other disease and incurs enormous costs for the health care system. In this study, we present a benchmark comparison of various artificial intelligence (AI) architectures for predicting the mortality rate of patients with CVD using structured medical claims data. Compared with other research in the clinical literature, our models are more efficient because we use a smaller number of features, and this study could help health professionals accurately choose AI models to predict mortality among patients with CVD using only claims data before a clinic visit. Objective This study aims to support health clinicians in accurately predicting mortality among patients with CVD using only claims data before a clinic visit. Methods The data set was obtained from the Medicare Benefits Scheme and Pharmaceutical Benefits Scheme service information in the period between 2004 and 2014, released by the Department of Health Australia in 2016. It included 346,201 records, corresponding to 346,201 patients. A total of five AI algorithms, including four classical machine learning algorithms (logistic regression [LR], random forest [RF], extra trees [ET], and gradient boosting trees [GBT]) and a deep learning algorithm, which is a densely connected neural network (DNN), were developed and compared in this study. In addition, because of the minority of deceased patients in the data set, a separate experiment using the Synthetic Minority Oversampling Technique (SMOTE) was conducted to enrich the data. Results Regarding model performance, in terms of discrimination, GBT and RF were the models with the highest area under the receiver operating characteristic curve (97.8% and 97.7%, respectively), followed by ET (96.8%) and LR (96.4%), whereas DNN was the least discriminative (95.3%). In terms of reliability, LR predictions were the least calibrated compared with the other four algorithms. In this study, despite increasing the training time, SMOTE was proven to further improve the model performance of LR, whereas other algorithms, especially GBT and DNN, worked well with class imbalanced data. Conclusions Compared with other research in the clinical literature involving AI models using claims data to predict patient health outcomes, our models are more efficient because we use a smaller number of features but still achieve high performance. This study could help health professionals accurately choose AI models to predict mortality among patients with CVD using only claims data before a clinic visit.

Interactions between macrophages and adipocytes are early molecular factors influencing adipose tissue (AT) dysfunction, resulting in high leptin, low adiponectin circulating levels and low-grade metaflammation, leading to insulin resistance (IR) with increased cardiovascular risk. We report the characterization of AT dysfunction through measurements of the adiponectin/leptin ratio (ALR), the adipo-insulin resistance index (Adipo-IRi), fasting/postprandial (F/P) immunometabolic phenotyping and direct F/P differential gene expression in AT biopsies obtained from symptom-free adults from the GEMM family study. AT dysfunction was evaluated through associations of the ALR with F/P insulin-glucose axis, lipid-lipoprotein metabolism, and inflammatory markers. A relevant pattern of negative associations between decreased ALR and markers of systemic low-grade metaflammation, HOMA, and postprandial cardiovascular risk hyperinsulinemic, triglyceride and GLP-1 curves was found. We also analysed their plasma non-coding microRNAs and shotgun lipidomics profiles finding trends that may reflect a pattern of adipose tissue dysfunction in the fed and fasted state. Direct gene differential expression data showed initial patterns of AT molecular signatures of key immunometabolic genes involved in AT expansion, angiogenic remodelling and immune cell migration. These data reinforce the central, early role of AT dysfunction at the molecular and systemic level in the pathogenesis of IR and immunometabolic disorders.

Key points During long‐duration spaceflights, some astronauts develop structural ocular changes including optic disc oedema that resemble signs of intracranial hypertension.In the present study, intracranial pressure was estimated non‐invasively (nICP) using a model‐based analysis of cerebral blood velocity and arterial blood pressure waveforms in 11 astronauts before and after long‐duration spaceflights.Our results show that group‐averaged estimates of nICP decreased significantly in nine astronauts without optic disc oedema, suggesting that the cephalad fluid shift during long‐duration spaceflight rarely increased postflight intracranial pressure.The results of the two astronauts with optic disc oedema suggest that both increases and decreases in nICP are observed post‐flight in astronauts with ocular alterations, arguing against a primary causal relationship between elevated ICP and spaceflight associated optical changes.Cerebral blood velocity increased independently of nICP and spaceflight‐associated ocular alterations. This increase may be caused by the reduced haemoglobin concentration after long‐duration spaceflight. Abstract Persistently elevated intracranial pressure (ICP) above upright values is a suspected cause of optic disc oedema in astronauts. However, no systematic studies have evaluated changes in ICP from preflight. Therefore, ICP was estimated non‐invasively before and after spaceflight to test whether ICP would increase after long‐duration spaceflight. Cerebral blood velocity in the middle cerebral artery (MCAv) was obtained by transcranial Doppler sonography and arterial pressure in the radial artery was obtained by tonometry, in the supine and sitting positions before and after 4−12 months of spaceflight in 11 astronauts (10 males and 1 female, 46 ± 7 years old at launch). Non‐invasive ICP (nICP) was computed using a validated model‐based estimation method. Mean MCAv increased significantly after spaceflight (ANOVA, P = 0.007). Haemoglobin decreased significantly after spaceflight (14.6 ± 0.8 to 13.3 ± 0.7 g/dL, P 90%) of astronauts, suggesting that the cephalad fluid shift during spaceflight does not systematically or consistently elevate postflight ICP in astronauts. Independently of nICP and ocular alterations, the present results of mean MCAv suggest that long‐duration spaceflight may increase cerebral blood flow, possibly due to reduced haemoglobin concentration., Key points During long‐duration spaceflights, some astronauts develop structural ocular changes including optic disc oedema that resemble signs of intracranial hypertension.In the present study, intracranial pressure was estimated non‐invasively (nICP) using a model‐based analysis of cerebral blood velocity and arterial blood pressure waveforms in 11 astronauts before and after long‐duration spaceflights.Our results show that group‐averaged estimates of nICP decreased significantly in nine astronauts without optic disc oedema, suggesting that the cephalad fluid shift during long‐duration spaceflight rarely increased postflight intracranial pressure.The results of the two astronauts with optic disc oedema suggest that both increases and decreases in nICP are observed post‐flight in astronauts with ocular alterations, arguing against a primary causal relationship between elevated ICP and spaceflight associated optical changes.Cerebral blood velocity increased independently of nICP and spaceflight‐associated ocular alterations. This increase may be caused by the reduced haemoglobin concentration after long‐duration spaceflight.

Key points Heart failure (HF), the leading cause of death in developed countries, occurs in the setting of reduced (HFrEF) or preserved (HFpEF) ejection fraction. Unlike HFrEF, there are no effective treatments for HFpEF, which accounts for ∼50% of heart failure.Abnormal intracellular calcium dynamics in cardiomyocytes have major implications for contractility and rhythm, but compared to HFrEF, very little is known about calcium cycling in HFpEF.We used rat models of HFpEF and HFrEF to reveal distinct differences in intracellular calcium regulation and excitation‐contraction (EC) coupling.While HFrEF is characterized by defective EC coupling at baseline, HFpEF exhibits enhanced coupling fidelity, further aggravated by a reduction in β‐adrenergic sensitivity.These differences in EC coupling and β‐adrenergic sensitivity may help explain why therapies that work in HFrEF are ineffective in HFpEF. Abstract Heart failure with reduced or preserved ejection fraction (respectively, HFrEF and HFpEF) is the leading cause of death in developed countries. Although numerous therapies improve outcomes in HFrEF, there are no effective treatments for HFpEF. We studied phenotypically verified rat models of HFrEF and HFpEF to compare excitation‐contraction (EC) coupling and protein expression in these two forms of heart failure. Dahl salt‐sensitive rats were fed a high‐salt diet (8% NaCl) from 7 weeks of age to induce HFpEF. Impaired diastolic relaxation and preserved ejection fraction were confirmed in each animal echocardiographically, and clinical signs of heart failure were documented. To generate HFrEF, Sprague‐Dawley (SD) rats underwent permanent left anterior descending coronary artery ligation which, 8–10 weeks later, led to systolic dysfunction (verified echocardiographically) and clinical signs of heart failure. Calcium (Ca2+) transients were measured in isolated cardiomyocytes under field stimulation or patch clamp. Ultra‐high‐speed laser scanning confocal imaging captured Ca2+ sparks evoked by voltage steps. Western blotting and PCR were used to assay changes in EC coupling protein and RNA expression. Cardiomyocytes from rats with HFrEF exhibited impaired EC coupling, including decreased Ca2+ transient (CaT) amplitude and defective couplon recruitment, associated with transverse (t)‐tubule disruption. In stark contrast, HFpEF cardiomyocytes showed saturated EC coupling (increased I Ca, high probability of couplon recruitment with greater Ca2+ release synchrony, increased CaT) and preserved t‐tubule integrity. β‐Adrenergic stimulation of HFpEF myocytes with isoprenaline (isoproterenol) failed to elicit robust increases in I Ca or CaT and relaxation kinetics. Fundamental differences in EC coupling distinguish HFrEF from HFpEF., Key points Heart failure (HF), the leading cause of death in developed countries, occurs in the setting of reduced (HFrEF) or preserved (HFpEF) ejection fraction. Unlike HFrEF, there are no effective treatments for HFpEF, which accounts for ∼50% of heart failure.Abnormal intracellular calcium dynamics in cardiomyocytes have major implications for contractility and rhythm, but compared to HFrEF, very little is known about calcium cycling in HFpEF.We used rat models of HFpEF and HFrEF to reveal distinct differences in intracellular calcium regulation and excitation‐contraction (EC) coupling.While HFrEF is characterized by defective EC coupling at baseline, HFpEF exhibits enhanced coupling fidelity, further aggravated by a reduction in β‐adrenergic sensitivity.These differences in EC coupling and β‐adrenergic sensitivity may help explain why therapies that work in HFrEF are ineffective in HFpEF.

Background Many patients do not meet the recommended levels of physical activity after completing a cardiac rehabilitation (CR) program. Wearable activity trackers and mobile phone apps are promising potential self-management tools for maintaining physical activity after CR completion. Objective This study aims to evaluate the acceptability of a wearable device, mobile app, and push messages to facilitate physical activity following CR completion. Methods We used semistructured interviews to assess the acceptability of various mobile technologies after participation in a pilot randomized controlled trial. Intervention patients in the randomized controlled trial wore the Fitbit Charge 2, used the Movn mobile app, and received push messages on cardiovascular disease prevention and physical activity for over 2 months. We asked 26 intervention group participants for feedback about their experience with the technology and conducted semistructured individual interviews with 7 representative participants. We used thematic analysis to create the main themes from individual interviews. Results Our sample included participants with a mean age of 66.7 (SD 8.6) years; 23% (6/26) were female. Overall, there were varying levels of satisfaction with different technology components. There were 7 participants who completed the satisfaction questionnaires and participated in the interviews. The Fitbit and Movn mobile app received high satisfaction scores of 4.86 and 4.5, respectively, whereas push messages had a score of 3.14 out of 5. We identified four main themes through the interviews: technology use increased motivation to be physically active, technology use served as a reminder to be physically active, recommendations for technology to improve user experience, and desire for personal feedback. Conclusions By applying a wearable activity tracker, mobile phone app, and push messages, our study showed strong potential for the adoption of new technologies by older adults to maintain physical activity after CR completion. Future research should include a larger sample over a longer period using a mixed methods approach to assess the efficacy of technology use for promoting long-term physical activity behavior in older adults.

BackgroundThere is significant interindividual variability in the rate of aortic stenosis (AS) progression that is not accounted for in the current surveillance algorithms. We sought to examine the association between changes in peak aortic jet velocity (Vmax) and mean gradient (MG) among patients with mild or moderate AS and risk of progression to severe disease.MethodsAdult subjects referred for echocardiography at a single academic referral center with a diagnosis of mild or moderate AS and ≥2 additional surveillance echocardiograms were included in the study. Changes in Vmax and MG between the first two echocardiograms were indexed to time and tested for association with future progression to severe AS.ResultsAmong three hundred and sixty-four subjects, the median time between first and second echocardiograms was 1.3years and initial changes in Vmax and MG indexed to time were +0.16m/s per year and +1.44mmHg per year, respectively. Fifty-three (15%) and fifty-six (15%) subjects progressed to severe AS defined by Vmax and MG, respectively. In multivariable logistic regression, initial increase in Vmax (OR=4.19, 95% CI 1.93-9.10, p&nbsp

The aim of this position paper is to provide a brief overview of the current status of cardiovascular modelling and of the processes required and some of the challenges to be addressed to see wider exploitation in both personal health management and clinical practice. In most branches of engineering the concept of the digital twin, informed by extensive and continuous monitoring and coupled with robust data assimilation and simulation techniques, is gaining traction: the Gartner Group listed it as one of the top ten digital trends in 2018. The cardiovascular modelling community is starting to develop a much more systematic approach to the combination of physics, mathematics, control theory, artificial intelligence, machine learning, computer science and advanced engineering methodology, as well as working more closely with the clinical community to better understand and exploit physiological measurements, and indeed to develop jointly better measurement protocols informed by model-based understanding. Developments in physiological modelling, model personalisation, model outcome uncertainty, and the role of models in clinical decision support are addressed and ‘where-next’ steps and challenges discussed. © 2019. This is the authors' manuscript to the article.

BACKGROUND AND PURPOSE: Pharmacotherapy of atrial fibrillation (AF), the most common cardiac arrhythmia, remains unsatisfactory due to low efficacy and safety concerns. New therapeutic strategies target atrial‐predominant ion‐channels and involve multichannel block (poly)therapy. As AF is characterized by rapid and irregular atrial activations, compounds displaying potent antiarrhythmic effects at fast and minimal effects at slow rates are desirable. We present a novel systems pharmacology framework to quantitatively evaluate synergistic anti‐AF effects of combined block of multiple atrial‐predominant K(+) currents (ultra‐rapid delayed rectifier K(+) current, I(Kur), small conductance Ca(2+)‐activated K(+) current, I(KCa), K(2P)3.1 2‐pore‐domain K(+) current, I(K2P)) in AF. EXPERIMENTAL APPROACH: We constructed experimentally calibrated populations of virtual atrial myocyte models in normal sinus rhythm and AF‐remodelled conditions using two distinct, well‐established atrial models. Sensitivity analyses on our atrial populations was used to investigate the rate dependence of action potential duration (APD) changes due to blocking I(Kur), I(K2P) or I(KCa) and interactions caused by blocking of these currents in modulating APD. Block was simulated in both single myocytes and one‐dimensional tissue strands to confirm insights from the sensitivity analyses and examine anti‐arrhythmic effects of multi‐atrial‐predominant K(+) current block in single cells and coupled tissue. KEY RESULTS: In both virtual atrial myocytes and tissues, multiple atrial‐predominant K(+)‐current block promoted favourable positive rate‐dependent APD prolongation and displayed positive rate‐dependent synergy, that is, increasing synergistic antiarrhythmic effects at fast pacing versus slow rates. CONCLUSION AND IMPLICATIONS: Simultaneous block of multiple atrial‐predominant K(+) currents may be a valuable antiarrhythmic pharmacotherapeutic strategy for AF.

Background Sleep Disordered Breathing (SDB) is associated with a wide range of pathophysiological changes due, in part, to hypoxemia during sleep. We sought to identify gene transcription associations with measures of SDB and hypoxemia during sleep, and study their response to treatment. Methods In two discovery cohorts, Framingham Offspring Study (FOS; N = 571) and the Multi-Ethnic Study of Atherosclerosis (MESA; N = 580), we studied gene expression in peripheral blood mononuclear cells in association with three measures of SDB: Apnea Hypopnea Index (AHI); average oxyhemoglobin saturation (avgO2) during sleep; and minimum oxyhemoglobin saturation (minO2) during sleep. Associated genes were used for analysis of gene expression in the blood of 15 participants with moderate or severe obstructive sleep apnea (OSA) from the Heart Biomarkers In Apnea Treatment (HeartBEAT) trial. These genes were studied pre- and post-treatment (three months) with continuous positive airway pressure (CPAP). We also performed Gene Set Enrichment Analysis (GSEA) on all traits and cohort analyses. Findings Twenty-two genes were associated with SDB traits in both MESA and FOS. Of these, lower expression of CD1D and RAB20 was associated with lower avgO2 in MESA and FOS. CPAP treatment increased the expression of these genes in HeartBEAT participants. Immunity and inflammation pathways were up-regulated in subjects with lower avgO2; i.e., in those with a more severe SDB phenotype (MESA), whereas immuno-inflammatory processes were down-regulated following CPAP treatment (HeartBEAT). Interpretation Low oxygen saturation during sleep is associated with alterations in gene expression and transcriptional programs that are partially reversed by CPAP treatment.

Although mutations in the Lamin A/C gene (LMNA) cause a variety of devastating diseases, the pathological mechanism is often unknown. Lamin A/C proteins play a crucial role in forming a meshwork under the nuclear membrane, providing the nucleus with mechanical integrity and interacting with other proteins for gene regulation. Most LMNA mutations result in heart diseases, including some types that primarily have heart disease as the main pathology. In this study, we used cells from patients with different LMNA mutations that primarily lead to heart disease. Indeed, it is a mystery why a mutation to the protein in every nucleus of the body manifests as a disease of primarily the heart in these patients. Here, we aimed to investigate if strains mimicking those within the myocardial environment are sufficient to cause differences in cells with and without the LMNA mutation. To test this, a stretcher device was used to induce cyclic strain upon cells, and viability/proliferation, cytoskeleton and extracellular matrix organization, and nuclear morphology were quantified. The properties of cells with Hutchinson-Gilford progeria syndrome (HGPS) were found to be significantly different from all other cell lines and were mostly in line with previous findings. However, the properties of cells from patients who primarily had heart diseases were not drastically different when compared to individuals without the LMNA mutation. Our results indicated that cyclic strain alone was insufficient to cause any significant differences that could explain the mechanisms that lead to heart diseases in these patients with LMNA mutations.

Background During the coronavirus disease (COVID-19) pandemic, a reduction in the presentation of acute coronary syndrome (ACS) has been noted in several countries. However, whether these trends reflect a reduction in ACS incidence or a decrease in emergency room visits is unknown. Using Google Trends, queries for chest pain that have previously been shown to closely correlate with coronary heart disease were compared with searches for myocardial infarction and COVID-19 symptoms. Objective The current study evaluates if search terms (or topics) pertaining to chest pain symptoms correlate with the reported decrease in presentations of ACS. Methods Google Trends data for search terms “chest pain,” “myocardial infarction,” “cough,” and “fever” were obtained from June 1, 2019, to May 31, 2020. Related queries were evaluated for a relationship to coronary heart disease. Results Following the onset of the COVID-19 pandemic, chest pain searches increased in all countries studied by at least 34% (USA P=.003, Spain P=.007, UK P=.001, Italy P=.002), while searches for myocardial infarction dropped or remained unchanged. Rising searches for chest pain included “coronavirus chest pain,” “home remedies for chest pain,” and “natural remedies for chest pain.” Searches on COVID-19 symptoms (eg, cough, fever) rose initially but returned to baseline while chest pain–related searches remained elevated throughout May. Conclusions Search engine queries for chest pain have risen during the pandemic as have related searches with alternative attribution for chest pain or home care for chest pain, suggesting that recent drops in ACS presentations may be due to patients avoiding the emergency room and potential treatment in the midst of the COVID-19 pandemic.

Introduction Nicotine Replacement Therapy (NRT) is an effective treatment for smoking cessation. However, medication usage and adherence remain a challenge that contributes to low smoking cessation rates. In Mexico, 8 in 10 smokers are interested in quitting. However, only 6% of Mexican smokers use medication for smoking cessation. The objective of this study is to assess the feasibility and acceptability of a mobile health (mHealth) intervention to increase usage and adherence of NRT in Mexico. Methods The study involves a secondary data analysis. Forty smokers were recruited to participate in a single-arm pilot study. Participants received an mHealth intervention that uses tablet-based decision support software to drive a 12-week text messaging smoking cessation program and pharmacotherapy support. The intervention allows two-way interactivity text messaging between participants and a tobacco treatment specialist. NRT was offered to participants in accordance with practice guidelines in Mexico. Outcome measures included utilization of NRT, text messaging interactivity with the program, and biochemically verified abstinence at 12 weeks. Results Thirty smokers met the criteria for use of NRT. Average age of participants was 38.1 years (SD=10.7), and they were primarily male (56.7%) with at least an undergraduate degree (60%). All participants requested NRT at baseline, and 60% requested a refill at week 4. During the 12-week intervention period, participants sent 620 messages to the program (mean=20.6, SD=18.34) of which 79 messages (12.7%) were related to NRT. Three themes were identified in the messages related to NRT: enthusiasm, instructions, and side effects. At 12 weeks, 40% of participants reported using NRT

Key points The aim of this study was to determine the effect of rotational axis position (RAP and thus g‐gradient) during short‐arm human centrifugation (SAHC) upon cardiovascular responses, cerebral perfusion and g‐tolerance.In 10 male and 10 female participants, 10 min passive SAHC runs were performed with the RAP above the head (P1), at the apex of the head (P2), or at heart level (P3), with foot‐level Gz at 1.0 g, 1.7 g and 2.4 g.We hypothesized that movement of the RAP from above the head (the conventional position) towards the heart might reduce central hypovolaemia, limit cardiovascular responses, aid cerebral perfusion, and thus promote g‐tolerance.Moving the RAP footward towards the heart decreased the cerebral tissue saturation index, calf circumference and heart rate responses to SAHC, thereby promoting g‐tolerance.Our results also suggest that RAP, and thus g‐gradient, warrants further investigation as it may support use as a holistic spaceflight countermeasure. Abstract Artificial gravity (AG) through short‐arm human centrifugation (SAHC) has been proposed as a holistic spaceflight countermeasure. Movement of the rotational axis position (RAP) from above the head towards the heart may reduce central hypovolaemia, aid cerebral perfusion, and thus promote g‐tolerance. This study determined the effect of RAP upon cardiovascular responses, peripheral blood displacement (i.e. central hypovolaemia), cerebral perfusion and g‐tolerance, and their inter‐relationships. Twenty (10 male) healthy participants (26.2 ± 4.0 years) underwent nine (following a familiarization run) randomized 10 min passive SAHC runs with RAP set above the head (P1), at the apex of the head (P2), or at heart level (P3) with foot‐level Gz at 1.0 g, 1.7 g and 2.4 g. Cerebral tissue saturation index (cTSI, cerebral perfusion surrogate), calf circumference (CC, central hypovolaemia), heart rate (HR) and digital heart‐level mean arterial blood pressure (MAP) were continuously recorded, in addition to incidence of pre‐syncopal symptoms (PSS). ΔCC and ΔHR increases were attenuated from P1 to P3 (ΔCC: 5.46 ± 0.54 mm to 2.23 ± 0.42 mm; ΔHR: 50 ± 4 bpm to 8 ± 2 bpm, P, Key points The aim of this study was to determine the effect of rotational axis position (RAP and thus g‐gradient) during short‐arm human centrifugation (SAHC) upon cardiovascular responses, cerebral perfusion and g‐tolerance.In 10 male and 10 female participants, 10 min passive SAHC runs were performed with the RAP above the head (P1), at the apex of the head (P2), or at heart level (P3), with foot‐level Gz at 1.0 g, 1.7 g and 2.4 g.We hypothesized that movement of the RAP from above the head (the conventional position) towards the heart might reduce central hypovolaemia, limit cardiovascular responses, aid cerebral perfusion, and thus promote g‐tolerance.Moving the RAP footward towards the heart decreased the cerebral tissue saturation index, calf circumference and heart rate responses to SAHC, thereby promoting g‐tolerance.Our results also suggest that RAP, and thus g‐gradient, warrants further investigation as it may support use as a holistic spaceflight countermeasure.

BACKGROUND AND PURPOSE: The kidney is essential in regulating sodium homeostasis and BP. The irreversible oxidation of Cys(674) (C674) in the sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) is increased in the renal cortex of hypertensive mice. Whether inactivation of C674 promotes hypertension is unclear. Here we have investigated the effects on BP of the inactivation of C674, and its role in the kidney. EXPERIMENTAL APPROACH: We used heterozygous SERCA2 C674S knock‐in (SKI) mice, where half of C674 was substituted by serine, to represent partial irreversible oxidation of C674. The BP, urine volume, and urine composition of SKI mice and their littermate wild‐type (WT) mice were measured. The kidneys were collected for cell culture, Na(+)/K(+)‐ATPase activity, protein expression, and immunohistological analysis. KEY RESULTS: Compared with WT mice, SKI mice had higher BP, lower urine volume and sodium excretion, up‐regulated endoplasmic reticulum (ER) stress markers and soluble epoxide hydrolase (sEH), and down‐regulated dopamine D(1) receptors in renal cortex and cells from renal proximal tubule. ER stress and sEH were mutually regulated, and both upstream of D(1) receptors. Inhibition of ER stress or sEH up‐regulated expression of D(1) receptors, decreased the activity of Na(+)/K(+)‐ATPase, increased sodium excretion, and lowered BP in SKI mice. CONCLUSIONS AND IMPLICATIONS: The inactivation of SERCA2 C674 promotes the development of hypertension by inducing ER stress and sEH. Our study highlights the importance of C674 redox status in BP control and the contribution of SERCA2 to sodium homeostasis and BP in the kidney.

BACKGROUND AND PURPOSE: Chloroquine is a traditional medicine to treat malaria. There is increasing evidence that chloroquine not only induces phagocytosis but regulates vascular tone. Few reports investigating the effect of chloroquine on vascular responsiveness of coronary arteries have been made. In this study, we examined how chloroquine affected endothelium‐dependent relaxation in coronary arteries under normal and diabetic conditions. EXPERIMENTAL APPROACH: We isolated coronary arteries from mice and examined endothelium‐dependent relaxation (EDR). Human coronary endothelial cells and mouse coronary endothelial cells isolated from control and diabetic mouse (TALLYHO/Jng [TH] mice, a spontaneous type 2 diabetic mouse model) were used for the molecular biological or cytosolic NO and Ca(2+) measurements. KEY RESULTS: Chloroquine inhibited endothelium‐derived NO‐dependent relaxation but had negligible effect on endothelium‐derived hyperpolarization (EDH)‐dependent relaxation in coronary arteries of control mice. Chloroquine significantly decreased NO production in control human coronary endothelial cells partly by phosphorylating eNOS(Thr495) (an inhibitory phosphorylation site of eNOS) and attenuating the rise of cytosolic Ca(2+) concentration after stimulation. EDR was significantly inhibited in diabetic mice in comparison to control mice. Interestingly, chloroquine enhanced EDR in diabetic coronary arteries by, specifically, increasing EDH‐dependent relaxation due partly to its augmenting effect on gap junction activity in diabetic mouse coronary endothelial cells. CONCLUSIONS AND IMPLICATIONS: These data indicate that chloroquine affects vascular relaxation differently under normal and diabetic conditions. Therefore, the patients' health condition such as coronary macrovascular or microvascular disease, with or without diabetes, must be taken account into the consideration when selecting chloroquine for the treatment of malaria.

Highlights • Age and fibrocalcific carotid plaques are associated with lower total brain volume. • Fibrocalcific carotid plaques are associated with lower gray matter volumes. • White matter volumes are associated with the extent of carotid atherosclerosis. • Grey and white matter likely have differential susceptibility to processes., Background and aims Extent of subclinical atherosclerosis has been associated with brain parenchymal loss in community-dwelling aged subjects. Identification of patient-related and plaque-related markers could identify subjects at higher risk of brain atrophy, independent of cerebrovascular accidents. Aim of the study was to investigate the relation between extent and characteristics of carotid plaques and brain atrophy in asymptomatic patients with no indication for revascularization. Methods and results Sixty-four patients (aged 69 ± 8 years, 45% females) with carotid stenosis

Highlights • There is a need for objective alcohol biomarkers in treatment and research settings. • Commercial urinary EtG tests are good candidates for objective biomarkers. • uEtG-based detection of past day alcohol use had good sensitivity and specificity. • uEtG-based detection of past 3-day drinking had poor sensitivity and specificity. • Commercial uEtG tests are not yet reliable enough to use as an objective biomarker., Introduction To advance the use of alcohol metabolites as biomarkers in the context of alcohol research, the present study tested the sensitivity and specificity of a commercially available urinary ethyl glucuronide (uEtG) test (DrugConfirm Advanced 80hr EtG) in a clinical research context. Methods A community sample of heavy drinkers (N = 68) completed the 30-day Timeline Follow-Back (TLFB) interview and provided a urine sample for uEtG analysis. Analyses of sensitivity and specificity of the uEtG assay were conducted using the following outcomes: (a) past day drinking, (b) past day binge drinking (defined as ≥4 drinks for women and ≥5 drinks for men), (c) past 3-day drinking, and (d) past 3-day binge drinking. Results The majority of participants reported past-3-day drinking (80.9%) and a sizeable minority reported past day drinking (33.8%). While uEtG-based detection of past day drinking and binge drinking was acceptable (sensitivity = 73.91%, and 83.33%; specificity = 80.00% and 66.13%, respectively), detection of any drinking and binge drinking in the past 3 days was poor (sensitivity and specificity of 43.64% and 84.62%, and 39.39% and 62.86%, respectively). Conclusions This study contributes to the mixed findings on the validity of EtG tests, which suggest that commercial uEtG tests with conservative detection thresholds are not a reliable alcohol biomarker without corroborating self-report data. Lower detection thresholds are recommended when using uEtG as an alcohol biomarker. Efforts to reach acceptable levels of sensitivity and specificity with commercial assays hold potential to advance the measurement of alcohol intake, overcoming the pitfalls of self-report data.

BackgroundHeart disease is the leading cause of death in schizophrenia. However, there has been little research directly examining cardiac function in schizophrenia.AimsTo investigate cardiac structure and function in individuals with schizophrenia using cardiac magnetic resonance imaging (CMR) after excluding medical and metabolic comorbidity.MethodIn total, 80 participants underwent CMR to determine biventricular volumes and function and measures of blood pressure, physical activity and glycated haemoglobin levels. Individuals with schizophrenia (‘patients’) and controls were matched for age, gender, ethnicity and body surface area.ResultsPatients had significantly smaller indexed left ventricular (LV) end-diastolic volume (effect size d = −0.82, P = 0.001), LV end-systolic volume (d = −0.58, P = 0.02), LV stroke volume (d = −0.85, P = 0.001), right ventricular (RV) end-diastolic volume (d = −0.79, P = 0.002), RV end-systolic volume (d = −0.58, P = 0.02), and RV stroke volume (d = −0.87, P = 0.001) but unaltered ejection fractions relative to controls. LV concentricity (d = 0.73, P = 0.003) and septal thickness (d = 1.13, P < 0.001) were significantly larger in the patients. Mean concentricity in patients was above the reference range. The findings were largely unchanged after adjusting for smoking and/or exercise levels and were independent of medication dose and duration.ConclusionsIndividuals with schizophrenia show evidence of concentric cardiac remodelling compared with healthy controls of a similar age, gender, ethnicity, body surface area and blood pressure, and independent of smoking and activity levels. This could be contributing to the excess cardiovascular mortality observed in schizophrenia. Future studies should investigate the contribution of antipsychotic medication to these changes.

Background: Cardiac rehabilitation (CR) is known for its beneficial effects on functional capacity and is a key component within current cardiovascular disease management strategies. In addition, a larger increase in functional capacity is accompanied by better clinical outcomes. However, not all patients respond in a similar way to CR. Therefore, a patient-tailored approach to CR could open up the possibility to achieve an optimal increase in functional capacity in every patient. Before treatment can be optimized, the differences in response of patients in terms of cardiac adaptation to exercise should first be understood. In addition, digital biomarkers to steer CR need to be identified. Objective: The aim of the study was to investigate the difference in cardiac response between patients characterized by a clear improvement in functional capacity and patients showing only a minor improvement following CR therapy. Methods: A total of 129 patients in CR performed a 6-minute walking test (6MWT) at baseline and during four consecutive short-term follow-up tests while being equipped with a wearable electrocardiogram (ECG) device. The 6MWTs were used to evaluate functional capacity. Patients were divided into high- and low-response groups, based on the improvement in functional capacity during the CR program. Commonly used heart rate parameters and cardiac digital biomarkers representative of the heart rate behavior during the 6MWT and their evolution over time were investigated. Results: All participating patients improved in functional capacity throughout the CR program (P

Background: E-cigarette and other novel electronic nicotine delivery systems (ENDS) have recently entered the market at a rapid pace. The community desperately needs answers about the health effects of ENDS. The present study tested the hypothesis that perinatal nicotine exposure (PNE) causes a gender-dependent increase in vulnerability of the heart to ischemia-reperfusion (I/R) injury and cardiac dysfunction in male rat offspring via reprogramming of the miRNA-181a (miR-181a)-mediated signaling pathway and that miR-181a antisense could rescue this phenotype. Methods: Nicotine or saline was administered to pregnant rats via subcutaneous osmotic minipumps from gestational day 4 until postnatal day 10. Cardiac function and molecular biological experiments were conducted in ~3- month-old offspring. Results: PNE enhanced I/R-induced cardiac dysfunction and infarction in adult male but not in female offspring, which was associated with miR-181a over-expression in left ventricle tissues. In addition, PNE enhanced offspring cardiac angiotensin receptor (ATR) expressions via specific CpG hypomethylation of AT1R/AT2R promoter. Furthermore, PNE attenuated cardiac lncRNA H19 levels, but up-regulated cardiac TGF-β/Smads family proteins and consequently up-regulated autophagy-related protein (Atg-5, beclin-1, LC3 II, p62) expression in the male offspring. Of importance, treatment with miR-181a antisense eliminated the PNE's effect on miR-181a expression/H19 levels and reversed PNE-mediated I/R-induced cardiac infarction and dysfunction in male offspring. Furthermore, miR-181a antisense also attenuated the effect of PNE on AT1R/AT2R/TGF-β/Smads/autophagy-related biomarkers in the male offspring. Conclusion: Our data suggest that PNE could induce a reprogramming of cardiac miR-181a expression/DNA methylation pattern, which epigenetically modulates ATR/TGF-β/autophagy signaling pathways, leading to gender-dependent development of ischemia-sensitive phenotype in postnatal life. Furthermore, miR-181a could severe as a potential therapeutic target for rescuing this phenotype.

Rationale: Cigarette smoking is a well-established risk factor for myocardial infarction and sudden cardiac death. The deleterious effects are mainly due to nicotine, but the mechanisms involved and theranostics remain unclear. Thus, we tested the hypothesis that nicotine exposure increases the heart sensitivity to ischemia/reperfusion injury and dysfunction, which can be rescued by autophagy inhibitor. Methods: Nicotine or saline was administered to adult rats via subcutaneous osmotic minipumps in the absence or presence of an autophagy inhibitor, 3-methyladenine (3-MA). After 30 days of nicotine treatment, the rats underwent the cardiac ischemia/reperfusion (I/R) procedure and echocardiography analysis, and the heart tissues were isolated for molecular biological studies. Results: Nicotine exposure increased I/R-induced cardiac injury and cardiac dysfunction as compared to the control. The levels of autophagy-related proteins including LC3 II, P62, Beclin1, and Atg5 were upregulated in the reperfused hearts isolated from nicotine-treated group. In addition, nicotine enhanced cardiac and plasma ROS production, and increased the phosphorylation of GSK3β (ser9) in the left ventricle tissues. Treatment with 3-MA abolished nicotine-mediated increase in the levels of autophagy-related proteins and phosphorylation of GSK3β, but had no effect on ROS production. Of importance, 3-MA ameliorated the augmented I/R-induced cardiac injury and dysfunction in the nicotine-treated group as compared to the control. Conclusion: Our results demonstrate that nicotine exposure enhances autophagy signaling pathway, resulting in development of ischemic-sensitive phenotype of heart. It suggests a potentially novel therapeutic strategy of autophagy inhibition for the treatment of ischemic heart disease.

Background Heart rate variability (HRV), or variation in beat-to-beat intervals of the heart, is a quantitative measure of autonomic regulation of the cardiovascular system. Low HRV derived from electrocardiogram (ECG) recordings is reported to be related to physical frailty in older adults. Recent advances in wearable technology offer opportunities to more easily integrate monitoring of HRV into regular clinical geriatric health assessments. However, signals obtained from ECG versus wearable photoplethysmography (PPG) devices are different, and a critical first step preceding their widespread use is to determine whether HRV metrics derived from PPG devices also relate to older adults’ physical function. Objective This study aimed to investigate associations between HRV measured with a wrist-worn PPG device, the Empatica E4 sensor, and validated clinical measures of both objective and self-reported physical function in a cohort of older adults living independently within a continuing care senior housing community. Our primary hypothesis was that lower HRV would be associated with lower physical function. In addition, we expected that HRV would explain a significant proportion of variance in measures of physical health status. Methods We evaluated 77 participants from an ongoing study of older adults aged between 65 and 95 years. The assessments encompassed a thorough examination of domains typically included in a geriatric health evaluation. We collected HRV data with the Empatica E4 device and examined bivariate correlations between HRV quantified with the triangular index (HRV TI) and 3 widely used and validated measures of physical functioning—the Short Physical Performance Battery (SPPB), Timed Up and Go (TUG), and Medical Outcomes Study Short Form 36 (SF-36) physical composite scores. We further investigated the additional predictive power of HRV TI on physical health status, as characterized by SF-36 physical composite scores and Cumulative Illness Rating Scale for Geriatrics (CIRS-G) scores, using generalized estimating equation regression analyses with backward elimination. Results We observed significant associations of HRV TI with SPPB (n=52; Spearman ρ=0.41; P=.003), TUG (n=51; ρ=−0.40; P=.004), SF-36 physical composite scores (n=49; ρ=0.37; P=.009), and CIRS-G scores (n=52, ρ=−0.43; P=.001). In addition, the HRV TI explained a significant proportion of variance in SF-36 physical composite scores (R2=0.28 vs 0.11 without HRV) and CIRS-G scores (R2=0.33 vs 0.17 without HRV). Conclusions The HRV TI measured with a relatively novel wrist-worn PPG device was related to both objective (SPPB and TUG) and self-reported (SF-36 physical composite) measures of physical function. In addition, the HRV TI explained additional variance in self-reported physical function and cumulative illness severity beyond traditionally measured aspects of physical health. Future steps include longitudinal tracking of changes in both HRV and physical function, which will add important insights regarding the predictive value of HRV as a biomarker of physical health in older adults.

Background Heart failure is a serious public health concern that afflicts millions of individuals in the United States. Development of behaviors that promote heart failure self-care may be imperative to reduce complications and avoid hospital re-admissions. Mobile health solutions, such as activity trackers and smartphone apps, could potentially help to promote self-care through remote tracking and issuing reminders. Objective The objective of this study was to ascertain heart failure patients’ interest in a smartphone app to assist them in managing their treatment and symptoms and to determine factors that influence their interest in such an app. Methods In the clinic waiting room on the day of their outpatient clinic appointments, 50 heart failure patients participated in a self-administered survey. The survey comprised 139 questions from previously published, institutional review board–approved questionnaires. The survey measured patients’ interest in and experience using technology as well as their function, heart failure symptoms, and heart failure self-care behaviors. The Minnesota Living with Heart Failure Questionnaire (MLHFQ) was among the 11 questionnaires and was used to measure the heart failure patients’ health-related quality of life through patient-reported outcomes. Results Participants were aged 64.5 years on average, 32% (16/50) of the participants were women, and 91% (41/45) of the participants were determined to be New York Heart Association Class II or higher. More than 60% (30/50) of the survey participants expressed interest in several potential features of a smartphone app designed for heart failure patients. Participant age correlated negatively with interest in tracking, tips, and reminders in multivariate regression analysis (P Conclusions The majority of heart failure patients showed interest in activity tracking, heart failure symptom management tips, and reminder features of a smartphone app. Desirable features and an understanding of factors that influence patient interest in a smartphone app for heart failure self-care may allow researchers to address common concerns and to develop apps that demonstrate the potential benefits of mobile technology.