Stroke risk in women with atrial fibrillation.

BACKGROUND AND AIMS: Female sex is associated with higher rates of stroke in atrial fibrillation (AF) after adjustment for other CHA2DS2-VASc factors. This study aimed to describe sex differences in age and cardiovascular care to examine their relationship with stroke hazard in AF. METHODS: Population-based cohort study using administrative datasets of people aged ≥66 years diagnosed with AF in Ontario between 2007 and 2019. Cause-specific hazard regression was used to estimate the adjusted hazard ratio (HR) for stroke associated with female sex over a 2-year follow-up. Model 1 included CHA2DS2-VASc factors, with age modelled as 66-74 vs. ≥ 75 years. Model 2 treated age as a continuous variable and included an age-sex interaction term. Model 3 further accounted for multimorbidity and markers of cardiovascular care. RESULTS: The cohort consisted of 354 254 individuals with AF (median age 78 years, 49.2% female). Females were more likely to be diagnosed in emergency departments and less likely to receive cardiologist assessments, statins, or LDL-C testing, with higher LDL-C levels among females than males. In Model 1, the adjusted HR for stroke associated with female sex was 1.27 (95% confidence interval 1.21-1.32). Model 2 revealed a significant age-sex interaction, such that female sex was only associated with increased stroke hazard at age >70 years. Adjusting for markers of cardiovascular care and multimorbidity further decreased the HR, so that female sex was not associated with increased stroke hazard at age ≤80 years. CONCLUSION: Older age and inequities in cardiovascular care may partly explain higher stroke rates in females with AF.

Ambulatory Cardiology or General Internal Medicine Assessment Prior to Scheduled Major Vascular Surgery is Associated with Improved Outcomes.

OBJECTIVE: To characterize the association between ambulatory cardiology or general internal medicine (GIM) assessment prior to surgery and outcomes following scheduled major vascular surgery. BACKGROUND: Cardiovascular risk assessment and management prior to high-risk surgery remains an evolving area of care. METHODS: This is population-based retrospective cohort study of all adults who underwent scheduled major vascular surgery in Ontario, Canada, April 1, 2004-March 31, 2019. Patients who had an ambulatory cardiology and/or GIM assessment within 6 months prior to surgery were compared to those who did not. The primary outcome was 30-day mortality. Secondary outcomes included: composite of 30-day mortality, myocardial infarction or stroke; 30-day cardiovascular death; 1-year mortality; composite of 1-year mortality, myocardial infarction or stroke; and 1-year cardiovascular death. Cox proportional hazard regression using inverse probability of treatment weighting (IPTW) was used to mitigate confounding by indication. RESULTS: Among 50,228 patients, 20,484 (40.8%) underwent an ambulatory assessment prior to surgery: 11,074 (54.1%) with cardiology, 8,071 (39.4%) with GIM and 1,339 (6.5%) with both. Compared to patients who did not, those who underwent an assessment had a higher Revised Cardiac Risk Index (N with Index over 2= 4,989[24.4%] vs. 4,587[15.4%], P<0.001) and more frequent pre-operative cardiac testing (N=7,772[37.9%] vs. 6,113[20.6%], P<0.001) but, lower 30-day mortality (N=551[2.7%] vs. 970[3.3%], P<0.001). After application of IPTW, cardiology or GIM assessment prior to surgery remained associated with a lower 30-day mortality (weighted Hazard Ratio [95%CI] = 0.73 [0.65-0.82]) and a lower rate of all secondary outcomes. CONCLUSIONS: Major vascular surgery patients assessed by a cardiology or GIM physician prior to surgery have better outcomes than those who are not. Further research is needed to better understand potential mechanisms of benefit.

Sodium-Glucose Cotransporter 2 Inhibitors During Cancer Therapy: Benefits, Risks, and Ongoing Clinical Trials.

PURPOSE OF REVIEW: The goal of this paper is to summarize the data pertaining to the use of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) for the prevention of cardiotoxicity in patients receiving anthracyclines for cancer treatment. We discuss the potential efficacy of this class of medications, incorporating insights from existing literature and ongoing studies. RECENT FINDINGS: SGLT2i are a class of medications which were initially developed for treatment of Type 2 diabetes and later extended to treat heart failure with reduced and preserved ejection fraction regardless of diabetes status. There remains a need for effective and safe treatments to preventing cardiotoxicity in anthracycline-treated patients. It has been proposed that SGLT2i may provide protection against the cardiotoxic effects of anthracyclines. Some of the proposed mechanisms include beneficial metabolic, neurohormonal, and hemodynamic effects, renal protection, as well as a decrease in inflammation, oxidative stress, apoptosis, mitochondrial dysfunction and ion homeostasis. There is emerging evidence from basic science and observational studies that SGLT2i may play a role in the prevention of chemotherapy-induced cardiotoxicity. Randomized controlled trials are needed to conclusively determine the role of SGLT2 inhibitors as a cardioprotective therapy in patients receiving anthracyclines for the treatment of cancer.

Arrhythmogenic Ventricular Remodeling by Next-Generation Bruton's Tyrosine Kinase Inhibitor Acalabrutinib.

Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton's tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a next-generation BTKi, is associated with reduced atrial arrhythmia events. However, the role of ABR in ventricular arrhythmia (VA) has not been adequately evaluated. Our study aimed to investigate VA vulnerability and ventricular electrophysiology following chronic ABR therapy in male Sprague-Dawley rats utilizing epicardial optical mapping for ventricular voltage and Ca2+ dynamics and VA induction by electrical stimulation in ex-vivo perfused hearts. Ventricular tissues were snap-frozen for protein analysis for sarcoplasmic Ca2+ and metabolic regulatory proteins. The results show that both ABR and IBR treatments increased VA vulnerability, with ABR showing higher VA regularity index (RI). IBR, but not ABR, is associated with the abbreviation of action potential duration (APD) and APD alternans. Both IBR and ABR increased diastolic Ca2+ leak and Ca2+ alternans, reduced conduction velocity (CV), and increased CV dispersion. Decreased SERCA2a expression and AMPK phosphorylation were observed with both treatments. Our results suggest that ABR treatment also increases the risk of VA by inducing proarrhythmic changes in Ca2+ signaling and membrane electrophysiology, as seen with IBR. However, the different impacts of these two BTKi on ventricular electrophysiology may contribute to differences in VA vulnerability and distinct VA characteristics.

Association of Neighborhood-Level Material Deprivation With Atrial Fibrillation Care in a Single-Payer Health Care System: A Population-Based Cohort Study.

BACKGROUND: There are limited data on the association of material deprivation with clinical care and outcomes after atrial fibrillation (AF) diagnosis in jurisdictions with universal health care. METHODS: This was a population-based cohort study of individuals ≥66 years of age with first diagnosis of AF between April 1, 2007, and March 31, 2019, in the Canadian province of Ontario, which provides public funding and prohibits private payment for medically necessary physician and hospital services. Prescription medications are subsidized for residents >65 years of age. The primary exposure was neighborhood material deprivation, a metric derived from Canadian census data to estimate inability to attain basic material needs. Neighborhoods were categorized by quintile from Q1 (least deprived) to Q5 (most deprived). Cause-specific hazards regression was used to study the association of material deprivation quintile with time to AF-related adverse events (death or hospitalization for stroke, heart failure, or bleeding), clinical services (physician visits, cardiac diagnostics), and interventions (anticoagulation, cardioversion, ablation) while adjusting for individual characteristics and regional cardiologist supply. RESULTS: Among 347 632 individuals with AF (median age 79 years, 48.9% female), individuals in the most deprived neighborhoods (Q5) had higher prevalence of cardiovascular disease, risk factors, and noncardiovascular comorbidity relative to residents of the least deprived neighborhoods (Q1). After adjustment, Q5 residents had higher hazards of death (hazard ratio [HR], 1.16 [95% CI, 1.13-1.20]) and hospitalization for stroke (HR, 1.16 [95% CI, 1.07-1.27]), heart failure (HR, 1.14 [95% CI, 1.11-1.18]), or bleeding (HR, 1.16 [95% CI, 1.07-1.25]) relative to Q1. There were small differences across quintiles in primary care physician visits (HR, Q5 versus Q1, 0.91 [95% CI, 0.89-0.92]), echocardiography (HR, Q5 versus Q1, 0.97 [95% CI, 0.96-0.99]), and dispensation of anticoagulation (HR, Q5 versus Q1, 0.97 [95% CI, 0.95-0.98]). There were more prominent disparities for Q5 versus Q1 in cardiologist visits (HR, 0.84 [95% CI, 0.82-0.86]), cardioversion (HR, 0.80 [95% CI, 0.76-0.84]), and ablation (HR, 0.45 [95% CI, 0.30-0.67]). CONCLUSIONS: Despite universal health care and prescription medication coverage, residents of more deprived neighborhoods were less likely to visit cardiologists or receive rhythm control interventions after AF diagnosis, even though they exhibited higher cardiovascular disease burden and higher risk of adverse outcomes.

Social Determinants of Health and Racial Disparities in Cardiac Events in Breast Cancer.

BACKGROUND: Racial disparities have been reported for breast cancer and cardiovascular disease (CVD) outcomes. The determinants of racial disparities in CVD outcomes are not yet fully understood. We aimed to examine the impact of individual and neighborhood-level social determinants of health (SDOH) on the racial disparities in major adverse cardiovascular events (MACE; consisting of heart failure, acute coronary syndrome, atrial fibrillation, and ischemic stroke) among female patients with breast cancer. METHODS: This 10-year longitudinal retrospective study was based on a cancer informatics platform with electronic medical record supplementation. We included women aged ≥18 years diagnosed with breast cancer. SDOH were obtained from LexisNexis, and consisted of the domains of social and community context, neighborhood and built environment, education access and quality, and economic stability. Race-agnostic (overall data with race as a feature) and race-specific machine learning models were developed to account for and rank the SDOH impact in 2-year MACE. RESULTS: We included 4,309 patients (765 non-Hispanic Black [NHB]; 3,321 non-Hispanic white). In the race-agnostic model (C-index, 0.79; 95% CI, 0.78-0.80), the 5 most important adverse SDOH variables were neighborhood median household income (SHapley Additive exPlanations [SHAP] score [SS], 0.07), neighborhood crime index (SS = 0.06), number of transportation properties in the household (SS = 0.05), neighborhood burglary index (SS = 0.04), and neighborhood median home values (SS = 0.03). Race was not significantly associated with MACE when adverse SDOH were included as covariates (adjusted subdistribution hazard ratio, 1.22; 95% CI, 0.91-1.64). NHB patients were more likely to have unfavorable SDOH conditions for 8 of the 10 most important SDOH variables for the MACE prediction. CONCLUSIONS: Neighborhood and built environment variables are the most important SDOH predictors for 2-year MACE, and NHB patients were more likely to have unfavorable SDOH conditions. This finding reinforces that race is a social construct.

Comorbidity-stratified estimates of 30-day mortality risk by age for unvaccinated men and women with COVID-19: a population-based cohort study.

BACKGROUND: The mortality risk following COVID-19 diagnosis in men and women with common comorbidities at different ages has been difficult to communicate to the general public. The purpose of this study was to determine the age at which unvaccinated men and women with common comorbidities have a mortality risk which exceeds that of 75- and 65-year-old individuals in the general population (Phases 1b/1c thresholds of the Centre for Disease Control Vaccine Rollout Recommendations) following COVID-19 infection during the first wave. METHODS: We conducted a population-based retrospective cohort study using linked administrative datasets in Ontario, Canada. We identified all community-dwelling adults diagnosed with COVID-19 between January 1 and October 31st, 2020. Exposures of interest were age (modelled using restricted cubic splines) and the following conditions: major cardiovascular disease (recent myocardial infarction or lifetime history of heart failure); 2) diabetes; 3) hypertension; 4) recent cancer; 5) chronic obstructive pulmonary disease; 6) Stages 4/5 chronic kidney disease (CKD); 7) frailty. Logistic regression in the full cohort was used to estimate the risk of 30-day mortality for 75- and 65-year-old individuals. Analyses were repeated after stratifying by sex and medical condition to determine the age at which 30-day morality risk in strata exceed that of the general population at ages 65 and 75 years. RESULTS: We studied 52,429 individuals (median age 42 years; 52.5% women) of whom 417 (0.8%) died within 30 days. The 30-day mortality risk increased with age, male sex, and comorbidities. The 65- and 75-year-old mortality risks in the general population were exceeded at the youngest age by people with CKD, cancer, and frailty. Conversely, women aged < 65 years who had diabetes or hypertension did not have higher mortality than 65-year-olds in the general population. Most people with medical conditions (except for Stage 4-5 CKD) aged < 45 years had lower predicted mortality than the general population at age 65 years. CONCLUSION: The mortality risk in COVID-19 increases with age and comorbidity but the prognostic implications varied by sex and condition. These observations can support communication efforts and inform vaccine rollout in jurisdictions with limited vaccine supplies.

Post-acute health care burden after SARS-CoV-2 infection: a retrospective cohort study.

BACKGROUND: The post-acute burden of health care use after SARS-CoV-2 infection is unknown. We sought to quantify the post-acute burden of health care use after SARS-CoV-2 infection among community-dwelling adults in Ontario by comparing those with positive and negative polymerase chain reaction (PCR) test results for SARS-CoV-2 infection. METHODS: We conducted a retrospective cohort study involving community-dwelling adults in Ontario who had a PCR test between Jan. 1, 2020, and Mar. 31, 2021. Follow-up began 56 days after PCR testing. We matched people 1:1 on a comprehensive propensity score. We compared per-person-year rates for health care encounters at the mean and 99th percentiles, and compared counts using negative binomial models, stratified by sex. RESULTS: Among 531 702 matched people, mean age was 44 (standard deviation [SD] 17) years and 51% were female. Females who tested positive for SARS-CoV-2 had a mean of 1.98 (95% CI 1.63 to 2.29) more health care encounters overall per-person-year than those who had a negative test result, with 0.31 (95% CI 0.05 to 0.56) more home care encounters to 0.81 (95% CI 0.69 to 0.93) more long-term care days. At the 99th percentile per-person-year, females who tested positive had 6.48 more days of hospital admission and 28.37 more home care encounters. Males who tested positive for SARS-CoV-2 had 0.66 (95% CI 0.34 to 0.99) more overall health care encounters per-person-year than those who tested negative, with 0.14 (95% CI 0.06 to 0.21) more outpatient encounters and 0.48 (95% CI 0.36 to 0.60) long-term care days, and 0.43 (95% CI -0.67 to -0.21) fewer home care encounters. At the 99th percentile, they had 8.69 more days in hospital per-person-year, with fewer home care (-27.31) and outpatient (-0.87) encounters. INTERPRETATION: We found significantly higher rates of health care use after a positive SARS-CoV-2 PCR test in an analysis that matched test-positive with test-negative people. Stakeholders can use these findings to prepare for health care demand associated with post-COVID-19 condition (long COVID).

Relationship of frailty with excess mortality during the COVID-19 pandemic: a population-level study in Ontario, Canada.

BACKGROUND: There is a paucity of the literature on the relationship between frailty and excess mortality due to the COVID-19 pandemic. METHODS: The entire community-dwelling adult population of Ontario, Canada, as of January 1st, 2018, was identified using the Cardiovascular Health in Ambulatory Care Research Team (CANHEART) cohort. Residents of long-term care facilities were excluded. Frailty was categorized through the Johns Hopkins Adjusted Clinical Groups (ACG® System) frailty indicator. Follow-up was until December 31st, 2020, with March 11th, 2020, indicating the beginning of the COVID-19 pandemic. Using multivariable Cox models with patient age as the timescale, we determined the relationship between frailty status and pandemic period on all-cause mortality. We evaluated the modifier effect of frailty using both stratified models as well as incorporating an interaction between frailty and the pandemic period. RESULTS: We identified 11,481,391 persons in our cohort, of whom 3.2% were frail based on the ACG indicator. Crude mortality increased from 0.75 to 0.87% per 100 person years from the pre- to post-pandemic period, translating to ~ 13,800 excess deaths among the community-dwelling adult population of Ontario (HR 1.11 95% CI 1.09-1.11). Frailty was associated with a statistically significant increase in all-cause mortality (HR 3.02, 95% CI 2.99-3.06). However, all-cause mortality increased similarly during the pandemic in frail (aHR 1.13, 95% CI 1.09-1.16) and non-frail (aHR 1.15, 95% CI 1.13-1.17) persons. CONCLUSION: Although frailty was associated with greater mortality, frailty did not modify the excess mortality associated with the pandemic.

Early invasive coronary angiography and acute ischaemic heart failure outcomes.

AIMS: While myocardial ischaemia plays a major role in the pathogenesis of heart failure (HF), the indications for coronary angiography during acute HF are not established. We determined the association of early coronary angiography during acute HF hospitalization with 2-year mortality, cardiovascular death, HF readmissions, and coronary revascularization. METHODS AND RESULTS: In a two-stage sampling process, we identified acute HF patients who presented to 70 emergency departments in Ontario (April 2010 to March 2013) and determined whether they underwent early coronary angiography within 14 days after presentation using administrative databases. After clinical record review, we defined a cohort with acute ischaemic HF as patients with at least one factor suggesting underlying ischaemic heart disease, including previous myocardial infarction, troponin elevation, or angina on presentation. We oversampled patients undergoing angiography. We used inverse-probability-of-treatment weighting (IPTW) to adjust for baseline differences. Of 7239 patients with acute HF, 2994 met inclusion criteria [median age 75 (interquartile range 65-83) years; 40.9% women]. Early angiography was performed in 1567 patients (52.3%) and was associated with lower all-cause mortality [hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.61-0.90, P = 0.002], cardiovascular death (HR 0.72, 95% CI 0.56-0.93, P = 0.012), and HF readmissions (HR 0.84, 95% CI 0.71-0.99, P = 0.042) after IPTW. Those undergoing early angiography experienced higher rates of percutaneous coronary intervention (HR 2.58, 95% CI 1.73-3.86, P < 0.001) and coronary artery bypass grafting (HR 2.94, 95% CI 1.75-4.93, P < 0.001) within 2 years. CONCLUSIONS: Early coronary angiography was associated with lower all-cause mortality, cardiovascular death, HF readmissions, and higher rates of coronary revascularization in acute HF patients with possible ischaemia.

Coronary artery disease in patients with cancer: challenges and opportunities for improvement.

PURPOSE OF REVIEW: Coronary artery disease (CAD) is a common comorbidity in patients with cancer. We review shared risk factors between the two diseases and cancer treatments that increase the risk of CAD. We also discuss outcomes and management considerations of patients with cancer who develop CAD. RECENT FINDINGS: Several traditional and novel risk factors promote the development of both CAD and cancer. Several cancer treatments further increase the risk of CAD. The presence of cancer is associated with a higher burden of comorbidities and thrombocytopenia, which predisposes patients to higher bleeding risks. Patients with cancer who develop acute coronary syndromes are less likely to receive timely revascularization or appropriate medical therapy, despite evidence showing that receipt of these interventions is associated with substantial benefit. Accordingly, a cancer diagnosis is associated with worse outcomes in patients with CAD. The risk-benefit balance of revascularization is becoming more favorable due to the improving prognosis of many cancers and safer revascularization strategies, including shorter requirements for dual antiplatelet therapy after revascularization. SUMMARY: Several factors increase the complexity of managing CAD in patients with cancer. A multidisciplinary approach is recommended to guide treatment decisions in this high-risk and growing patient group.

Association between antihypertensive medications and risk of skin cancer in people older than 65 years: a population-based study.

BACKGROUND: The risk of skin cancer associated with antihypertensive medication use is unclear, although thiazides have been implicated in regulatory safety warnings. We aimed to assess whether use of thiazides and other antihypertensives is associated with increased rates of keratinocyte carcinoma and melanoma. METHODS: We conducted a population-based inception cohort study using linked administrative health data from Ontario, 1998-2017. We matched adults aged ≥ 66 years with a first prescription for an antihypertensive medication (thiazides, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, ß-blockers) by age and sex to 2 unexposed adults who were prescribed a non-antihypertensive medication within 30 days of the index date. We evaluated each antihypertensive class in a separate cohort study. Our primary exposure was the cumulative dose within each class, standardized according to the World Health Organization's Defined Daily Dose. Outcomes were time to first keratinocyte carcinoma, advanced keratinocyte carcinoma and melanoma. RESULTS: The inception cohorts included a total of 302 634 adults prescribed an antihypertensive medication and 605 268 unexposed adults. Increasing thiazide exposure was associated with an increased rate of incident keratinocyte carcinoma (adjusted hazard ratios [HRs] per 1 Defined Annual Dose unit 1.08, 95% confidence interval [CI] 1.03-1.14), advanced keratinocyte carcinoma (adjusted HR 1.07, 95% CI 0.93-1.23) and melanoma (adjusted HR 1.34, 95% CI 1.01-1.78). We found no consistent evidence of association between other antihypertensive classes and keratinocyte carcinoma or melanoma. INTERPRETATION: Higher cumulative exposure to thiazides was associated with increased rates of incident skin cancer in people aged 66 years and older. Consideration of other antihypertensive treatments in patients at high risk of skin cancer may be warranted.

Cardiovascular Risk in Men with Prostate Cancer: Insights from the RADICAL PC Study.

PURPOSE: We describe the cardiovascular risk profile in a representative cohort of patients with prostate cancer treated with or without androgen deprivation therapy. MATERIALS AND METHODS: We prospectively characterized in detail 2,492 consecutive men (mean age 68 years) with prostate cancer (newly diagnosed or with a plan to prescribe androgen deprivation therapy for the first time) from 16 Canadian sites. Cardiovascular risk was estimated by calculating Framingham risk scores. RESULTS: Most men (92%) had new prostate cancer (intermediate risk 41%, high risk 50%). The highest level of education achieved was primary school in 12%. Most (58%) were current or former smokers, 22% had known cardiovascular disease, 16% diabetes, 45% hypertension, 31% body mass index 30 kg/m2 or greater, 24% low levels of physical activity, mean handgrip strength was 37.3 kg and 69% had a Framingham risk score consistent with high cardiovascular risk. Participants in whom androgen deprivation therapy was planned had higher Framingham risk scores than those not intending to receive androgen deprivation therapy, and this risk was abolished after adjustment for confounders. CONCLUSIONS: Two-thirds of men with prostate cancer are at high cardiovascular risk. There is a positive association between a plan to use androgen deprivation therapy and baseline cardiovascular risk factors. However, this association is explained by confounding factors.

Development and validation of a multivariable prediction model for major adverse cardiovascular events after early stage breast cancer: a population-based cohort study.

AIMS: Develop a score to predict the risk of major adverse cardiovascular events (MACE) after early stage breast cancer (EBC) to facilitate personalized decision-making about potentially cardiotoxic treatments and interventions to reduce cardiovascular risk. METHODS AND RESULTS: Using administrative databases, we assembled a cohort of women diagnosed with EBC in Ontario between 2003 and 2014, with follow-up through 2015. Two-thirds of the cohort were used for risk score derivation; the remainder were reserved for its validation. The outcome was a composite of hospitalizations for acute myocardial infarction, unstable angina, transient ischaemic attack, stroke, peripheral vascular disease, heart failure (HF), or cardiovascular death. We developed the score by regressing MACE incidence against candidate predictors in the derivation sample using a Fine-Gray model. Discrimination was assessed in the validation sample using Wolber's c-index for prognostic models with competing risks, while calibration was assessed by comparing predicted and observed MACE incidence. The risk score was derived in 60 294 women and validated in 29 810 women. Age, hypertension, diabetes, ischaemic heart disease, atrial fibrillation, HF, cerebrovascular disease, peripheral vascular disease, chronic obstructive pulmonary disease, and chronic kidney disease were significantly associated with MACE incidence and incorporated into the score. Ten-year MACE incidence was >40-fold higher for patients in the highest score decile compared to the lowest. The c-index was 81.9% (95% confidence interval 80.9-82.9%) at 5 years and 79.8% (78.8-80.8%) at 10 years in the validation cohort, with good agreement between predicted and observed MACE incidence. CONCLUSION: Cardiovascular prognosis after EBC can be estimated using patients' pre-treatment characteristics.

Percutaneous coronary intervention for the management of stable ischemic heart disease.

PURPOSE OF REVIEW: The purpose of this review is to summarize landmark studies and recent evidence in support for and against benefits of routine percutaneous coronary intervention (PCI) in the management of patients with stable ischemic heart disease (SIHD). RECENT FINDINGS: Randomized controlled trials have raised uncertainty regarding the prognostic benefits of routine PCI in patients with SIHD. The benefits of PCI to improve symptoms and quality of life (QOL), thought to be more established, was brought into question recently by the ORBITA trial. Two hundred participants with single vessel SIHD optimized first on antianginal therapy were randomized to PCI or sham PCI procedure. At 6 weeks, there was no significant difference in the primary endpoint of exercise time increment (PCI minus sham PCI 16.6 s, 95% confidence interval -8.9 to 42.0 s, P = 0.20), or secondary endpoints of change in angina or QOL scores between the groups. SUMMARY: Findings from this first placebo-controlled trial of PCI in patients with single vessel SIHD suggest that PCI need not necessarily be the first line or default strategy for symptomatic improvement. Results from the ongoing ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial will provide further guidance regarding symptomatic and prognostic benefits of early angiography and revascularization for higher risk SIHD patients with moderate-severe ischemia.

Evaluation of left ventricular reverse remodeling in patients with severe aortic regurgitation undergoing aortic valve replacement: Comparison between diameters and volumes.

BACKGROUND: In patients with severe aortic regurgitation (AR), the left ventricular ejection fraction (LVEF) and left ventricle (LV) size are crucial for determining clinical prognosis and timing of valve intervention. In clinical practice, LV internal diameters obtained at end-diastole are used to assess the degree of LV dilatation. Whether quantification of LV volumes would provide more robust information as compared to LV linear dimensions is unknown. METHODS: We retrospectively analyzed preoperative and postoperative transthoracic echocardiograms of patients who underwent aortic valve replacement (AVR) for severe AR. Indexed linear LV end-diastolic and end-systolic diameters along with indexed LV end-diastolic and end-systolic volumes were obtained as per current guidelines. Post-AVR LV reverse remodeling, defined as ≥10% reduction in measures of LV volumes (Teichholz and Simpson's methods), was determined. Positive and negative agreement was calculated between the volume- and diameter-based LV reverse remodeling. RESULTS: Sixty-two consecutive patients were included. Nine patients (17%) without LV reverse remodeling based on Teichholz were reclassified as having LV reverse remodeling based on Simpson (positive agreement 0.846 [95% CI 0.772, 0.921], negative agreement 0.200 [95% CI -0.350, 0.435]). Left ventricle (LV) reverse remodeling assessed by the Teichholz method was underestimated by a mean of 31 mL/m2 (ß = -0.65 [95% CI -1.06 to -0.24], P = .003) compared to Simpson method. CONCLUSION: Compared to the volume-based method, diameter-based LV measurement incorrectly identified LV reverse remodeling post-AVR in 17% of patients with severe AR. Left ventricle (LV) volume may be a better measure to assess LV remodeling post-AVR than LV diameter-based measurements.

Skin-derived precursors from human subjects with Type 2 diabetes yield dysfunctional vascular smooth muscle cells.

Objective: Few methods enable molecular and cellular studies of vascular aging or Type 2 diabetes (T2D). Here, we report a new approach to studying human vascular smooth muscle cell (VSMC) pathophysiology by examining VSMCs differentiated from progenitors found in skin. Approach and results: Skin-derived precursors (SKPs) were cultured from biopsies (N=164, ∼1 cm2) taken from the edges of surgical incisions of older adults (N=158; males 72%; mean age 62.7 ± 13 years) undergoing cardiothoracic surgery, and differentiated into VSMCs at high efficiency (>80% yield). The number of SKPs isolated from subjects with T2D was ∼50% lower than those without T2D (cells/g: 0.18 ± 0.03, N=58 versus 0.40 ± 0.05, N=100, P<0.05). Importantly, SKP-derived VSMCs from subjects with T2D had higher Fluo-5F-determined baseline cytosolic Ca2+ concentrations (AU: 1,968 ± 160, N=7 versus 1,386 ± 170, N=13, P<0.05), and a trend toward greater Ca2+ cycling responses to norepinephrine (NE) (AUC: 177,207 ± 24,669, N=7 versus 101,537 ± 15,881, N=20, P<0.08) despite a reduced frequency of Ca2+ cycling (events s-1 cell-1: 0.011 ± 0.004, N=8 versus 0.021 ± 0.003, N=19, P<0.05) than those without T2D. SKP-derived VSMCs from subjects with T2D also manifest enhanced sensitivity to phenylephrine (PE) in an impedance-based assay (EC50 nM: 72.3 ± 63.6, N=5 versus 3,684 ± 3,122, N=9, P<0.05), and impaired wound closure in vitro (% closure: 21.9 ± 3.6, N=4 versus 67.0 ± 10.3, N=4, P<0.05). Compared with aortic- and saphenous vein-derived primary VSMCs, SKP-derived VSMCs are functionally distinct, but mirror defects of T2D also exhibited by primary VSMCs. CONCLUSION: Skin biopsies from older adults yield sufficient SKPs to differentiate VSMCs, which reveal abnormal phenotypes of T2D that survive differentiation and persist even after long-term normoglycemic culture.