Background

An increase in beat‐to‐beat variability of repolarization (BVR) predicts arrhythmia onset in experimental models, but its clinical translation is not well established. We investigated the temporal changes in BVR before nonsustained ventricular tachycardia (nsVT) in patients with implantable cardioverter defibrillator (ICD).

Methods and Results

Patients with nsVT on 24‐hour Holter before ICD implantation for ischemic cardiomyopathy (ischemic cardiomyopathy+nsVT, n=43) or dilated cardiomyopathy (dilated cardiomyopathy+nsVT, n=37), matched ICD candidates without nsVT (ischemic cardiomyopathy‐nsVT, n=29 and dilated cardiomyopathy‐nsVT, n=26), and patients without ICD without structural heart disease (n=50) were studied. Digital Holter recordings from these patients were analyzed using a modified fiducial segment averaging technique to detect the QT interval. The nsVT episodes were semi‐automatically identified and QT‐BVR was assessed 1‐, 5‐, and 30‐minutes before nsVT, and at rest (at 3:00 am). Resting BVR was higher in ICD patients compared with controls without structural heart disease. In ICD patients with nsVT, BVR increased significantly 1‐minute pre‐nsVT in ischemic cardiomyopathy (2.21±0.59 ms, versus 5 minutes pre‐nsVT: 1.78±0.50 ms, P<0.001) and dilated cardiomyopathy (2.09±0.57 ms, versus 5‐minutes pre‐nsVT: 1.58±0.51 ms, P<0.001), but not in patients without nsVT. In multivariable Cox regression analysis, pre‐nsVT BVR was a significant predictor for appropriate therapy during follow‐up.

Conclusions

Baseline BVR is elevated and temporal changes in BVR predict imminent nsVT events in patients with ICD independent of underlying cause. Real‐time BVR monitoring could be used to predict impending ventricular arrhythmia and allow preventive therapy to be incorporated into ICDs.

Background

The association between alcohol consumption, atrial substrate, and outcomes after atrial fibrillation (AF) ablation remains controversial. This study evaluated the impacts of drinking on left atrial substrate and AF recurrence after ablation.

Methods and Results

We prospectively enrolled 110 patients with AF without structural heart disease (64±12 years) from 2 institutions. High‐density left atrial electroanatomic mapping was performed using a high‐density grid multipolar catheter. We investigated the impact of alcohol consumption on left atrial voltage, left atrial conduction velocity, and AF ablation outcome. Patients were classified as abstainers (<1 drink/wk), mild drinkers (1–7 drinks/wk), or moderate‐heavy drinkers (>7 drinks/wk). High‐density mapping (mean 2287±600 points/patient) was performed on 49 abstainers, 27 mild drinkers, and 34 moderate‐heavy drinkers. Low‐voltage zone and slow‐conduction zone were identified in 39 (35%) and 54 (49%) patients, respectively. There was no significant difference in the proportions of low‐voltage zone and slow‐conduction zone among the 3 groups. The success rate after a single ablation was significantly lower in drinkers than in abstainers (79.3% versus 95.9% at 12 months; mean follow‐up, 18±8 months; P=0.013). The success rate after a single or multiple ablations was not significantly different among abstainers and drinkers. In multivariate analysis, alcohol consumption (P=0.02) and the presence of a low‐voltage zone (P=0.032) and slow‐conduction zone (P=0.02) were associated with AF recurrence after a single ablation, while low‐voltage zone (P=0.023) and slow‐conduction zone (P=0.024) were associated with AF recurrence after a single or multiple ablations.

Conclusions

Alcohol consumption was associated with AF recurrence after a single ablation but not changes in atrial substrate.

Background

As patients derive variable benefit from generator changes (GCs) of implantable cardioverter‐defibrillators (ICDs) with an original primary prevention (PP) indication, better predictors of outcomes are needed.

Methods and Results

In the National Cardiovascular Data Registry ICD Registry, patients undergoing GCs of initial non‐cardiac resynchronization therapy PP ICDs in 2012 to 2016, predictors of post‐GC survival and survival benefit versus control heart failure patients without ICDs were assessed. These included predicted annual mortality based on the Seattle Heart Failure Model, left ventricular ejection fraction (LVEF) >35%, and the probability that a patient's death would be arrhythmic (proportional risk of arrhythmic death [PRAD]). In 40 933 patients undergoing GCs of initial noncardiac resynchronization therapy PP ICDs (age 67.7±12.0 years, 24.5% women, 34.1% with LVEF >35%), Seattle Heart Failure Model–predicted annual mortality had the greatest effect size for decreased post‐GC survival (P<0.0001). Patients undergoing GCs of initial noncardiac resynchronization therapy PP ICDs with LVEF >35% had a lower Seattle Heart Failure Model–adjusted survival versus 23 472 control heart failure patients without ICDs (model interaction hazard ratio, 1.21 [95% CI, 1.11–1.31]). In patients undergoing GCs of initial noncardiac resynchonization therapy PP ICDs with LVEF ≤35%, the model indicated worse survival versus controls in the 21% of patients with a PRAD <43% and improved survival in the 10% with PRAD >65%. The association of the PRAD with survival benefit or harm was similar in patients with or without pre‐GC ICD therapies.

Conclusions

Patients who received replacement of an ICD originally implanted for primary prevention and had at the time of GC either LVEF >35% alone or both LVEF ≤35% and PRAD <43% had worse survival versus controls without ICDs.

Background

Despite improved outcomes associated with ticagrelor compared with clopidogrel in acute coronary syndrome (ACS), many studies have demonstrated slow adoption of ticagrelor in the United States because of its increased cost. Less is known about how ticagrelor is adopted when there is no added cost consideration. Our objectives were to determine patterns of use of ticagrelor, hospital‐level adoption of ticagrelor use, and factors associated with its use after ACS in a publicly funded health care system.

Methods and Results

We conducted a population‐based cohort study including patients (≥65 years) hospitalized with their first ACS from April 2014 to March 2018 in Ontario, Canada. We determined temporal trends in ticagrelor use and hospital‐level adoption of its use post‐ACS discharge. Using hierarchical regression models, we identified significant predictors of ticagrelor use. There were 23 962 patients with ACS (mean age 76.3 years, 59.7% men) hospitalized in 156 hospitals. Overall ticagrelor use increased from 32.6% in 2014/2015 to 51.8% in 2017/2018. There was substantial variation in ticagrelor use post‐ACS across hospitals, with hospital‐specific prescribing rates ranging from 0% to 83.6%. Lower odds of ticagrelor use was associated with advanced age and the presence of comorbidities. Besides patient factors, being admitted to a rurally located hospital more than halved the odds of being prescribed ticagrelor (odds ratio [OR], 0.49; 95% CI, 0.32–0.77). Being managed by a cardiologist during the index ACS hospitalization was associated with higher odds of having a ticagrelor prescription after ACS (OR, 2.80; 95% CI, 2.36–3.33).

Conclusions

Ticagrelor use rates varied substantially across hospitals and were strongly associated with physician and hospital factors independent of patient characteristics.

Background

The sympathetic cotransmitter, neuropeptide Y (NPY), is released into the coronary sinus during ST‐segment–elevation myocardial infarction and can constrict the coronary microvasculature. We sought to establish whether peripheral venous (PV) NPY levels, which are easy to obtain and measure, are associated with microvascular obstruction, myocardial recovery, and prognosis.

Methods and Results

NPY levels were measured immediately after primary percutaneous coronary intervention and compared with angiographic and cardiovascular magnetic resonance indexes of microvascular function. Patients were prospectively followed up for 6.4 (interquartile range, 4.1–8.0) years. PV (n=163) and coronary sinus (n=68) NPY levels were significantly correlated (r=0.92; P<0.001) and associated with multiple coronary and imaging parameters of microvascular function and infarct size (such as coronary flow reserve, acute myocardial edema, left ventricular ejection fraction, and late gadolinium enhancement 6 months later). We therefore assessed the prognostic value of PV NPY during follow‐up, where 34 patients (20.7%) developed heart failure or died. Kaplan‐Meier survival analysis demonstrated that high PV NPY levels (>21.4 pg/mL by binary recursive partitioning) were associated with increased incidence of heart failure and mortality (hazard ratio, 3.49 [95% CI, 1.65–7.4]; P<0.001). This relationship was maintained after adjustment for age, cardiovascular risk factors, and previous myocardial infarction.

Conclusions

Both PV and coronary sinus NPY levels correlate with microvascular function and infarct size after ST‐segment–elevation myocardial infarction. PV NPY levels are associated with the subsequent development of heart failure or mortality and may therefore be a useful prognostic marker. Further research is required to validate these findings.

Background

The plasma concentration of B‐type natriuretic peptide (BNP) is a strong predictor of adverse cardiovascular events. The aim of this study was to determine whether the association between plasma BNP concentration and cardiovascular mortality is sustained or diminishes with increasing time after BNP is measured.

Methods and Results

Six thousand seven hundred forty patients with a history of myocardial infarction or unstable angina who participated in the LIPID (Long‐Term Intervention with Pravastatin in Ischemic Disease) trial had plasma BNP concentration measured at baseline and after 1 year. Associations with cardiovascular mortality were evaluated in landmark analyses 1 to <5, 5 to <10, and 10 to 16 years after randomization. There were 1640 cardiovascular deaths. The cardiovascular mortality rate increased progressively from 10.2 to 19.1 to 26.3/1000 patient‐years from 1 to <5, 5 to <10, and 10 to 16 years after baseline, respectively. The average of baseline and 1‐year BNP concentration was more strongly associated with cardiovascular mortality compared with baseline or 1‐year BNP only. The hazard ratio (HR) for cardiovascular death associated with each doubling of average BNP concentration was similar during years 1 to <5 (HR, 1.53 [95% CI, 1.44–1.63]), years 5 to <10 (HR, 1.52 [95% CI, 1.44–1.60]), and years 10–16 (HR, 1.43 [95% CI, 1.36–1.50]), P<0.0001 for all.

Conclusions

BNP concentration remains an independent predictor of cardiovascular mortality more than a decade after it is measured. Because of random variation in plasma concentrations, the average of >1 BNP measurement improves long‐term risk prediction.

Background

Experimental studies show that high‐sodium intake affects the innate immune system, among others with increased circulating granulocytes. Whether this relationship exists on a population level and whether this relates to disease outcomes is unclear. We aimed to test the hypotheses that (1) sodium intake is associated with granulocytes on a population level; (2) granulocytes are associated with the presence of hypertension and both cardiovascular and renal outcomes; and (3) the relation between high‐sodium intake and these outcomes is mediated by granulocytes.

Methods and Results

We performed an analysis in 13 804 participants from the prospective EPIC (European Prospective Investigation into Cancer)‐Norfolk cohort, with a mean age of 58 years and median follow‐up of 19.3 years. Analyses were carried out using calculated estimated sodium intake and sodium‐to‐potassium ratios from spot urines at baseline. The main outcomes were hypertension at baseline, and composite cardiovascular (mortality or cardiovascular events) and renal (mortality or renal events) outcomes during follow‐up. Sodium intake and urine sodium‐to‐potassium ratio were positively associated with circulating granulocyte concentrations after adjustment for confounders (β=0.03; P=0.028 and β=0.06; P<0.001, respectively). Granulocytes significantly mediated the associations of, respectively, sodium intake and urine sodium‐to‐potassium ratio with hypertension at baseline, and cardiovascular and renal outcomes.

Conclusions

Sodium intake is positively associated with circulating granulocyte concentrations, and higher granulocyte concentrations associate with worse long‐term cardiovascular and renal outcomes. Given the recently established immune‐modulating effects of sodium and the role of immune cells in both cardiovascular and renal disease, causality for this pathway may need consideration in further studies.

Background

Rheumatic heart disease (RHD) takes a heavy toll in low‐ and middle‐income countries. We aimed to present worldwide estimates for the burden of the RHD during 1990 to 2019 using the GBD (Global Burden of Disease) study.

Methods and Results

Sociodemographic index (SDI) and age‐period‐cohort analysis were used to assess inequity. The age‐standardized death, disability‐adjusted life years, incidence, and prevalence rates of RHD were 3.9 (95% uncertainty interval, 3.3–4.3), 132.9 (95% uncertainty interval, 115.0–150.3), 37.4 (28.6–46.7), and 513.7 (405.0–636.3) per 100 000 in 2019, respectively. The age‐standardized incidence and prevalence rates increased by 14.4% and 13.8%, respectively. However, disability‐adjusted life years and death rates decreased by 53.1% and 56.9%, respectively. South Asia superregion had the highest age‐standardized disability‐adjusted life years and deaths. Sub‐Saharan Africa had the highest age‐standardized incidence and prevalence rates. There was a steep decline in RHD burden among higher‐SDI countries. However, only age‐standardized deaths and disability‐adjusted life years rates decreased in lower‐SDI countries. The age‐standardized years of life lost and years lived with disability rates for RHD significantly declined as countries' SDI increased. The coefficients of birth cohort effect on the incidence of RHD showed an increasing trend from 1960 to 1964 to 2015 to 2019; however, the birth cohort effect on deaths attributable to RHD showed unfailingly decreasing trends from 1910 to 1914 to 2015 to 2019.

Conclusions

There was a divergence in the burden of RHD among countries based on SDI levels, which calls for including RHD in global assistance and funding. Indeed, many countries are still dealing with an unfinished infectious disease agenda, and there is an urgency to act now to prevent an increase in future RHD burden.

Background

Cardiac rehabilitation (CR) is associated with improved cardiovascular outcomes. Racial and ethnic differences in CR have been identified, but whether income may attenuate these disparities remains unknown. We evaluated (1) racial/ethnic differences in CR participation in a contemporary sample of insured US adults, and (2) assessed how household income modifies associations between race or ethnicity and CR participation.

Methods and Results

We identified 107 199 individuals with a CR‐qualifying diagnosis between January 1, 2016 and December 31, 2018 in Optum’s de‐identified Clinformatics database. We evaluated associations between race or ethnicity and participation in CR, and assessed interaction between race or ethnicity and annual household income. The mean±SD age of all participants was 70.4±11.6 years; 37.4% were female and 76.0% were White race. Overall, 28 443 (26.5%) attended ≥1 CR sessions. After adjustment, compared with White individuals, the probability of attending CR was 31% lower for Asian individuals (95% CI, 27%–36%), 19% lower for Black individuals (95% CI, 16%–22%), and 43% lower for Hispanic individuals (95% CI, 40%–45%), all P<0.0001. The time to CR attendance was also significantly longer for Asian, Black, and Hispanic individuals. Associations between race or ethnicity and attendance at CR differed significantly across household income categories (P interaction=0.0005); however, Asian, Black, and Hispanic individuals were less likely to attend CR at all incomes.

Conclusions

In a geographically and racially diverse cohort, participation in CR was low overall, and was lowest among Asian, Black, and Hispanic candidates. Household income may impact the link between race or ethnicity and attendance at CR, but substantial racial and ethnic disparities exist across incomes.

Background

Acute aortic syndromes may be prone to misdiagnosis by nonreferral aortic centers with less diagnostic experience. We evaluated regional variability in these misdiagnosis trends among patients transferred to different regional quaternary care centers with presumed acute aortic syndromes.

Methods and Results

Two institutional aortic center databases were retrospectively reviewed for emergency transfers in patients diagnosed with acute aortic dissection, intramural hematoma, penetrating aortic ulcer, thoracic aortic aneurysm, or aortic pseudoaneurysm between 2008 and 2020. Transferring diagnoses versus actual diagnoses were reviewed using physician notes and radiology reports. Misdiagnoses were confirmed by a board‐certified cardiothoracic surgeon. A total of 3772 inpatient transfers were identified, of which 1762 patients were classified as emergency transfers. The mean age was 64 years (58% male). Patients were transferred from 203 medical centers by ground (51%) or air (49%). Differences in transfer diagnosis and actual diagnosis were identified in 188 (10.7%) patients. Of those, incorrect classification of Type A versus B dissections was identified among 23%, and 30% of patients with a referring diagnosis of an acute aortic dissection did not have one. In addition, 14% transferred for contained/impending rupture did not have signs of rupture. All misdiagnoses were secondary to misinterpretation of imaging, with motion artifacts (n=32, 17%) and postsurgical changes (n=44, 23%) being common sources of diagnostic error.

Conclusions

Misdiagnosis of acute aortic syndromes commonly occurred in patients transferred to 2 separate large aortic referral centers. Although diagnostic accuracy may be improving, there are opportunities for improved physician awareness through standardized web‐based imaging education.

Background

COVID‐19 is an infectious illness, featured by an increased risk of thromboembolism. However, no standard antithrombotic therapy is currently recommended for patients hospitalized with COVID‐19. The aim of this study was to evaluate safety and efficacy of additional therapy with aspirin over prophylactic anticoagulation (PAC) in patients hospitalized with COVID‐19 and its impact on survival.

Methods and Results

A total of 8168 patients hospitalized for COVID‐19 were enrolled in a multicenter‐international prospective registry (HOPE COVID‐19). Clinical data and in‐hospital complications, including mortality, were recorded. Study population included patients treated with PAC or with PAC and aspirin. A comparison of clinical outcomes between patients treated with PAC versus PAC and aspirin was performed using an adjusted analysis with propensity score matching. Of 7824 patients with complete data, 360 (4.6%) received PAC and aspirin and 2949 (37.6%) PAC. Propensity‐score matching yielded 298 patients from each group. In the propensity score‐matched population, cumulative incidence of in‐hospital mortality was lower in patients treated with PAC and aspirin versus PAC (15% versus 21%, Log Rank P=0.01). At multivariable analysis in propensity matched population of patients with COVID‐19, including age, sex, hypertension, diabetes, kidney failure, and invasive ventilation, aspirin treatment was associated with lower risk of in‐hospital mortality (hazard ratio [HR], 0.62; [95% CI 0.42–0.92], P=0.018).

Conclusions

Combination PAC and aspirin was associated with lower mortality risk among patients hospitalized with COVID‐19 in a propensity score matched population compared to PAC alone.

Background

P2Y12 inhibitor medications are critical following percutaneous coronary intervention (PCI); however, adherence remains suboptimal. Our objective was to assess the effectiveness of a multifaceted intervention to improve P2Y12 inhibitor adherence following PCI.

Methods and Results

This was a modified stepped wedge trial of 52 eligible hospitals, of which 15 were randomly selected and agreed to participate (29 hospitals declined, and 8 eligible hospitals were not contacted). At each intervention hospital, patient recruitment occurred for 6 months and enrolled patients were followed up for 1 year after PCI. Three control groups were used: patients at intervention hospitals undergoing PCI (1) before the intervention period (preintervention); (2) after the intervention period (postintervention); or (3) at the 8 hospitals not contacted (concurrent controls). The intervention consisted of 4 components: (1) P2Y12 inhibitor delivered to patients’ bedside after PCI; (2) education on importance of P2Y12 inhibitors; (3) automated reminder telephone calls to refill medication; and (4) outreach to patients if they delayed refilling P2Y12 inhibitor. The primary outcomes were as follows: (1) proportion of patients with delays filling P2Y12 inhibitor at hospital discharge and (2) proportion of patients who were adherent in the year after PCI using pharmacy refill data. Primary analysis compared intervention with preintervention control patients. There were 1377 (intent‐to‐treat) potentially eligible patients, of whom 803 (per protocol) were approached at intervention sites versus 5910 preintervention, 2807 postintervention, and 4736 concurrent control patients. In the intent‐to‐treat analysis, intervention patients were less likely to delay filling P2Y12 at hospital discharge (−3.4%; 98.3% CI, −1.2% to −5.6%) and more likely to be adherent to P2Y12 (4.1%; 98.3% CI, 1.0%–7.1%) at 1 year, but had more clinical events (3.2%; 98.3% CI, 2.3%–4.1%) driven by repeated PCI compared with preintervention patients. In post hoc analysis looking at myocardial infarction, stroke, and death, intervention patients had lower event rates compared with preintervention patients (−1.7%; 98.3% CI, −2.3% to –1.1%).

Conclusions

A 4‐component intervention targeting P2Y12 inhibitor adherence was difficult to implement. The intervention produced mixed results. It improved P2Y12 adherence, but there was also an increase in repeat PCI.

Registration

URL: https://www.clinicaltrials.gov; Unique identifier: NCT01609842.

Background

Sorbin and SH3 domain containing 2 (Sorbs2) protein is a cytoskeletal adaptor with an emerging role in cardiac biology and disease; yet, its potential relevance to adult‐onset cardiomyopathies remains underexplored. Sorbs2 global knockout mice display lethal arrhythmogenic cardiomyopathy; however, the causative mechanisms remain unclear. Herein, we examine Sorbs2 dysregulation in heart failure, characterize novel Sorbs2 cardiomyocyte‐specific knockout mice (Sorbs2‐cKO), and explore associations between Sorbs2 genetic variations and human cardiovascular disease.

Methods and Results

Bioinformatic analyses show myocardial Sorbs2 mRNA is consistently upregulated in humans with adult‐onset cardiomyopathies and in heart failure models. We generated Sorbs2‐cKO mice and report that they develop progressive systolic dysfunction and enlarged cardiac chambers, and they die with congestive heart failure at about 1 year old. After 3 months, Sorbs2‐cKO mice begin to show atrial enlargement and P‐wave anomalies, without dysregulation of action potential–associated ion channel and gap junction protein expressions. After 6 months, Sorbs2‐cKO mice exhibit impaired contractility in dobutamine‐treated hearts and skinned myofibers, without dysregulation of contractile protein expressions. From our comprehensive survey of potential mechanisms, we found that within 4 months, Sorbs2‐cKO hearts have defective microtubule polymerization and compensatory upregulation of structural cytoskeletal and adapter proteins, suggesting that this early intracellular structural remodeling is responsible for contractile dysfunction. Finally, we identified genetic variants that associate with decreased Sorbs2 expression and human cardiac phenotypes, including conduction abnormalities, atrial enlargement, and dilated cardiomyopathy, consistent with Sorbs2‐cKO mice phenotypes.

Conclusions

Our studies show that Sorbs2 is essential for maintaining structural integrity in cardiomyocytes, likely through strengthening the interactions between microtubules and other cytoskeletal proteins at cross‐link sites.

Background

Because body mass index (BMI) is generally used clinically to define obesity and to estimate body adiposity, BMI likely is positively correlated with epicardial adipose tissue (EAT) level. Based on echocardiography, previous outcomes on this matter have varied from almost absent to rather strong correlations between BMI and EAT. The purpose of our study was to unambiguously examine EAT content and determine if correlations exist between EAT content and BMI, cause of heart failure, or contractile force.

Methods and Results

We qualitatively scored 150 human hearts ex vivo on EAT distribution. From each heart, multiple photographs of the heart were taken, and both atrial and ventricular adipose tissue levels were semiquantitatively scored. Main findings include a generally higher EAT content on nonfailing hearts compared with end‐stage failing hearts (atrial adipose tissue level 5.70±0.13 vs. 5.00±0.12, P<0.001; ventricular adipose tissue level 5.14±0.16 vs. 4.57±0.12, P=0.0048). The results also suggest that EAT quantity is not strongly correlated with BMI in nonfailing (atrial adipose tissue level r=0.069, ventricular adipose tissue level r=0.14) or failing (atrial adipose tissue level r=−0.022, ventricular adipose tissue level r=0.051) hearts. Atrial EAT is closely correlated with ventricular EAT in both nonfailing (r=0.92, P<0.001) and failing (r=0.87, P<0.001) hearts.

Conclusions

EAT volume appears to be inversely proportional to severity of or length of time with heart failure based on our findings. Based on a lack of correlation with BMI, it is incorrect to assume high EAT volume given high body fat percentage.

Background

The HeartFull Collaborative is a regionally organized model of care which involves specialist palliative care and cardiology health care providers (HCPs) in a collaborative, home‐based palliative care approach for patients with advanced heart failure (AHF). We evaluated HCP perspectives of barriers and facilitators to providing coordinated palliative care for patients with AHF at home.

Methods and Results

We conducted a qualitative study with 17 HCPs (11 palliative care and 6 cardiology) who were involved in the HeartFull Collaborative from April 2013 to March 2020. Individual, semi‐structured interviews were held with each practitioner from November 2019 to March 2020. We used an interpretivist and inductive thematic analysis approach. We identified facilitators at 2 levels: (1) individual HCP level (on‐going professional education to expand competency) and (2) interpersonal level (shared care between specialties, effective communication within the care team). Ongoing barriers were identified at 2 levels: (1) individual HCP level (e.g. apprehension of cardiology practitioners to introduce palliative care) and (2) system level (e.g. lack of availability of personal support worker hours).

Conclusions

Our results suggest that a collaborative shared model of care delivery between palliative care and cardiology improves knowledge exchange, collaboration and communication between specialties, and leads to more comprehensive patient care. Addressing ongoing barriers will help improve care delivery. Findings emphasize the acceptability of the program from a provider perspective, which is encouraging for future implementation. Further research is needed to improve prognostication, assess patient and caregiver perspectives regarding this model of care, and assess the economic feasibility and impact of this model of care.

Background

Exercise‐induced high heart rate may impair exercise tolerance by reducing diastolic filling time and ventricular filling in heart failure with preserved ejection fraction (HFpEF). Given the importance of chronotropic response, we hypothesized that reduction in diastolic filling time because of exercise‐induced increased heart rate would not impair cardiac output reserve and exercise capacity. We sought to determine the association between heart rate, diastolic filling time, hemodynamics, and exercise capacity in HFpEF.

Methods and Results

Patients with HFpEF (n=66) and controls without HF (n=107) underwent bicycle exercise echocardiography with simultaneous expired gas analysis to measure oxygen consumption. Diastolic filling time was assessed by the overlap time between mitral E‐ and A‐waves (longer overlap time indicates shorter diastolic filling duration). Overlap time increased (ie, diastolic filling time shortened) in HFpEF and controls as heart rate increased with exercise, and the relationship was similar between the groups. Greater heart rate response correlated with higher cardiac output (r=0.51, P<0.0001) and oxygen consumption (r=0.50, P<0.0001) during peak exercise. Shorter diastolic filling time, as assessed by longer overlap time, was correlated with higher cardiac output (r=0.47, P<0.0001) and peak oxygen consumption (r=0.38, P=0.007), not with E/e′ or right ventricular‐pulmonary artery uncoupling. Longer overlap time was associated with mitral A velocity (r=0.53, P<0.0001) and left atrial booster pump strain (r=0.42, P<0.0001).

Conclusions

Shortening of diastolic filling interval in tandem with increased heart rate during exercise does not limit cardiac output reserve or exercise capacity in HFpEF.

Background

Dilated cardiomyopathy remains a leading cause of heart failure worldwide. Immune inflammation response is recognized as a significant player in the progression of heart failure; however, immunomodulatory strategies remain a long‐term challenge. Colchicine, a potent anti‐inflammatory drug, has many benefits in ischemic cardiovascular events, but its role in nonischemic heart failure remains unclear.

Methods and Results

Doxorubicin administration was used to establish a murine dilated cardiomyopathy model, and colchicine or saline was orally given. At the end point, cardiac function and fibrosis were measured to investigate the effects of colchicine. Inflammatory cytokine levels, neutrophil recruitment, and NLRP3 (NOD‐like receptor protein 3) inflammasome activation were detected to evaluate the inflammatory response. Furthermore, to examine the downstream target of colchicine, SIRT2 (Sirtuin 2) was pharmacologically inhibited in vitro; thus, changes in the NLRP3 inflammasome were detected by immunoblotting. These results showed that murine cardiac function was significantly improved and fibrosis was significantly alleviated after colchicine treatment. Moreover, the infiltration of neutrophils and the levels of inflammatory cytokines in the failing myocardium were both decreased by colchicine treatment. Mechanistically, colchicine upregulated the expression of SIRT2, leading to the inactivation of the NLRP3 inflammasome in an NLRP3 deacetylated manner. Conversely, the inhibition of SIRT2 attenuated the suppressive effect of colchicine on NLRP3 inflammasome activation.

Conclusions

This study indicated that colchicine could be a promising therapeutic candidate for dilated cardiomyopathy and other nonischemic heart failure associated with the inflammatory response.

Background

Patients with arrhythmogenic right ventricular cardiomyopathy are at risk for life‐threatening ventricular tachyarrhythmias, but progressive heart failure (HF) may occur in later stages of disease. This study aimed to characterize potential risk predictors and develop a model for individualized assessment of adverse HF outcomes in arrhythmogenic right ventricular cardiomyopathy.

Methods and Results

Longitudinal and observational cohorts with 290 patients with arrhythmogenic right ventricular cardiomyopathy from the Fuwai Hospital in Beijing, China, and 99 patients from the University Heart Center in Zurich, Switzerland, with follow‐up data were studied. The primary end point of the study was heart transplantation or death attributable to HF. The model was developed by Cox regression analysis for predicting risk and was internally validated. During 4.92±3.03 years of follow‐up, 48 patients reached the primary end point. The determinants of the risk prediction model were left ventricular ejection fraction, serum creatinine levels, moderate‐to‐severe tricuspid regurgitation, and atrial fibrillation. Implantable cardioverter‐defibrillators did not reduce the occurrence of adverse HF outcomes.

Conclusions

A novel risk prediction model for arrhythmogenic right ventricular cardiomyopathy has been developed using 2 large and well‐established cohorts, incorporating common clinical parameters such as left ventricular ejection fraction, serum creatinine levels, tricuspid regurgitation, and atrial fibrillation, which can identify patients who are at risk for terminal HF events, and may guide physicians to assess individualized HF risk and to optimize management strategies.

Background

In the population with cardiac sarcoidosis (CS), approximately one third lacks extracardiac involvement and is considered to have isolated CS. Recently, the Japanese Circulation Society updated the diagnostic criteria for CS, providing a methodology for diagnosing isolated CS. We aimed to assess the characteristics of isolated CS diagnosed using a multimodal imaging approach according to the updated Japanese Circulation Society guidelines.

Methods and Results

We retrospectively identified 161 consecutive patients who underwent 18F‐fluorodeoxyglucose positron emission tomography for suspected CS between 2012 and 2019. According to the guidelines, patients were classified as having CS with extracardiac involvement, isolated CS, or no CS. We compared the characteristics of multimodality imaging and the prevalence of major adverse cardiovascular events. The Japanese Circulation Society criteria classified 28 patients (17%) as having CS with 4 (2%) with histological confirmation, 21 (13%) as isolated CS, and 112 (70%) as no CS. Compared with CS, isolated CS showed higher left ventricular volume and reduced left ventricular ejection fraction (P<0.01 for all). During the median follow‐up period of 522 days, 24 patients had major adverse cardiovascular events. Isolated CS (hazard ratio, 3.35; [95% CI, 1.08–10.39], P=0.036) was independently associated with major adverse cardiovascular events after adjusting for reduced left ventricular ejection fraction and steroid. In the subgroup of 41 patients with serial 18F‐fluorodeoxyglucose positron emission tomography evaluation, only updated CS criteria were associated with improvement in myocardial inflammation on 18F‐fluorodeoxyglucose positron emission tomography.

Conclusions

Isolated CS detected using the updated Japanese Circulation Society guidelines was associated with poor event‐free survival and should be managed with caution.

Background

Short chain fatty acids (SCFAs) are microbially derived end products of dietary fiber fermentation. The SCFA butyrate reduces blood pressure (BP) in mouse models. The association of SCFAs, including butyrate, with BP in humans is unclear, due in part to predominantly cross‐sectional analyses and different biospecimens (blood versus fecal) for SCFA measurement. Longitudinal studies including both circulating and fecal SCFAs are lacking.

Methods and Results

We leveraged existing data from the SPIRIT (Survivorship Promotion In Reducing IGF‐1 Trial), which randomized 121 adult cancer survivors with overweight/obesity to a behavioral weight‐loss intervention, metformin, or self‐directed weight‐loss. Of participants with baseline serum and fecal SCFAs measured (n=111), a subset had serum (n=93) and fecal (n=89) SCFA measurements 12 months later. We used Poisson regression with robust error variance to estimate baseline associations of SCFAs with hypertension, and we assessed the percent change in SCFAs from baseline with corresponding 12‐month changes in BP using multiple linear regression. Baseline fecal butyrate was inversely associated with prevalent hypertension (standardized PR [95%CI]: 0.71 [0.54, 0.92]). A 10% increase in fecal butyrate from baseline was associated with decreased systolic BP (β [95%CI]: −0.56 [−1.01, −0.10] mm Hg), and a 10% increase in serum butyrate was associated with decreased systolic (β [95%CI]: −1.39 [−2.15, −0.63] mm Hg) and diastolic (β [95%CI]: −0.55 [−1.03, −0.08] mm Hg) BPs. Butyrate associations with systolic BP were linear and not modified by sex, race, or intervention arm.

Conclusions

Increased serum or fecal butyrate is associated with lowered BP. Butyrate may be a target for SCFA‐centered BP‐lowering interventions.

Registration

URL: https://www.clinicaltrials.gov; Unique identifier: NCT02431676.

Background

Primary aldosteronism can cause cardiac dysfunction, including left ventricular hypertrophy, left ventricular diastolic dysfunction, and left atrial enlargement. A few studies have compared the cardioprotective effects between surgery and medication for primary aldosteronism, although most have not adjusted for baseline disease status. In this study, we investigated the difference in cardiovascular outcomes between surgery and medication treatment for primary aldosteronism after adjusting for baseline clinical characteristics, including aldosterone level and pretreatment echocardiographic information.

Methods and Results

We retrospectively analyzed 220 patients diagnosed with primary aldosteronism who underwent adrenalectomy (n=144) or medication treatment (n=76) between 2009 and 2019. Echocardiographic changes were evaluated pretreatment and 1 year posttreatment. The surgery group had lower potassium, lower plasma renin activity, and higher plasma aldosterone concentration than the medication group, indicating a severe primary aldosteronism phenotype in the former. The decrease in left ventricular mass index after treatment was significantly greater in the surgery group than in the medication group (P=0.047). However, this relationship was not noted after multivariable regression analysis (standard β=−0.08, P=0.17). Additionally, decreased parameter values related to left ventricular diastolic dysfunction and left atrial enlargement were not different between the groups. Pretreatment echocardiographic values were most associated with changes in all echocardiographic parameters. The findings were consistent in the propensity score‐matched analysis.

Conclusions

This study's findings suggest that there is no difference in cardioprotective efficacy between surgical and medication treatment under similar disease severity; however, it should be considered that several study participants with severe hyperaldosteronism were managed surgically.

Background

Hypertension and diabetes frequently coexist; however, it has not yet been clarified if the bidirectional longitudinal relationships between arterial stiffness and hypertension are independent of those between arterial stiffness and diabetes.

Methods and Results

In this 16‐year prospective observational study, 3960 middle‐aged employees of a Japanese company without hypertension/diabetes at the study baseline underwent annual repeated measurements of blood pressure, serum glycosylated hemoglobin A_1c levels, and brachial‐ankle pulse wave velocity. By the end of the study period, 664, 779, 154, and 406 subjects developed hypertension, prehypertension, diabetes, and prediabetes, respectively. Increased brachial‐ankle pulse wave velocity at the baseline was associated with a significant odds ratio (per 1 SD increase) for new onset of prehypertension/hypertension with (2.45/3.28; P<0.001) or without (2.49/2.76; P<0.001) coexisting prediabetes/diabetes, but not for new onset of prediabetes/diabetes without coexisting hypertension. Analyses using the latent growth curve model confirmed the bidirectional relationships between brachial‐ankle pulse wave velocity and hypertension, but no such relationship was observed between brachial‐ankle pulse wave velocity and abnormal glucose metabolism.

Conclusions

In middle‐aged employees of a Japanese company, while bidirectional relationships were found to exist between increased arterial stiffness and hypertension, such a relationship was not found between increased arterial stiffness and diabetes. Therefore, it appears that increased arterial stiffness may be associated with the development of hypertension but not with that of diabetes.

Background

Chagas disease is a neglected tropical disease that is still considered a global health emergency. In the Amazon region, most of the reports are of acute cases that are associated with oral transmission. This study aimed to evaluate myocardial injury in patients with acute Chagas disease before and after treatment.

Methods and Results

We evaluated 23 patients with acute Chagas disease in 3 different stages of progression. Group 1 had 12 patients evaluated during the acute phase, at the time of diagnosis, and 1 year after treatment, and Group 2 had 11 patients in the late postacute phase who were evaluated 5.2 years on average after diagnosis and treatment. ECGs with the Selvester score, 24‐hour Holter exam, and cardiovascular magnetic resonance imaging were performed. The mean age of the 23 patients was 44.3±18.9 years, and they were mostly men (15/65.24%) from Amazonas state (22/95.6%). In 69.6% (n=16) of the patients, some ECG alterations were found, the most frequent being left anterior fascicular block and ventricular repolarization. In Group 1, the 24‐hour Holter exam showed atrial tachycardia in 3 (25%) patients and ventricular extrasystoles in 2 (16.7%) patients. In Group 2, 1 patient had ventricular extrasystoles. Myocardial injury was observed in 7 patients (58.3%) at the acute phase and in 5 (50%) patients at the 1‐year follow‐up in Group 1 and in 2 (18.2%) patients in Group 2.

Conclusions

This article describes, for the first time, myocardial injury shown by cardiovascular magnetic resonance imaging in a group of patients with acute Chagas disease and reveals the importance of early detection and follow‐up of the cardiac impairment in these patients.

Background

Patients with suspected ST‐segment–elevation myocardial infarction (STEMI) and cardiac catheterization laboratory nonactivation (CCL‐NA) or cancellation have reportedly similar crude and higher adjusted risks of death compared with those with CCL activation, though reasons for these poor outcomes are not clear. We determined late clinical outcomes among patients with prehospital ECG STEMI criteria who had CCL‐NA compared with those who had CCL activation.

Methods and Results

We identified consecutive prehospital ECG transmissions between June 2, 2010 to October 6, 2016. Diagnoses according to the Fourth Universal Definition of myocardial infarction (MI), particularly rates of myocardial injury, were adjudicated. The primary outcome was all‐cause death. Secondary outcomes included cardiovascular death/MI/stroke and noncardiovascular death. To explore competing risks, cause‐specific hazard ratios (HRs) were obtained. Among 1033 included ECG transmissions, there were 569 (55%) CCL activations and 464 (45%) CCL‐NAs (1.8% were inappropriate CCL‐NAs). In the CCL activation group, adjudicated index diagnoses included MI (n=534, 94%, of which 99.6% were STEMI and 0.4% non‐STEMI), acute myocardial injury (n=15, 2.6%), and chronic myocardial injury (n=6, 1.1%). In the CCL‐NA group, diagnoses included MI (n=173, 37%, of which 61% were non‐STEMI and 39% STEMI), chronic myocardial injury (n=107, 23%), and acute myocardial injury (n=47, 10%). At 2 years, the risk of all‐cause death was higher in patients who had CCL‐NA compared with CCL activation (23% versus 7.9%, adjusted risk ratio, 1.58, 95% CI, 1.24–2.00), primarily because of an excess in noncardiovascular deaths (adjusted HR, 3.56, 95% CI, 2.07–6.13). There was no significant difference in the adjusted risk for cardiovascular death/MI/stroke between the 2 groups (HR, 1.23, 95% CI, 0.87–1.73).

Conclusions

CCL‐NA was not primarily attributable to missed STEMI, but attributable to “masquerading” with high rates of non‐STEMI and myocardial injury. These patients had worse late outcomes than patients who had CCL activation, mainly because of higher rates of noncardiovascular deaths.

Background

Few studies have examined the association between the early diastolic mitral inflow velocity/early diastolic mitral annulus velocity ratio (E/e’) and chronic kidney disease progression.

Methods and Results

We reviewed data from 2238 patients with nondialysis chronic kidney disease from the KNOW‐CKD (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease); data from 163 patients were excluded because of missing content. A >50% decrease in estimated glomerular filtration rate from baseline, doubling of serum creatinine, or dialysis initiation and/or kidney transplantation were considered renal events. At baseline, median (interquartile range) ejection fraction and E/e’ were 64.0% (60.0%–68.0%) and 9.1 (7.4–11.9), respectively. Proportions of ejection fraction <50% and E/e’ ≥15 were 1.3% and 9.6%, respectively. More than one quarter of patients (27.2%) had an estimated glomerular filtration rate <30 mL/min per 1.73 m². During the mean 59.1‐month follow‐up period, 724 patients (34.9%) experienced renal events. In multivariable Cox proportional hazard regression analysis, the hazard ratio with 95% CI per 1‐unit increase in E/e’ was 1.027 (1.005–1.050; P=0.016). Penalized spline curve analysis yielded a suggested threshold of E/e’ for renal events of 12; in our data set, the proportion of E/e’ ≥12 was 4.1%.

Conclusions

Increased E/e’ was associated with an increased hazard of renal events, suggesting that diastolic heart dysfunction is a novel risk factor for chronic kidney disease progression.

Background

Mice with cardiomyocyte‐specific deletion of Bmal1, a core clock gene, had spontaneous abnormal cardiac metabolism, dilated cardiomyopathy, and shortened lifespan. However, the role of cardiomyocyte Bmal1 in pressure overload induced cardiac remodeling is unknown. Here we aimed to understand the contribution of cardiomyocyte Bmal1 to cardiac remodeling in response to pressure overload induced by transverse aortic constriction or chronic angiotensin Ⅱ (AngⅡ) infusion.

Methods and Results

By generating a tamoxifen‐inducible cardiomyocyte‐specific Bmal1 knockout mouse line (cKO) and challenging the mice with transverse aortic constriction or AngⅡ, we found that compared to littermate controls, the cKO mice displayed remarkably increased cardiac hypertrophy and augmented fibrosis both after transverse aortic constriction and AngⅡ induction, as assessed by echocardiographic, gravimetric, histologic, and molecular analyses. Mechanistically, RNA‐sequencing analysis of the heart after transverse aortic constriction exposure revealed that the PI3K/AKT signaling pathway was significantly activated in the cKOs. Consistent with the in vivo findings, in vitro study showed that knockdown of Bmal1 in cardiomyocytes significantly promoted phenylephrine‐induced cardiomyocyte hypertrophy and triggered fibroblast‐to‐myofibroblast differentiation, while inhibition of AKT remarkedly reversed the pro‐hypertrophy and pro‐fibrosis effects of Bmal1 knocking down.

Conclusions

These results suggest that postnatal deletion of Bmal1 in cardiomyocytes may promote pressure overload‐induced cardiac remodeling. Moreover, we identified PI3K/AKT signaling pathway as the potential mechanistic ties between Bmal1 and cardiac remodeling.

Background

Histidyl dipeptides such as carnosine are present in a micromolar to millimolar range in mammalian hearts. These dipeptides facilitate glycolysis by proton buffering. They form conjugates with reactive aldehydes, such as acrolein, and attenuate myocardial ischemia–reperfusion injury. Although these dipeptides exhibit multifunctional properties, a composite understanding of their role in the myocardium is lacking.

Methods and Results

To identify histidyl dipeptide–mediated responses in the heart, we used an integrated triomics approach, which involved genome‐wide RNA sequencing, global proteomics, and unbiased metabolomics to identify the effects of cardiospecific transgenic overexpression of the carnosine synthesizing enzyme, carnosine synthase (Carns), in mice. Our result showed that higher myocardial levels of histidyl dipeptides were associated with extensive changes in the levels of several microRNAs, which target the expression of contractile proteins, β‐fatty acid oxidation, and citric acid cycle (TCA) enzymes. Global proteomic analysis showed enrichment in the expression of contractile proteins, enzymes of β‐fatty acid oxidation, and the TCA in the Carns transgenic heart. Under aerobic conditions, the Carns transgenic hearts had lower levels of short‐ and long‐chain fatty acids as well as the TCA intermediate—succinic acid; whereas, under ischemic conditions, the accumulation of fatty acids and TCA intermediates was significantly attenuated. Integration of multiple data sets suggested that β‐fatty acid oxidation and TCA pathways exhibit correlative changes in the Carns transgenic hearts at all 3 levels.

Conclusions

Taken together, these findings reveal a central role of histidyl dipeptides in coordinated regulation of myocardial structure, function, and energetics.

Background

The metabolite succinate accumulates during cardiac ischemia. Within 5 minutes of reperfusion, succinate returns to baseline levels via both its release from cells and oxidation by mitochondrial complex II. The latter drives reactive oxygen species (ROS) generation and subsequent opening of the mitochondrial permeability transition (PT) pore, leading to cell death. Targeting succinate dynamics (accumulation/oxidation/release) may be therapeutically beneficial in cardiac ischemia–reperfusion (IR) injury. It has been proposed that blocking MCT1 (monocarboxylate transporter 1) may be beneficial in IR injury, by preventing succinate release and subsequent engagement of downstream inflammatory signaling pathways. In contrast, herein we hypothesized that blocking MCT1 would retain succinate in cells, exacerbating ROS generation and IR injury.

Methods and Results

Using the mitochondrial ROS probe mitoSOX and a custom‐built murine heart perfusion rig built into a spectrofluorometer, we measured ROS generation in situ during the first moments of reperfusion. We found that acute MCT1 inhibition enhanced mitochondrial ROS generation at reperfusion and worsened IR injury (recovery of function and infarct size). Both of these effects were abrogated by tandem inhibition of mitochondrial complex II, suggesting that succinate retention worsens IR because it drives more mitochondrial ROS generation. Furthermore, using the PT pore inhibitor cyclosporin A, along with monitoring of PT pore opening via the mitochondrial membrane potential indicator tetramethylrhodamine ethyl ester, we herein provide evidence that ROS generation during early reperfusion is upstream of the PT pore, not downstream as proposed by others. In addition, pore opening was exacerbated by MCT1 inhibition.

Conclusions

Together, these findings highlight the importance of succinate dynamics and mitochondrial ROS generation as key determinants of PT pore opening and IR injury outcomes.

Background

The aim of this study was to investigate the association between hsCRP (high‐sensitivity C‐reactive protein) and prognosis over time after stroke onset.

Methods and Results

In this prespecified prospective substudy of the Third China National Stroke Registry, a total of 9438 patients with acute ischemic stroke or transient ischemic attack and measured hsCRP were included. Patients were categorized into 3 groups according to the sampling time after index onset (<24 hours, 24–72 hours, 72 hours–8 days). The outcomes consisted of stroke recurrence and combined vascular events within 1 year, and dependence or death defined as modified Rankin Scale score of 3 to 6 at 1 year. The associations between hsCRP and outcomes in different groups were analyzed by using Cox proportional hazards and logistic regression models. The median levels of hsCRP within 24 hours, between 24 and 72 hours and between 72 hours and 8 days were 2.01, 1.72, and 1.72 mg/L, respectively (P < 0.05). Compared with the bottom quartile, patients in the top quartile measured within 72 hours were at increased risk of recurrent stroke (<24 hours: adjusted hazard ratio [HR], 1.57 [95% CI, 1.05–2.35], P = 0.03; 24–72 hours: adjusted HR, 1.60 [95% CI, 1.18–2.17], P = 0.003). Association was attenuated after further adjusting for the Org 10 172 test in the Treatment of Acute Stroke classification (<24 hours: adjusted HR, 1.51 [95% CI, 1.01–2.27]; P = 0.05; 24–72 hours: adjusted HR, 1.55 [95% CI, 1.14–2.10]; P = 0.01). The association only existed in patients with large‐artery atherosclerosis (adjusted HR, 1.68 [95% CI, 1.06–2.64]; P = 0.03). However, the association was not found in the hsCRP level measured between 72 hours and 8 days. Similar results were found for the outcome of combined vascular events. Additionally, hsCRP levels measured between 24 and 72 hours were associated with an increased risk of poor functional outcomes.

Conclusions

Elevated levels of hsCRP measured in the first 72 hours after ischemic stroke or transient ischemic attack but not 72 hours to 8 days, were associated with an increased risk of 1‐year stroke recurrence.

Background

Many patients with symptomatic severe aortic stenosis do not undergo aortic valve replacement (AVR) despite clinical guidelines. This study analyzed the association of managing provider type with cardiac specialist follow‐up, AVR, and mortality for patients with newly diagnosed severe aortic stenosis (sAS).

Methods and Results

We identified adults with newly diagnosed sAS per echocardiography performed between January 2017 and March 2019 using Optum electronic health record data. We then selected from those meeting all eligibility criteria patients managed by a primary care provider (n=1707 [25%]) or cardiac specialist (n=5039 [75%]). We evaluated the association of managing provider type with cardiac specialist follow‐up, AVR, and mortality, as well as the independent association of cardiac specialist follow‐up and AVR with mortality, within 1 year of echocardiography detecting sAS. A subgroup analysis was limited to patients with symptomatic sAS. Patient characteristics and comorbidities at baseline were used for covariate‐adjusted cause‐specific and multivariable Cox proportional hazard models assessing group differences in outcomes by managing provider type. An adjusted Cox proportional hazard model with additional time‐dependent covariates for follow‐up and AVR was used to assess these practices' association with mortality. Within 1 year of echocardiography detecting sAS, data revealed that primary care provider management was associated with lower rates of cardiac specialist follow‐up (hazard ratio [HR], 0.47 [95% CI, 0.43–0.50], P<0.0001) and AVR (HR, 0.58 [95% CI, 0.53–0.64], P<0.0001) and with higher 1‐year mortality (HR, 1.45 [95% CI, 1.26–1.66], P<0.0001). Cardiac specialist follow‐up and AVR were independently associated with lower mortality (follow‐up: HR, 0.55 [95% CI, 0.48–0.63], P<0.0001; AVR: HR, 0.70 [95% CI, 0.60–0.83], P<0.0001). Results were similar for patients with symptomatic sAS. All analyses were adjusted for baseline patient characteristics and comorbidities.

Conclusions

For patients newly diagnosed with sAS, we observed differences in rates of cardiac specialist follow‐up and AVR and risk of mortality between primary care provider‐ versus cardiologist‐managed patients with sAS. In addition, a lower likelihood of receiving follow‐up and AVR was independently associated with higher mortality.

Background

Pulmonary embolism (PE) has a long‐term risk of adverse events, which can be prevented by extended anticoagulation. We compared clinical characteristics and outcomes between patients treated with 2‐year extended anticoagulation and those who were not, in a population who had completed an initial phase of 3 to 6 months of anticoagulant therapy after acute PE.

Methods and Results

Observational cohort analysis of patients with PE who survived an initial phase of 3 to 6 months anticoagulation. Primary efficacy outcome was all‐cause death or recurrent venous thromboembolism. Primary safety outcome was major bleeding. In total, 858 (71.5%) patients were treated with and 341 (28.5%) were treated without extended anticoagulant therapy during the active study period. Age <65 years, intermediate‐high or high‐risk index PE, normal platelet count, and the absence of concomitant antiplatelet treatment were independently associated with the prescription of extended anticoagulation. The mean duration of the active phase was 2.1±0.3 years. The adjusted rate of the primary efficacy outcome was 2.1% in the extended group and 7.7% in the nonextended group (P<0.001) for patients treated with extended anticoagulant therapy. Rate of bleeding were similar between the extended anticoagulant group and the nonextended group.

Conclusions

Extended oral anticoagulation over 2 and a half years after index PE seems to provide a net clinical benefit compared with no anticoagulation in patients with PE selected to receive extended anticoagulation. Randomized clinical trials are warranted to explore the potential benefit of extended anticoagulation in patients with PE, especially those with transient provoking factors but residual risk.

Background

Sex‐specific differences in vasodilation are mediated in part by differences in cytosolic Ca²⁺ handling, but how variations in mitochondrial Ca²⁺ contributes to this effect remains unknown. Here, we investigated the extent to which mitochondrial Ca²⁺ entry via the MCU (mitochondrial Ca²⁺ uniporter) drives sex differences in vasoreactivity in resistance arteries.

Methods and Results

Enhanced vasodilation of mesenteric resistance arteries to acetylcholine (ACh) was reduced to larger extent in female compared with male mice in 2 genetic models of endothelial MCU ablation. Ex vivo Ca²⁺ imaging of mesenteric arteries with Fura‐2AM confirmed higher cytosolic Ca²⁺ transients triggered by ACh in arteries from female mice versus male mice. MCU inhibition both strongly reduced cytosolic Ca²⁺ transients and blocked mitochondrial Ca²⁺ entry. In cultured human aortic endothelial cells, treatment with physiological concentrations of estradiol enhanced cytosolic Ca²⁺ transients, Ca²⁺ buffering capacity, and mitochondrial Ca²⁺ entry in response to ATP or repeat Ca²⁺ boluses. Further experiments to establish the mechanisms underlying these effects did not reveal significant differences in the expression of MCU subunits, at either the mRNA or protein level. However, estradiol treatment was associated with an increase in mitochondrial mass, mitochondrial fusion, and the mitochondrial membrane potential and reduced mitochondrial superoxide production.

Conclusions

Our data confirm that mitochondrial function in endothelial cells differs by sex, with female mice having enhanced Ca²⁺ uptake capacity, and that these differences are attributable to the presence of more mitochondria and a higher mitochondrial membrane potential in female mice rather than differences in composition of the MCU complex.

Background

Health state utility values are commonly used to provide summary measures of health‐related quality of life in studies of stroke. Contemporaneous summaries are needed as a benchmark to contextualize future observational studies and inform the effectiveness of interventions aimed at improving post‐stroke quality of life.

Methods and Results

We conducted a systematic search of the literature using Medline, EMBASE, and Web of Science from January 1995 until October 2020 using search terms for stroke, health‐related quality of life, and indirect health utility metrics. We calculated pooled estimates of health utility values for EQ‐5D‐3L, EQ‐5D‐5L, AQoL, HUI2, HUI3, 15D, and SF‐6D using random effects models. For the EQ‐5D‐3L we conducted stratified meta‐analyses and meta‐regression by key subgroups. We screened 14 251 abstracts and 111 studies met our inclusion criteria (sample size range 11 to 12 447). EQ‐5D‐3L was reported in 78% of studies (study n=87; patient n=56 976). The pooled estimate for EQ‐5D‐3L at ≥3 months following stroke was 0.65 (95% CI, 0.63–0.67), which was ≈20% below population norms. There was high heterogeneity (I²>90%) between studies, and estimates differed by study size, case definition of stroke, and country of study. Women, older individuals, those with hemorrhagic stroke, and patients prior to discharge had lower pooled EQ‐5D‐3L estimates.

Conclusions

Pooled estimates of health utility for stroke survivors were substantially below population averages. We provide reference values for health utility in stroke to support future clinical and economic studies and identify subgroups with lower healthy utility.

Registration

URL: https://www.crd.york.ac.uk/prospero/. Unique Identifier: CRD42020215942.

Background

Several studies investigated the role of selective serotonin reuptake inhibitors (SSRIs) in improving poststroke recovery; thus, we have decided to conduct this systematic review and meta‐analysis to investigate the efficacy and safety of SSRIs in poststroke recovery.

Methods and Results

In this meta‐analysis we searched the following databases: PubMed, Cochrane, Scopus, and Google Scholar. The studies were included if they were placebo‐controlled trials in design and reported SSRIs’ effects on poststroke depression, anxiety, disability, dependence, motor abilities, and cognitive functions. The quality of the included studies was assessed using the revised Cochrane risk‐of‐bias tool for randomized trials. The search yielded 44 articles that included 16 164 patients, and about half of the participants were treated with SSRIs. Our results showed that SSRIs had a significant effect on preventing depression (weighted mean difference [WMD], −7.05 [95% CI, −11.78 to −2.31]), treating depression according to the Hamilton Rating Scale for Depression score (WMD, −1.45 [95% CI, −2.77 to −0.14]), anxiety (relative risk, 0.23 [95% CI, 0.09–0.61]), dependence (WMD, 8.86 [95% CI, 1.23–16.48]), motor abilities according to National Institutes of Health Stroke Scale score (WMD, −0.79 [95% CI, −1.42 to −0.15]), and cognitive functions (WMD, 1.00 [95% CI, 0.12–1.89]). On the other hand, no significant effect of SSRIs on disability was observed. Additionally, we found that treating with SSRIs increased the risk of seizures (relative risk, 1.44 [95% CI, 1.13–1.83]), whereas there was no difference in the incidence of gastrointestinal symptoms or bleeding between SSRIs and a placebo.

Conclusions

Our study showed that SSRIs are effective in preventing and treating depression, and improving anxiety, motor function, cognitive function, and dependence in patients after stroke. These benefits were only reproducible with the citalopram subanalysis but not fluoxetine. Further well‐conducted placebo‐controlled trials are needed to investigate the safety and efficacy of citalopram among patients after stroke.

Registration

URL: www.crd.york.ac.uk/prospero/; Unique identifier: CRD42021285766.

Background

In patients with ductal‐dependent pulmonary blood flow, initial palliation includes catheter‐based patent ductus arteriosus (PDA) stent or surgical aortopulmonary shunt (APS). This meta‐analysis aimed to compare outcomes between PDA stent and APS.

Methods and Results

A comprehensive literature search yielded six retrospective observational studies. Pooled adjusted hazard ratios (HR) were included to control for covariates and assess time to event analysis. Of 757 patients, 243 (32.1%) underwent PDA stent and 514 (67.9%) underwent APS. Pulmonary atresia with intact ventricular septum and expected biventricular repair were more common with PDA stent compared with APS (39.6% versus 21.2%, P<0.001 and 57.9% versus 46.6%, P=0.007, respectively). There was no statistically significant difference in mortality between PDA stent and APS (HR, 0.71; [95% CI, 0.26–1.93]; P=0.50). PDA stent was associated with lower risk of postprocedural complications (odds ratio [OR], 0.45; [95% CI, 0.25–0.81]; P=0.008), mechanical circulatory support (OR, 0.27; [95% CI, 0.09–0.79]; P=0.02), and shorter intensive care unit length of stay (−4.03 days; [95% CI, −5.99 to −2.07]; P<0.001), hospital length of stay (−5.54 days; [95% CI, −9.20 to −1.88]; P=0.003), and duration of mechanical ventilation (−3.41 days; [95% CI, −5.29 to −1.52]; P<0.001). There was no difference in pulmonary artery growth or hazard of unplanned reintereventions.

Conclusions

PDA stent has a similar hazard of mortality compared with APS. Benefits to PDA stent include shorter duration of mechanical ventilation, shorter hospital length of stay, and fewer complications. Differences in patient characteristics exist with more patients with pulmonary atresia with intact ventricular septum and expected biventricular repair undergoing PDA stent.

Background

The GWTG (Get With The Guidelines)‐Stroke registry supports clinical research and quality improvement projects that often rely on past medical history elements, the reliability of which remains largely unknown. Here, we evaluated the reliability of specific past medical history elements in a local GWTG–Stroke data set, with particular attention to calculating the CHA₂DS₂‐VASc score.

Methods and Results

A single‐center cohort was identified by querying the Hospital of the University of Pennsylvania’s GWTG IQVIA Registry Platform for patients admitted with acute ischemic stroke between January 2017 and December 2020, with a previously known history of atrial fibrillation. Demographics and previously known medical history elements were retrieved from the registry to calculate the CHA₂DS₂‐VASc score. Five neurologists abstracted the same medical history elements from the health records. The κ statistics quantified the reliability of medical history elements and CHA₂DS₂‐VASc score. Four hundred fifty‐three patients with acute ischemic stroke and previously known atrial fibrillation were included in the cohort. In comparison with manual reabstraction, registry‐based medical history elements were only moderately reliable: congestive heart failure (κ=0.53), hypertension (κ=0.42), diabetes (κ=0.80), prior stroke (κ=0.45), and vascular disease (κ=0.48). However, leveraging these variables to calculate the CHA₂DS₂‐VASc score was more reliable (κ=0.73).

Conclusions

Previously known medical history elements in the GWTG‐Stroke registry were only modestly reliable in this single‐center study, suggesting caution should be exercised when relying on any individual history elements in registry‐based research. Combining these variables to calculate the CHA₂DS₂‐VASc score was somewhat more reliable. Multicenter data are needed before assuming generalizability.

Background

The evidence linking vitamin D (VitD) levels and spontaneous intracerebral hemorrhage (ICH) remains inconclusive. We tested the hypothesis that lower genetically determined VitD levels are associated with higher risk of ICH.

Methods and Results

We conducted a 2 sample Mendelian Randomization (MR) study using publicly available summary statistics from published genome‐wide association studies of VitD levels (417 580 study participants) and ICH (1545 ICH cases and 1481 matched controls). We used the inverse‐variance weighted approach to generate causal estimates and the MR Pleiotropy Residual Sum and Outlier and MR‐Egger approaches to assess for horizontal pleiotropy. To account for known differences in their underlying mechanism, we implemented stratified analysis based on the location of the hemorrhage within the brain (lobar or nonlobar). Our primary analysis indicated that each SD decrease in genetically instrumented VitD levels was associated with a 60% increased risk of ICH (odds ratio [OR], 1.60; [95% CI, 1.05–2.43]; P=0.029). We found no evidence of horizontal pleiotropy (MR‐Egger intercept and MR Pleiotropy Residual Sum and Outlier global test with P>0.05). Stratified analyses indicated that the association was stronger for nonlobar ICH (OR, 1.87; [95% CI, 1.18–2.97]; P=0.007) compared with lobar ICH (OR, 1.43; [95% CI, 0.86–2.38]; P=0.17).

Conclusions

Lower levels of genetically proxied VitD levels are associated with higher ICH risk. These results provide evidence for a causal role of VitD metabolism in ICH.

This review examines key studies published in 2021 that are related to primary prevention of atherosclerotic cardiovascular disease (ASCVD). Major randomized clinical trials (RCTs) concerning traditional risk factors or ASCVD events, meta‐analyses, and key observational studies related to primary prevention of ASCVD were considered. The review includes interventions for weight loss, cardiometabolic and renal disease, blood pressure control, diet, and the occurrence of cardiovascular disease events. A few studies considered both primary and secondary prevention populations. The review is not exhaustive. We did not include studies that focused on heart failure or clinical presentations that may be difficult to classify, such as acute or chronic ischemic cardiovascular disease without myocardial infarction. Our purpose was to highlight recent research that will help the reader stay abreast of the changing field of cardiovascular prevention.