Physician assessment of aortic stenosis severity, quantitative parameters, and long-term outcomes: Results from the KP-VALVE project.

BACKGROUND: Contemporary outcomes for aortic stenosis (AS) and the association between physician-assessed AS severity and quantitative parameters is poorly understood. We aimed to evaluate AS natural history, compare outcomes for physicians' AS assessment vs. quantitative parameters, and identify AS parameters with the most explanatory power. METHODS: We ascertained physician-assessed AS severity, echocardiographic parameters, and clinical data for 546,769 patients from 2008-2018, examined multivariable associations of physician-assessed AS severity and number of quantitative severe AS parameters with death, cardiovascular hospitalization, and aortic valve replacement, and estimated the relative contribution of different quantitative AS parameters on outcomes. RESULTS: Among 49,604 AS patients (mean [SD] age 77 [11] years), 17.6% had moderate, 3.6% moderate-severe, and 9.4% severe AS. During median 3.7 [IQR 1.7-6.8] years, physician-assessed AS severity strongly correlated with outcomes, with moderate AS patients tracking closest to mild AS, and moderate-to-severe AS patients more comparable to severe AS. Although the number of quantitative severe AS parameters strongly predicted outcomes (adjusted HR [95% CI] for death 1.40 [1.34-1.46], 1.70 [1.56-1.85], and 1.78 [1.63-1.94] for 1, 2, and 3 parameters, respectively), aortic valve area <1.0 cm2 was the most frequent severe AS parameter, explained the largest relative contribution (67%), and was common in patients classified as moderate (21%) or moderate-severe (56%) AS. CONCLUSIONS: Physician-assessed AS severity predicts outcomes, with cumulative effects for each severe AS parameter. Moderate AS includes a wide spectrum of patients, with discordant AVA <1.0 cm2 being both common and predictive. Better identification of non-classical severe AS phenotypes may improve outcomes.

Challenges encountered in conducting donor-based research: Lessons learned from the Donor Heart Study.

Solid organ transplantation continues to be constrained by a lack of suitable donor organs. Advances in donor management and evaluation are needed to address this shortage, but the performance of research studies in deceased donors is fraught with challenges. Here we discuss several of the major obstacles we faced in the conduct of the Donor Heart Study-a prospective, multi-site, observational study of donor management, evaluation, and acceptance for heart transplantation. These included recruitment and engagement of participating organ procurement organizations, ambiguities related to study oversight, obtaining authorization for donor research, logistical challenges encountered during donor management, sustaining study momentum, and challenges related to study data management. By highlighting these obstacles encountered, as well as the solutions implemented, we hope to stimulate further discussion and actions that will facilitate the design and execution of future donor research studies.

Torsade de pointes: A nested case-control study in an integrated healthcare delivery system.

BACKGROUND: TdP is a form of polymorphic ventricular tachycardia which develops in the setting of a prolonged QT interval. There are limited data describing risk factors, treatment, and outcomes of this potentially fatal arrhythmia. OBJECTIVE: Our goals were as follows: (1) to validate cases presenting with Torsade de Pointes (TdP), (2) to identify modifiable risk factors, and (3) to describe the management strategies used for TdP and its prognosis in a real-world healthcare setting. METHODS: Case-control study (with 2:1 matching on age, sex, and race/ethnicity) nested within the Genetic Epidemiology Research on Aging (GERA) cohort. Follow-up of the cohort for case ascertainment was between January 01, 2005 and December 31, 2018. RESULTS: A total of 56 cases of TdP were confirmed (incidence rate = 3.6 per 100,000 persons/years). The average (SD) age of the TdP cases was 74 (13) years, 55 percent were female, and 16 percent were non-white. The independent predictors of TdP were potassium concentration <3.6 mEq/L (OR = 10.6), prior history of atrial fibrillation/flutter (OR = 6.2), QTc >480 ms (OR = 4.4) and prior history of coronary artery disease (OR = 2.6). Exposure to furosemide and amiodarone was significantly greater in cases than in controls. The most common treatment for TdP was IV magnesium (78.6%) and IV potassium repletion (73.2%). The in-hospital and 1-year mortality rates for TdP cases were 10.7% and 25.0% percent, respectively. CONCLUSIONS: These findings may inform quantitative multivariate risk indices for the prediction of TdP and could guide practitioners on which patients may qualify for continuous ECG monitoring and/or electrolyte replacement therapy.

Cardiac valvular abnormalities associated with use and cumulative exposure of cabergoline for hyperprolactinemia: the CATCH study.

BACKGROUND: Whether lower dose cabergoline therapy for hyperprolactinemia increases risk of valvular dysfunction remains controversial. We examined valvular abnormalities among asymptomatic adults with hyperprolactinemia treated with dopamine agonists. METHODS: This cross-sectional study was conducted among adults receiving cabergoline or bromocriptine for > 12 months for hyperprolactinemia and had no cardiac-related symptoms. Cardiac valve morphology and function were assessed from transthoracic echocardiograms at the study visit (except for two participants) with evaluation performed blinded to type and duration of dopamine agonist received. RESULTS: Among 174 participants (mean age 49 ± 13 years, 63% women) without known structural heart disease before starting therapy, 62 received only cabergoline, 63 received only bromocriptine, and 49 received both. Median cabergoline use was 2.8 years in cabergoline only users and 3.2 years for those exposed to both cabergoline and bromocriptine; median bromocriptine use was 5.5 years in bromocriptine only users and 1.1 years for those exposed to both cabergoline and bromocriptine. Compared with bromocriptine only users (17.5%), regurgitation of ≥1 valve was more common for cabergoline only (37.1%, P = 0.02) but not for combined exposure (26.5%, P = 0.26). Compared with bromocriptine only exposure (1.6%), regurgitation of ≥2 valves was more common for cabergoline only (11.3%, P = 0.03) and combined exposure (12.2%, P = 0.04). Cabergoline only users had higher age-sex-adjusted odds for ≥1 valve with grade 2+ regurgitation compared to bromocriptine only users (adjusted odds ratio [aOR] 3.2, 95% confidence interval [CI]:1.3-7.5, P = 0.008), but the association for combined exposure to cabergoline and bromocriptine was not significant (aOR 1.7, 95%CI:0.7-4.3, P = 0.26). Compared to bromocriptine only, age-sex-adjusted odds of ≥2 valves with grade 2+ regurgitation were higher for both cabergoline only (aOR 8.4, 95% CI:1.0-72.2, P = 0.05) and combined exposure (aOR 8.8, 95% CI:1.0-75.8, P = 0.05). Cumulative cabergoline exposure > 115 mg was associated with a higher age-sex adjusted odds of ≥2 valves with grade 2+ regurgitation (aOR 9.6, 95%CI:1.1-81.3, P = 0.04) compared to bromocriptine only. CONCLUSIONS: Among community-based adults treated for hyperprolactinemia, cabergoline use and greater cumulative cabergoline exposure were associated with a higher prevalence of primarily mild valvular regurgitation compared with bromocriptine. Research is needed to clarify which patients treated with dopamine agonists may benefit from echocardiographic screening and surveillance.

Assessment of Heart Transplant Waitlist Time and Pre- and Post-transplant Failure: A Mixed Methods Approach.

BACKGROUND: Over the past two decades, there have been increasingly long waiting times for heart transplantation. We studied the relationship between heart transplant waiting time and transplant failure (removal from the waitlist, pretransplant death, or death or graft failure within 1 year) to determine the risk that conservative donor heart acceptance practices confer in terms of increasing the risk of failure among patients awaiting transplantation. METHODS: We studied a cohort of 28,283 adults registered on the United Network for Organ Sharing heart transplant waiting list between 2000 and 2010. We used Kaplan-Meier methods with inverse probability censoring weights to examine the risk of transplant failure accumulated over time spent on the waiting list (pretransplant). In addition, we used transplant candidate blood type as an instrumental variable to assess the risk of transplant failure associated with increased wait time. RESULTS: Our results show that those who wait longer for a transplant have greater odds of transplant failure. While on the waitlist, the greatest risk of failure is during the first 60 days. Doubling the amount of time on the waiting list was associated with a 10% (1.01, 1.20) increase in the odds of failure within 1 year after transplantation. CONCLUSIONS: Our findings suggest a relationship between time spent on the waiting list and transplant failure, thereby supporting research aimed at defining adequate donor heart quality and acceptance standards for heart transplantation.

Genome-wide association study of sporadic brain arteriovenous malformations.

BACKGROUND: The pathogenesis of sporadic brain arteriovenous malformations (BAVMs) remains unknown, but studies suggest a genetic component. We estimated the heritability of sporadic BAVM and performed a genome-wide association study (GWAS) to investigate association of common single nucleotide polymorphisms (SNPs) with risk of sporadic BAVM in the international, multicentre Genetics of Arteriovenous Malformation (GEN-AVM) consortium. METHODS: The Caucasian discovery cohort included 515 BAVM cases and 1191 controls genotyped using Affymetrix genome-wide SNP arrays. Genotype data were imputed to 1000 Genomes Project data, and well-imputed SNPs (>0.01 minor allele frequency) were analysed for association with BAVM. 57 top BAVM-associated SNPs (51 SNPs with p<10(-05) or p<10(-04) in candidate pathway genes, and 6 candidate BAVM SNPs) were tested in a replication cohort including 608 BAVM cases and 744 controls. RESULTS: The estimated heritability of BAVM was 17.6% (SE 8.9%, age and sex-adjusted p=0.015). None of the SNPs were significantly associated with BAVM in the replication cohort after correction for multiple testing. 6 SNPs had a nominal p<0.1 in the replication cohort and map to introns in EGFEM1P, SP4 and CDKAL1 or near JAG1 and BNC2. Of the 6 candidate SNPs, 2 in ACVRL1 and MMP3 had a nominal p<0.05 in the replication cohort. CONCLUSIONS: We performed the first GWAS of sporadic BAVM in the largest BAVM cohort assembled to date. No GWAS SNPs were replicated, suggesting that common SNPs do not contribute strongly to BAVM susceptibility. However, heritability estimates suggest a modest but significant genetic contribution.

Permanent Pacemaker Implantation Early After Cardiac Surgery: A Descriptive Study of Pacemaker Utility After One Year of Follow-Up.

BACKGROUND: Complete heart block (CHB) is a common complication of cardiac surgery, which may resolve spontaneously. The optimal number of days to wait for resolution of CHB prior to proceeding with a permanent pacemaker (PPM) and the long-term utility of PPMs placed in this setting remain uncertain. METHODS AND RESULTS: This was a retrospective cohort study, which included members of Kaiser Permanente Northern California who had cardiac surgery, a PPM placed within 30 days after surgery, and one year of follow-up time. Chart review was performed to determine the frequency of ventricular pacing at each PPM interrogation visit up to one year after surgery. A PPM was categorized as underutilized at the time of an interrogation if none of the following were present: underlying rhythm <40 bpm, persistent CHB, or >1% ventricular pacing. The study included 247 patients with a mean time from cardiac surgery to PPM of 6.5 days. In 33 cases (13%), underutilized status was confirmed. The time from surgery to PPM implant was significantly higher in the underutilized group (8.1 ± 4.2 days vs. 6.2 ± 4.2 days, p = 0.003). CONCLUSIONS: The majority of PPMs placed early after cardiac surgery are not underutilized. In this retrospective, observational study, longer delay from surgery to PPM implantation was not associated with a greater likelihood that the PPM would be utilized long term. A prospective study is required to determine optimal timing of PPM implantation in this setting.

Common variants on 9p21.3 are associated with brain arteriovenous malformations with accompanying arterial aneurysms.

OBJECTIVE: To investigate whether previously reported 9p21.3 single nucleotide polymorphisms (SNPs) are associated with risk of brain arteriovenous malformations (BAVM), which often have accompanying arterial aneurysms. Common variants in the 9p21.3 locus have been reported to be associated with multiple cardiovascular phenotypes, including coronary artery disease and intracranial aneurysms (rs10757278 and rs1333040). METHODS: We used data from 338 BAVM cases participating in the University of California, San Francisco (UCSF)-Kaiser Brain AVM Study Project and 504 healthy controls to evaluate genotypes for seven common SNPs (minor allele frequency>0.05) that were imputed using 1000 Genomes Phase 1 European data (R(2)>0.87). Association with BAVM was tested using logistic regression adjusting for age, sex and the top three principal components of ancestry. Subgroup analysis included 205 BAVM cases with aneurysm data: 74 BAVM with aneurysm versus 504 controls and 131 BAVM without aneurysm versus 504 controls. RESULTS: We observed suggestive association with BAVM and rs10757278-G (OR=1.23, 95% CI 0.99 to 1.53, p=0.064) and rs1333040-T (OR=1.27, 95% CI 1.01 to 1.58, p=0.04). For rs10757278-G, the association was stronger in BAVM cases with aneurysm (OR=1.52, 95% CI 1.03 to 2.22, p=0.032) than in BAVM without aneurysm (OR=0.98, 95% CI 0.72 to 1.34, p=0.91). Similar patterns of effects were observed for rs1333040 and for other SNPs in linkage disequilibrium (r(2)>0.8) with rs10757278. CONCLUSIONS: Common 9p21.3 variants showed similar effect sizes for association with BAVM as previously reported for aneurysmal disease. The association with BAVM appears to be explained by known associations with aneurysms, suggesting that BAVM-associated aneurysms share similar vascular pathology mechanisms with other aneurysm types.

Short QT in a cohort of 1.7 million persons: prevalence, correlates, and prognosis.

BACKGROUND: Short QT syndrome (QTc ≤ 300 ms) is a novel hereditary channelopathy linked to syncope, paroxysmal atrial fibrillation, and sudden cardiac death. However, its epidemiological features remain unsettled. OBJECTIVES: (1) To assess the prevalence of short QT in a large population-based sample; (2) to evaluate its demographic and clinical correlates and; (3) to determine its prognosis. METHODS: A database of 6.4 million electrocardiograms (ECGs) obtained between 1995 and 2008 among 1.7 million persons was used. An internal, population-based method for heart rate correction (QTcreg ) was used and all ECGs with QTcreg ≤300 ms were manually validated. Linked health plan databases were used for covariate and survival ascertainment. RESULTS: Of 6,387,070 ECGs, 1086 had an ECG with machine-read QTcreg ≤300 ms. Only 4% (45/1086) were validated yielding a prevalence of 0.7 per 100,000 or 1 of 141,935 ECGs. At the person level, the overall prevalence of QTcreg ≤300 ms was 2.7 per 100,000 or 1 of 37,335. The factors independently and significantly associated with validated QTcreg ≤300 ms were age over 65 years, Black race, prior history of ventricular dysrhythmias, chronic obstructive pulmonary disease, ST-T abnormalities, ischemia, bigeminy pattern, and digitalis effect. After 8.3 years of median follow-up and relative to normal QTcreg , validated QTcreg ≤300 ms was associated after multivariate adjustment with a 2.6-fold (95% confidence interval [CI] = 1.9-3.7) increased risk of death. CONCLUSION: QTcreg ≤300 ms was extraordinarily rare and was associated with significant ECG abnormalities and reduced survival.

Eligibility and Potential Benefit of Transcatheter Edge-to-Edge Repair in a Contemporary Cohort With Heart Failure: Evidence From a Large Integrated Health Care Delivery System.

Background: The eligibility and potential benefit of transcatheter edge-to-edge repair (TEER) in addition to guideline-directed medical therapy to treat moderate-severe or severe secondary mitral regurgitation (MR) has not been reported in a contemporary heart failure (HF) population. Methods: Eligibility for TEER based on Food and Drug Administration (FDA) labeling: (1) HF symptoms, (2) moderate-severe or severe MR, (3) left ventricular ejection fraction (LVEF) 20% to 50%, (4) left ventricular end-systolic dimension 7.0 cm, and (5) receiving GDMT (blocker + angiotensin-converting enzyme inhibitor/angiotensin receptor blocker). The proportion (%) of patients eligible for TEER. The hypothetical number needed to treat to prevent or postpone adverse outcomes was estimated using relative risk reductions from published hazard ratios in the registration trial and the observed event rates. Results: We identified 50,841 adults with HF and known LVEF. After applying FDA criteria, 2461 patients (4.8%) were considered eligible for transcatheter mitral valve replacement (FDA+), with the vast majority of patients excluded (FDA-) based on a lack of clinically significant MR (N = 47,279). FDA+ patients had higher natriuretic peptide levels and were more likely to have a prior HF hospitalization compared to FDA- patients. Although FDA+ patients had a more dilated left ventricle and lower LVEF, median (25th-75th) left ventricular end-systolic dimension (cm) was low at 4.4 (3.7-5.1) and only 30.8% had severely reduced LVEF. FDA+ patients were at higher risk of HF-related morbidity and mortality. The estimated number needed to treat to potentially prevent or postpone all-cause hospitalization was 4.4, 8.8 for HF hospitalization, and 5.3 for all-cause death at 24 months in FDA+ patients. Conclusions: There is a low prevalence of TEER eligibility based on FDA criteria primarily due to absence of moderate-severe or severe MR. FDA+ patients are a high acuity population and may potentially derive a robust clinical benefit from TEER based on pivotal studies. Additional research is necessary to validate the scope of eligibility and comparative effectiveness of TEER in real-world populations.

Echocardiographic Outcomes With Transcatheter Edge-to-Edge Repair for Degenerative Mitral Regurgitation in Prohibitive Surgical Risk Patients.

BACKGROUND: The CLASP IID randomized trial (Edwards PASCAL TrAnScatheter Valve RePair System Pivotal Clinical Trial) demonstrated the safety and effectiveness of the PASCAL system for mitral transcatheter edge-to-edge repair (M-TEER) in patients at prohibitive surgical risk with significant symptomatic degenerative mitral regurgitation (DMR). OBJECTIVES: This study describes the echocardiographic methods and outcomes from the CLASP IID trial and analyzes baseline variables associated with residual mitral regurgitation (MR) ≤1+. METHODS: An independent echocardiographic core laboratory assessed echocardiographic parameters based on American Society of Echocardiography guidelines focusing on MR mechanism, severity, and feasibility of M-TEER. Factors associated with residual MR ≤1+ were identified using logistic regression. RESULTS: In 180 randomized patients, baseline echocardiographic parameters were well matched between the PASCAL (n = 117) and MitraClip (n = 63) groups, with flail leaflets present in 79.2% of patients. Baseline MR was 4+ in 76.4% and 3+ in 23.6% of patients. All patients achieved MR ≤2+ at discharge. The proportion of patients with MR ≤1+ was similar in both groups at discharge but diverged at 6 months, favoring PASCAL (83.7% vs 71.2%). Overall, patients with a smaller flail gap were significantly more likely to achieve MR ≤1+ at discharge (adjusted OR: 0.70; 95% CI: 0.50-0.99). Patients treated with PASCAL and those with a smaller flail gap were significantly more likely to sustain MR ≤1+ to 6 months (adjusted OR: 2.72 and 0.76; 95% CI: 1.08-6.89 and 0.60-0.98, respectively). CONCLUSIONS: The study used DMR-specific echocardiographic methodology for M-TEER reflecting current guidelines and advances in 3-dimensional echocardiography. Treatment with PASCAL and a smaller flail gap were significant factors in sustaining MR ≤1+ to 6 months. Results demonstrate that MR ≤1+ is an achievable benchmark for successful M-TEER. (Edwards PASCAL TrAnScatheter Valve RePair System Pivotal Clinical Trial [CLASP IID]; NCT03706833).

Validation of a population-based method to assess drug-induced alterations in the QT interval: a self-controlled crossover study.

PURPOSE: The purpose of this study was to ascertain, in the context of an integrated health care delivery system, the association between a comprehensive list of drugs known to have potential QT liability and QT prolongation or shortening. METHODS: By using a self-controlled crossover study with 59 467 subjects, we ascertained intra-individual change in log-linear regression-corrected QT (QTcreg ) during the period between 1995 and mid-2008 for 90 drugs while adjusting for age, gender, race/ethnicity, comorbid conditions, number of electrocardiograms (ECGs), and time between pre-ECG and post-ECG. The proportion of users of each drug-developing incident long QT was also estimated. RESULTS: Two drugs (nicardipine and levalbuterol) had no statistically significant intra-individual QTcreg shortening effects, 10 drugs had no statistically significant prolonging effect, and 78 (87%) of the drugs had statistically significant intra-individual mean QTcreg lengthening effects, ranging from 7.6 ms for aripiprazole to 25.2 ms for amiodarone. Three drugs were associated with mean QTcreg prolongation of 20 ms or greater: amiodarone (antiarrhythmic), terfenadine (antihistaminic), and quinidine (antiarrhythmic); whereas 11 drugs were associated with mean QTcreg prolongation of 15 ms or greater but less than 20 ms: trimipramine (tricyclic antidepressant), clomipramine (tricyclic antidepressant), disopyramide (antiarrhythmic), chlorpromazine (antipsychotic), sotalol (beta blocker), itraconazole (antifungal), phenylpropanolamine (decongestant/anorectic), fenfluramine (appetite suppressant), midodrine (antihypotensive), digoxin (cardiac glycoside/antiarrhythmic), and procainamide (antiarrhythmic). CONCLUSIONS: QT prolonging effects were common and varied in strength. Our results lend support to past Food and Drug Administration regulatory actions and support the role for ongoing surveillance of drug-induced QT prolongation.

Association between serum albumin and outcomes in heart failure and secondary mitral regurgitation: the COAPT trial.

AIMS: Low serum albumin levels are associated with poor prognosis in numerous chronic disease states but the relationship between albumin and outcomes in patients with heart failure (HF) and secondary mitral regurgitation (SMR) has not been described. METHODS AND RESULTS: The randomized COAPT trial evaluated the safety and effectiveness of transcatheter edge-to-edge repair (TEER) with the MitraClipTM plus guideline-directed medical therapy (GDMT) versus GDMT alone in patients with symptomatic HF and moderate-to-severe or severe SMR. Baseline serum albumin levels were measured at enrolment. Among 614 patients enrolled in COAPT, 559 (91.0%) had available baseline serum albumin levels (median 4.0 g/dl, interquartile range 3.7-4.2 g/dl). Patients with albumin <4.0 g/dl compared with ≥4.0 g/dl were older and more likely to have ischaemic cardiomyopathy and a hospitalization within the year prior to enrolment. After multivariable adjustment, patients with albumin <4.0 g/dl had higher 4-year rates of all-cause death (63.7% vs. 47.6%; adjusted hazard ratio 1.34, 95% confidence interval 1.02-1.74; p = 0.032), but there were no significant differences in HF hospitalizations (HFH) or all-cause hospitalizations according to baseline serum albumin level. The relative effectiveness of TEER plus GDMT versus GDMT alone was consistent in patients with low and high albumin levels (pinteraction  = 0.19 and 0.35 for death and HFH, respectively). CONCLUSION: Low baseline serum albumin levels were independently associated with reduced 4-year survival in patients with HF and severe SMR enrolled in the COAPT trial, but not with HFH. Patients treated with TEER derived similarly robust reductions in both death and HFH regardless of baseline albumin level.

Incidence, Predictors, and Outcomes Associated With Worsening Renal Function in Patients With Heart Failure and Secondary Mitral Regurgitation: The COAPT Trial.

Background The incidence and implications of worsening renal function (WRF) after mitral valve transcatheter edge-to-edge repair (TEER) in patients with heart failure (HF) are unknown. Therefore, the aim of this study was to determine the proportion of patients with HF and secondary mitral regurgitation who develop persistent WRF within 30 days following TEER, and whether this development portends a worse prognosis. Methods and Results In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial, 614 patients with HF and severe secondary mitral regurgitation were randomized to TEER with the MitraClip plus guideline-directed medical therapy (GDMT) versus GDMT alone. WRF was defined as serum creatinine increase ≥1.5× or ≥0.3 mg/dL from baseline persisting to day 30 or requiring renal replacement therapy. All-cause death and HF hospitalization rates between 30 days and 2 years were compared in patients with and without WRF. WRF at 30 days was present in 11.3% of patients (9.7% in the TEER plus GDMT group and 13.1% in the GDMT alone group; P=0.23). WRF was associated with all-cause death (hazard ratio [HR], 1.98 [95% CI, 1.3-3.03]; P=0.001) but not HF hospitalization (HR, 1.47 [ 95% CI, 0.97-2.24]; P=0.07) between 30 days and 2 years. Compared with GDMT alone, TEER reduced both death and HF hospitalization consistently in patients with and without WRF (Pinteraction=0.53 and 0.57, respectively). Conclusions Among patients with HF and severe secondary mitral regurgitation, the incidence of WRF at 30 days was not increased after TEER compared with GDMT alone. WRF was associated with greater 2-year mortality but did not attenuate the treatment benefits of TEER in reducing death and HF hospitalization compared with GDMT alone. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01626079.

Cardiovascular predictors of long-term outcomes after non-traumatic subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Cardiac injury is common after subarachnoid hemorrhage (SAH) and is associated with adverse early outcomes, but long-term effects are unknown. The first aim of this study was to compare the long-term rates of death, stroke, and cardiac events in SAH survivors versus a matched population without SAH. The second aim was to quantify the effects of cardiac injury on the outcome rates. METHODS: This was a retrospective cohort study of patients with and without non-traumatic SAH. For aim #1, the predictor variable was SAH and the outcome variables were all-cause and cerebrovascular mortality, stroke, cardiac mortality, acute coronary syndrome (ACS), and heart failure (HF) admission. A multivariable Cox proportional hazards analysis was performed. For aim #2, the predictor variables were cardiac injury (elevated serum cardiac enzymes or a diagnosis code for ACS) and dysfunction (pulmonary edema on X-Ray or a diagnosis code for HF). RESULTS: Compared with 4,695 members without SAH, the 910 SAH patients had higher rates of all-cause mortality (hazard ratio [HR 2.6], 95% confidence intervals [CI] 2.0-3.4), cerebrovascular mortality (HR 30.6, CI 13.5-69.4), and stroke (HR 10.2, CI 7.5-13.8). Compared with the non-SAH group, the SAH patients with cardiac injury had increased rates of all-cause mortality (HR 5.3, CI 3.0-9.3), cardiac mortality (HR 7.3, CI 1.7-31.6), and heart failure (HR 4.3, CI 1.53-11.88). CONCLUSIONS: SAH survivors have increased long-term mortality and stroke rates compared with a matched non-SAH population. SAH-induced cardiac injury is associated with an increased risk of death and heart failure hospitalization.

Angiopoietin-like 4 (ANGPTL4) gene polymorphisms and risk of brain arteriovenous malformations.

BACKGROUND: Brain arteriovenous malformations (BAVM) are high-flow vascular lesions prone to intracranial hemorrhage (ICH). Abnormal angiogenesis is a key characteristic of BAVM tissue. Angiopoietin-like 4 (ANGPTL4), a secreted glycoprotein, is thought to be involved in angiogenesis and required for proper postnatal blood vessel partitioning. We investigated whether common single nucleotide polymorphisms (SNPs) in ANGPTL4 were associated with risk of BAVM or ICH. METHODS AND RESULTS: We conducted a case-control study of 216 Caucasian BAVM cases and 246 healthy controls, and a secondary case-only analysis, comparing 83 ruptured (ICH) with 133 unruptured BAVM cases at presentation. Four tagSNPs in ANGPTL4 captured variation over a 10-kb region (rs2278236, rs1044250, rs11672433, and rs1808536) and were tested for association with BAVM or ICH. The minor allele (A) of rs11672433 (exon 6, Pro389Pro) was associated with an increased risk of BAVM (p = 0.006), which persisted after adjusting for multiple comparisons (p = 0.03). After adjustments for age and sex, carriers of the minor allele (A) remained at higher risk for BAVM compared to noncarriers (odds ratio, OR = 1.56; 95% confidence interval, CI = 1.01-2.41; p = 0.046) and risk of BAVM was increased with increasing copy of the minor A allele (OR = 1.49, 95% CI = 1.03-2.15; p(trend) = 0.03). Five common haplotypes (frequency >1%) were inferred; overall haplotype distribution differed between BAVM cases and controls (χ(2) = 12.2, d.f. = 4, p = 0.02). Neither SNPs (p > 0.05) nor haplotype distribution (χ(2) = 1.1, d.f. = 4, p = 0.89) were associated with risk of ICH among BAVM cases. CONCLUSION: A synonymous SNP in ANGPTL4 and haplotypes carrying it are associated with risk of BAVM but not with ICH presentation in BAVM cases.

Elevated BNP is associated with vasospasm-independent cerebral infarction following aneurysmal subarachnoid hemorrhage.

BACKGROUND: Elevated levels of B-type natriuretic peptide (BNP) have been associated with cardiac dysfunction and adverse neurological outcomes after subarachnoid hemorrhage (SAH). We sought to determine whether elevated levels of BNP are independently associated with radiographic cerebral infarction after SAH. METHODS: Plasma BNP levels were measured after admission, a mean of 5.5 ± 3.0 days after SAH onset. Cerebral infarction was determined by retrospective review of computerized tomography (CT) scans. Cerebral vasospasm was confirmed by the presence of vascular narrowing on cerebral angiogram. The association between BNP and cerebral infarction was quantified using multivariable logistic regression and reverse stepwise elimination of clinical covariates. A stratified analysis was performed to quantify the association between BNP levels and infarction in patients with and without angiographic vasospasm. RESULTS: BNP levels were measured from 119 subjects. The median BNP level was 105 pg/ml (interquartile range 37-275 pg/ml). In our multivariable model, the top quartile of BNP levels (≥ 276 pg/ml) were associated with an increased odds of cerebral infarction (OR 4.2, P = 0.009). The stratified analysis showed that the association between BNP and infarction was strongest in patients without angiographic vasospasm (OR 7.8, P = 0.006). CONCLUSIONS: Elevated levels of BNP are strongly and independently associated with cerebral infarction, and the association is most pronounced in patients without angiographic vasospasm. These results provide further evidence that other mechanisms can contribute to infarction, and BNP may be a useful biomarker in detecting patients at risk for adverse outcomes without large vessel vasospasm.

QT Interval Dynamics and Cardiovascular Outcomes: A Cohort Study in an Integrated Health Care Delivery System.

Background Long QT has been associated with ventricular dysrhythmias, cardiovascular disease (CVD) mortality, and sudden cardiac death. However, no studies to date have investigated the dynamics of within-person QT change over time in relation to risk of incident CVD and all-cause mortality in a real-world setting. Methods and Results A cohort study among members of an integrated health care delivery system in Northern California including 61 455 people (mean age, 62 years; 60% women, 42% non-White) with 3 or more ECGs (baseline in 2005-2009; mean±SD follow-up time, 7.6±2.6 years). In fully adjusted models, tertile 3 versus tertile 1 of average QT corrected (using the Fridericia correction) was associated with cardiac arrest (hazard ratio [HR], 1.66), heart failure (HR, 1.62), ventricular dysrhythmias (HR, 1.56), all CVD (HR, 1.31), ischemic heart disease (HR, 1.28), total stroke (HR, 1.18), and all-cause mortality (HR, 1.24). Tertile 3 versus tertile 2 of the QT corrected linear slope was associated with cardiac arrest (HR, 1.22), ventricular dysrhythmias (HR, 1.12), and all-cause mortality (HR, 1.09). Tertile 3 versus tertile 1 of the QT corrected root mean squared error was associated with ventricular dysrhythmias (HR, 1.34), heart failure (HR, 1.28), all-cause mortality (HR, 1.20), all CVD (HR, 1.14), total stroke (HR, 1.08), and ischemic heart disease (HR, 1.07). Conclusions Our results demonstrate improved predictive ability for CVD outcomes using longitudinal information from serial ECGs. Long-term average QT corrected was more strongly associated with CVD outcomes than the linear slope or the root mean squared error. This new evidence is clinically relevant because ECGs are frequently used, noninvasive, and inexpensive.

Ten-year detection rate of brain arteriovenous malformations in a large, multiethnic, defined population.

BACKGROUND AND PURPOSE: To evaluate whether increased neuroimaging use is associated with increased brain arteriovenous malformation (BAVM) detection, we examined detection rates in the Kaiser Permanente Medical Care Program of northern California between 1995 and 2004. METHODS: We reviewed medical records, radiology reports, and administrative databases to identify BAVMs, intracranial aneurysms (IAs: subarachnoid hemorrhage [SAH] and unruptured aneurysms), and other vascular malformations (OVMs: dural fistulas, cavernous malformations, Vein of Galen malformations, and venous malformations). Poisson regression (with robust standard errors) was used to test for trend. Random-effects meta-analysis generated a pooled measure of BAVM detection rate from 6 studies. RESULTS: We identified 401 BAVMs (197 ruptured, 204 unruptured), 570 OVMs, and 2892 IAs (2079 SAHs and 813 unruptured IAs). Detection rates per 100 000 person-years were 1.4 (95% CI, 1.3 to 1.6) for BAVMs, 2.0 (95% CI, 1.8 to 2.3) for OVMs, and 10.3 (95% CI, 9.9 to 10.7) for IAs. Neuroimaging utilization increased 12% per year during the time period (P<0.001). Overall, rates increased for IAs (P<0.001), remained stable for OVMs (P=0.858), and decreased for BAVMs (P=0.001). Detection rates increased 15% per year for unruptured IAs (P<0.001), with no change in SAHs (P=0.903). However, rates decreased 7% per year for unruptured BAVMs (P=0.016) and 3% per year for ruptured BAVMs (P=0.005). Meta-analysis yielded a pooled BAVM detection rate of 1.3 (95% CI, 1.2 to 1.4) per 100 000 person-years, without heterogeneity between studies (P=0.25). CONCLUSIONS: Rates for BAVMs, OVMs, and IAs in this large, multiethnic population were similar to those in other series. During 1995 to 2004, a period of increasing neuroimaging utilization, we did not observe an increased rate of detection of unruptured BAVMs, despite increased detection of unruptured IAs.

Perioperative hypothermia (33 degrees C) does not increase the occurrence of cardiovascular events in patients undergoing cerebral aneurysm surgery: findings from the Intraoperative Hypothermia for Aneurysm Surgery Trial.

BACKGROUND: Perioperative hypothermia has been reported to increase the occurrence of cardiovascular complications. By increasing the activity of sympathetic nervous system, perioperative hypothermia also has the potential to increase cardiac injury and dysfunction associated with subarachnoid hemorrhage. METHODS: The Intraoperative Hypothermia for Aneurysm Surgery Trial randomized patients undergoing cerebral aneurysm surgery to intraoperative hypothermia (n = 499, 33.3 degrees +/- 0.8 degrees C) or normothermia (n = 501, 36.7 degrees +/- 0.5 degrees C). Cardiovascular events (hypotension, arrhythmias, vasopressor use, myocardial infarction, and others) were prospectively followed until 3-month follow-up and were compared in hypothermic and normothermic patients. A subset of 62 patients (hypothermia, n = 33; normothermia, n = 29) also had preoperative and postoperative (within 24 h) measurement of cardiac troponin-I and echocardiography to explore the association between perioperative hypothermia and subarachnoid hemorrhage-associated myocardial injury and left ventricular function. RESULTS: There was no difference between hypothermic and normothermic patients in the occurrence of any single cardiovascular event or in composite cardiovascular events. There was no difference in mortality (6%) between groups, and there was only a single primary cardiovascular death (normothermia). There was no difference between hypothermic and normothermic patients in postoperative versus preoperative left ventricular regional wall motion or ejection fraction. Compared with preoperative values, hypothermic patients had no postoperative increase in cardiac troponin-I (median change 0.00 microg/l), whereas normothermic patients had a small postoperative increase (median change + 0.01 microg/l, P = 0.038). CONCLUSION: In patients undergoing cerebral aneurysm surgery, perioperative hypothermia was not associated with an increased occurrence of cardiovascular events.