Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.

Incidence rates of cardiovascular outcomes in a community-based population of cancer patients.

BACKGROUND: There are limited data on the incidence of cardiovascular disease among cancer patients in the pre-tyrosine kinase inhibitor (TKI) era. Such data are important in order to contextualize the incidence of various cardiovascular outcomes among cancer patients enrolled in clinical trials of new agents and for postmarketing surveillance. METHODS: A retrospective cohort study was conducted using data from the Kaiser Permanente Northern California (KPNC) population of cancer patients. The inclusion criterion was a KPNC Cancer Registry diagnosis of any of several selected solid and hematologic tumors between 1997 and 2009 not treated with a TKI. Endpoints were identified using ICD-9 codes and included acute coronary syndrome, heart failure, stroke, cardiac arrest, hypertension, venous thromboembolism, all-cause mortality, and cardiovascular mortality. Event rates were calculated according to type of cancer and number of cardiovascular risk factors. RESULTS: The study included almost 165 000 individuals with a broad variety of tumor types. The parent cohort was 54% female and 35% were ≥70 years old. Cardiovascular risk factors such as diabetes mellitus (14% of patients with solid tumors, 15% of patients with liquid tumors), dyslipidemia (33%, 31%), hypertension (50%, 49%), and smoking (35%, 32%) were common. The most frequent adverse outcomes were incident hypertension (26.8-61.0 cases per 1000 person-years, depending on the type of cancer), heart failure (9.4-78.7), and acute coronary syndrome (2.6-48.1). These event rates are high compared to what has been reported in prior KPNC cohort studies of patients without cancer. The rates of acute coronary syndrome, heart failure, and ischemic stroke increased with increasing numbers of cardiovascular risk factors. CONCLUSIONS: In a population of patients with cancer not exposed to TKIs, cardiovascular risk factors and outcomes are very common, regardless of cancer type. These data can inform the evaluation of potential excess cardiovascular risks from new interventions.

Echocardiographic Outcomes After Transcatheter Leaflet Approximation in Patients With Secondary Mitral Regurgitation: The COAPT Trial.

BACKGROUND: In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial among patients with heart failure (HF) and moderate-to-severe (3+) or severe (4+) secondary mitral regurgitation, patients treated with transcatheter mitral valve repair (TMVr) through leaflet approximation had reduced rates of HF hospitalization and mortality compared with guideline-directed medical therapy (GDMT) alone. OBJECTIVES: The purpose of this study was to describe the echocardiographic patient qualification process for the COAPT trial, baseline echocardiographic characteristics, changes over time, and the interaction between treatment group and echocardiographic parameters on clinical outcomes. METHODS: A novel echocardiographic algorithm was implemented for grading mitral regurgitation severity during the screening process. Standardized echocardiograms were obtained at baseline and during regular follow-up intervals through 2 years, and were analyzed by a core laboratory. RESULTS: A total of 614 patients were randomized to TMVr plus maximally tolerated GDMT or GDMT alone. Mean baseline left ventricular (LV) ejection fraction was 31.3 ± 9.3%, LV end-diastolic volume was 192.7 ± 71 ml, and effective regurgitant orifice area was 0.41 ± 0.15 cm2. The beneficial effect of TMVr compared with GDMT alone was consistent in all echocardiographic subgroups, independent of the severity of LV dysfunction, LV dilatation, pulmonary hypertension, severity of tricuspid regurgitation, or individual mitral regurgitation characteristics. The LV ejection fraction decreased and the LV volumes progressively increased in both groups during follow-up, although less after TMVr (p < 0.05). CONCLUSIONS: HF patients in the COAPT trial with 3+ or 4+ secondary mitral regurgitation, selected using strict echocardiographic criteria, benefitted from TMVr with reduced 2-year rates of death and HF hospitalization. Strict application of these echocardiographic criteria should enable the COAPT results to be translated to clinical practice. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] [COAPT]; NCT01626079).

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.

A genome-wide investigation of copy number variation in patients with sporadic brain arteriovenous malformation.

BACKGROUND: Brain arteriovenous malformations (BAVM) are clusters of abnormal blood vessels, with shunting of blood from the arterial to venous circulation and a high risk of rupture and intracranial hemorrhage. Most BAVMs are sporadic, but also occur in patients with Hereditary Hemorrhagic Telangiectasia, a Mendelian disorder caused by mutations in genes in the transforming growth factor beta (TGFß) signaling pathway. METHODS: To investigate whether copy number variations (CNVs) contribute to risk of sporadic BAVM, we performed a genome-wide association study in 371 sporadic BAVM cases and 563 healthy controls, all Caucasian. Cases and controls were genotyped using the Affymetrix 6.0 array. CNVs were called using the PennCNV and Birdsuite algorithms and analyzed via segment-based and gene-based approaches. Common and rare CNVs were evaluated for association with BAVM. RESULTS: A CNV region on 1p36.13, containing the neuroblastoma breakpoint family, member 1 gene (NBPF1), was significantly enriched with duplications in BAVM cases compared to controls (P = 2.2×10(-9)); NBPF1 was also significantly associated with BAVM in gene-based analysis using both PennCNV and Birdsuite. We experimentally validated the 1p36.13 duplication; however, the association did not replicate in an independent cohort of 184 sporadic BAVM cases and 182 controls (OR = 0.81, P = 0.8). Rare CNV analysis did not identify genes significantly associated with BAVM. CONCLUSION: We did not identify common CNVs associated with sporadic BAVM that replicated in an independent cohort. Replication in larger cohorts is required to elucidate the possible role of common or rare CNVs in BAVM pathogenesis.

Surgical candidacy and selection biases in nonemergent left main stenting: implications for observational studies.

OBJECTIVES: This study sought to characterize reasons for surgical ineligibility in patients undergoing nonemergent unprotected left main (ULM) percutaneous coronary intervention (PCI) and to assess the potential for these reasons to confound comparative effectiveness studies of coronary revascularization. BACKGROUND: Although both PCI and coronary artery bypass graft surgery are treatments for ULM disease, some patients are not eligible for both treatments, which may result in treatment selection biases. METHODS: In 101 consecutive patients undergoing nonemergent ULM PCI, mixed methods were used to determine the prevalence of treatment selection dictated by surgical ineligibility and to identify the reasons cited for avoiding coronary artery bypass graft surgery. We then determined whether these reasons were captured by the ACC-NCDR (American College of Cardiology-National Cardiovascular Data Registry) Cath-PCI dataset to assess the ability of this registry to account for biases in treatment selection. Finally, the association of surgical eligibility with long-term outcomes after ULM PCI was assessed. RESULTS: Treatment selection was dictated by surgical ineligibility in over half the ULM PCI cohort with the majority having reasons for ineligibility not captured by the ACC-NCDR. Surgical ineligibility was a significant predictor of mortality after adjustment for Society of Thoracic Surgeons (hazard ratio [HR]: 5.4, 95% confidence interval [CI]: 1.2 to 25), EuroSCORE (European System for Cardiac Operative Risk Evaluation) (HR: 5.9, 95% CI: 1.3 to 27), or NCDR mortality scores (HR: 6.2, 95% CI: 1.4 to 27). CONCLUSIONS: Surgical ineligibility dictating treatment selection is common in patients undergoing nonemergent ULM PCI, occurs on the basis of risk factors not captured by the ACC-NCDR, and is independently associated with worse long-term outcomes after adjusting for standard risk scores.

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.

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.

Independent associations between electrocardiographic abnormalities and outcomes in patients with aneurysmal subarachnoid hemorrhage: findings from the intraoperative hypothermia aneurysm surgery trial.

BACKGROUND AND PURPOSE: Electrocardiographic abnormalities are common after subarachnoid hemorrhage, but their significance remains uncertain. The aim of this study was to determine whether any specific electrocardiographic abnormalities are independently associated with adverse neurological outcomes. METHODS: This was a substudy of the Intraoperative Hypothermia Aneurysm Surgery Trial, which was designed to determine whether intraoperative hypothermia would improve neurological outcome in patients with subarachnoid hemorrhage undergoing aneurysm surgery. The outcome was the 3-month Glasgow Outcome Score treated as both a categorical measure (Glasgow Outcome Score 1 [good outcome] to 5 [death]) and dichotomously (mortality/Glasgow Outcome Score 5 versus Glasgow Outcome Score 1 to 4). The predictor variables were preoperative electrocardiographic characteristics, including heart rate, corrected QT interval, and ST- and T-wave abnormalities. Univariate logistic regression was performed to screen for significant electrocardiographic variables, which were then tested for associations with the outcome by multivariate logistic regression adjusting for clinical covariates. RESULTS: The study included 588 patients, of whom 31 (5%) died. There was a significant, nonlinear association between heart rate and mortality such that lowest quartile (80 beats/min; OR, 8.8; P=0.006) were associated with higher risk. There was also a significant association between nonspecific ST- and T-wave abnormalities and mortality (OR, 3.1; P=0.031). CONCLUSIONS: Bradycardia, relative tachycardia, and nonspecific ST- and T-wave abnormalities are strongly and independently associated with 3-month mortality after subarachnoid hemorrhage. Further research should be performed to determine whether there is a causal relationship between cardiac dysfunction and neurological outcome after subarachnoid hemorrhage.

Interleukin-6 and atrial fibrillation in patients with coronary artery disease: data from the Heart and Soul Study.

BACKGROUND: Previous studies suggest that markers of inflammation are elevated in patients with atrial fibrillation (AF). However, because inflammation has been implicated in contributing to risk of both AF and coronary artery disease (CAD), which are often present in the same populations, it is important to control for confounding by the presence of CAD. We therefore examined several biomarkers of inflammation and ultimately genotyped IL-6 polymorphisms in patients with AF in a cohort of subjects with known CAD. METHODS: We performed a cross-sectional analysis of 971 participants in the Heart and Soul Study, 46 of whom had AF. Interleukin-6, C-reactive protein, tumor necrosis factor-alpha, CD-40 ligand, monocyte chemoattractant protein-1, and fibrinogen levels were measured. RESULTS: In both unadjusted and adjusted analyses, IL-6 was the only biomarker significantly associated with AF (median IL-6 3.76 and 2.52 pg/mL in those with and without AF, respectively, P = .0005; adjusted odds ratio 1.77, P = .032). The IL-6-174CC genotype was significantly associated with the presence of AF in the adjusted analysis (odds ratio 2.34, P = .04) and with higher IL-6 levels (P = .002). CONCLUSIONS: In this cohort of subjects with CAD, AF was significantly associated with elevated IL-6 levels and the IL-6-174CC genotype. No associations were found with other biomarkers, including C-reactive protein. This suggests that IL-6 is a uniquely important mediator in the pathophysiology of AF.

Association of tumor necrosis factor-alpha-238G>A and apolipoprotein E2 polymorphisms with intracranial hemorrhage after brain arteriovenous malformation treatment.

OBJECTIVE: We previously reported specific genotypes of polymorphisms in two genes, tumor necrosis factor-alpha (TNF-alpha-238G > A) and Apolipoprotein E (ApoE e2), as independent predictors of new intracranial hemorrhage (ICH) in the natural course of untreated brain arteriovenous malformations. We hypothesized that the risk of posttreatment ICH would also be greater in patients with brain arteriovenous malformations with these genotypes. METHODS: Two hundred fifteen patients undergoing brain arteriovenous malformation treatment (embolization, arteriovenous malformation resection, radiosurgery, or any combination of these) were genotyped and followed longitudinally. Association of genotype with new symptomatic ICH after initiation of treatment was assessed using Cox proportional hazards adjusted for treatment type, demographics, and established ICH risk factors censored at the time of the last follow-up evaluation or death. RESULTS: The cohort was 48% male and 55% Caucasian, and 52% had an ICH before the initiation of treatment; the mean age +/- standard deviation was 36.6 +/- 17.2 years. Posttreatment ICH occurred in 34 (16%) patients with a median follow-up period of 1.9 years (interquartile range, 1.6 yr). After adjustment, the risk of posttreatment ICH was greater for TNF-alpha-238 AG genotype (hazard ratio [HR], 3.5; 95% confidence interval [CI], 1.3-9.8; P = 0.016) and ApoE e2 (HR, 3.2; 95% CI, 1.0-9.7; P = 0.042). Similar trends for the TNF-alpha-238 AG genotype were seen in surgery (HR, 4.2; 95% CI, 0.6-28.8; P = 0.14) and radiosurgery subsets (HR, 3.8; 95% CI, 0.7-19.4; P = 0.11). An effect of ApoE e2 was seen in radiosurgery subsets (HR, 10.9; 95% CI, 1.3-93.7; P = 0.030), but not in surgery subsets (HR, 1.4; 95% CI, 0.3-7.4; P = 0.67). CONCLUSION: Despite a variety of different mechanisms for posttreatment hemorrhage, these data suggest that the TNF-alpha and ApoE genotypes may contribute common phenotypes of enhanced vascular instability that increase the risk of hemorrhagic outcome.

Tumor necrosis factor-alpha-238G>A promoter polymorphism is associated with increased risk of new hemorrhage in the natural course of patients with brain arteriovenous malformations.

BACKGROUND AND PURPOSE: Identification of single-nucleotide polymorphisms (SNPs) associated with increased risk of new intracranial hemorrhage (ICH) after brain arteriovenous malformation (BAVM) diagnosis would facilitate risk stratification and identify potential targets for therapeutic intervention. METHODS: Patients with BAVM were longitudinally followed. Primary outcome was new ICH after diagnosis; censoring events were last follow-up or any BAVM treatment. We genotyped 4 promoter SNPs in 2 inflammatory cytokine genes: interleukin-6 (IL-6-174G>C; IL-6-572G>C) and tumor necrosis factor-alpha (TNF-alpha-238G>A; TNF-alpha-308G>A). Association of genotype with risk of new ICH was screened using chi2; SNPs associated with new ICH were further characterized using Cox proportional hazards. RESULTS: We genotyped 280 patients (50% female; 59% white, mean+/-SD age at diagnosis 37+/-17 years; 40% presenting with ICH). TNF-alpha-238G>A was associated with increased risk of new ICH after diagnosis (chi2; P=0.003). After adjusting for age, race/ethnicity, and clinical presentation, the risk of new ICH was increased for patients with TNF-alpha-238 AG genotype (hazard ratio, 4.01; P=0.015). No other SNP was found to be associated with new ICH. CONCLUSIONS: A TNF-alpha SNP was associated with increased risk of new ICH in the natural course of BAVMs. The role of inflammatory cytokines in the pathogenesis of BAVM hemorrhage merits further study.

Cardiac injury after subarachnoid hemorrhage is independent of the type of aneurysm therapy.

OBJECTIVE: Subarachnoid hemorrhage (SAH) is associated with cardiac injury and dysfunction. Whether aneurysm clipping versus coiling has a differential effect on the risk of troponin release and left ventricular (LV) dysfunction after SAH is unknown. It is hypothesized that aneurysm treatment does not affect the risk of developing cardiac injury and dysfunction. METHODS: The study included 172 consecutive SAH patients who underwent clipping (n = 109) or coiling (n = 63) aneurysm therapy. Hemodynamic data were collected, cardiac troponin I was measured, and echocardiography was performed on the 1st, 3rd, and 6th days after enrollment. A cardiac troponin I measurement of more than 1.0 microg/L was considered abnormal. For each echocardiographic examination, a blinded observer measured LV ejection fraction (abnormal if <50%) and quantified LV regional wall motion abnormalities. The incidence of cardiac outcomes in the treatment groups was compared using odds ratios (ORs). RESULTS: The coiled patients were older than the clipped patients (mean age, 59 +/- 13 yr versus 53 +/- 12 yr; t test, P < 0.001) and were more likely to have posterior aneurysms (33% versus 18%; chi(2) test, P = 0.019). There were no significant between-group differences in the risk of cardiac troponin I release (coil 21% versus clip 19%; OR = 0.89, P = 0.789), regional wall motion abnormalities (33% versus 28%; OR = 0.76, P = 0.422), or LV ejection fraction lower than 50% (16% versus 17%; OR = 1.06, P = 0.892). No patient died of cardiac causes (heart failure, myocardial infarction, or arrhythmia). CONCLUSION: Surgical and endovascular aneurysm therapies were associated with similar risks of cardiac injury and dysfunction after SAH. The presence of neurocardiogenic injury should not affect aneurysm treatment decisions.

A risk model derived from the National Registry of Myocardial Infarction 2 database for predicting mortality after coronary artery bypass grafting during acute myocardial infarction.

The mortality risk associated with coronary artery bypass grafting (CABG) after acute myocardial infarction (AMI) remains controversial. Although elective CABG is quite safe, the effects of recent myocardial infarction, gender, and other clinical factors on perioperative mortality rates are not completely understood. The objective of this study was to determine in-hospital mortality rates for patients with AMI receiving CABG and to generate a model to predict the risk for any individual patient with specific risk factors. Using the National Registry of Myocardial Infarction 2 database, we identified 71,774 subjects (21,270 women) with AMI who underwent CABG; we excluded those subjects who received immediate surgery as reperfusion therapy. Multivariate logistic regression was used to quantify the independent effects of age, recent myocardial infarction, gender, and other covariates on mortality. A risk score was then generated from the regression model to quantify the mortality risk. The results of logistic regression modeling determined that age was an independent predictor of in-hospital death (adjusted odds ratio [OR] 3.05, 95% confidence interval [CI] 2.76 to 3.37 for age >75), as were previous CABG (OR 2.84, 95% CI 2.55 to 3.16), heart failure on presentation (OR 1.73, 95% CI 1.57 to 1.91 for Killip class II), and female gender (OR 1.58, 95% CI 1.45 to 1.71). The mortality risk score showed that 55% of patients had risk scores of 2 to 5 and mortality rates of 4% to 13%. This moderate risk group experienced 76% of the total predicted mortality. Thus, in-hospital CABG mortality rates after AMI are high compared with elective surgery. Using the described risk score, clinicians can quantify the impact of patient risk factors in making decisions about referral for and timing of CABG.