CYP2C19 Genotype Is Associated With Adverse Cardiovascular Outcomes in Black Patients Treated With Clopidogrel Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Cytochrome P450 2C19 (CYP2C19) intermediate and poor metabolizer patients exhibit diminished clopidogrel clinical effectiveness after percutaneous coronary intervention (PCI). However, outcome studies to date have lacked racial diversity. Thus, the impact of CYP2C19 genotype on cardiovascular outcomes in patients treated with clopidogrel who identify as Black or African American remains unclear. METHODS AND RESULTS: Adults among 5 institutions who self-identified as Black or African American, underwent PCI and clinical CYP2C19 genotyping, and were treated with clopidogrel were included. Data were abstracted from health records. Major atherothrombotic (composite of death, myocardial infarction, ischemic stroke, stent thrombosis, or revascularization for unstable angina) and bleeding event rates within 1 year after PCI were compared across CYP2C19 metabolizer groups using multivariable Cox regression adjusted for potential confounders and baseline variables meeting a threshold of P<0.10. The population included 567 Black patients treated with clopidogrel (median age, 62 years; 46% women; 70% with an acute coronary syndrome indication for PCI). Major atherothrombotic events rates were significantly higher among clopidogrel-treated intermediate and poor metabolizers (24 of 125 [19.2%]) versus patients treated with clopidogrel without a no function allele (43 of 442 [9.7%]; 35.1 versus 15.9 events per 100 person-years; adjusted hazard ratio, 2.00 [95% CI, 1.20-3.33], P=0.008). Bleeding event rates were low overall (23 of 567 [4.1%]) and did not differ among the metabolizer groups. CONCLUSIONS: Black patients with CYP2C19 intermediate and poor metabolizer phenotypes who are treated with clopidogrel exhibit increased risk of adverse cardiovascular outcomes after PCI in a real-world clinical setting. Bleeding outcomes should be interpreted cautiously. Prospective studies are needed to determine whether genotype-guided use of prasugrel or ticagrelor in intermediate and poor metabolizers improves outcomes in Black patients undergoing PCI.

Impact of age and comorbidities on the effect of transcatheter versus surgical mitral valve repair on inpatient outcomes.

BACKGROUND: Transcatheter mitral valve repair (TMVR) has shown to be a safe and effective treatment option for symptomatic severe mitral regurgitation (MR) in patients who are at prohibitive surgical risk. Whether age and comorbidities impact the inpatient safety outcomes of TMVR versus surgical mitral valve repair (SMVR) is unknown. METHODS: Using the national inpatient sample, patients undergoing either elective TMVR or SMVR between 2012 and 2015 were analyzed. Logistic, generalized logistic, and linear regression were used to compare inpatient complications, discharge disposition, and length of stay (LOS). Heterogeneity in the effect of TMVR versus SMVR across Charlson comorbidity index (CCI, categorized as <2 and ≥2) and age (categorized as <75 years old and ≥75 years old) were assessed for effect modification. RESULTS: Overall, 8,716 hospitalizations were included, 7,950 (91%) SMVR and 766 (9%) TMVR. Compared with SMVR, patients undergoing TMVR were older (median age 79 vs. 62 years) and more likely to be female (45% vs. 40%) with a higher CCI score (median CCI 2 vs. 1). Despite being older with a higher comorbidity burden, patients undergoing TMVR had a lower incidence of permanent pacemaker implantation (OR 0.23, 95% CI: 0.11, 0.50), cerebrovascular accidents (OR 0.37, 95% CI: 0.15, 0.92), and major bleeding (OR 0.39, 95% CI: 0.32, 0.47). TMVR patients were also discharged 3 days earlier (CIE -3.26; 95% CI: -3.72, -2.80) and were less likely to be discharged to a skilled nursing facility (OR 0.72, 95% CI 0.55, 0.93). Additionally, the relative reduction in complications after TMVR versus SMVR was significantly higher in older (age ≥75 years) and more comorbid (CCI ≥2) patients (p for interaction <.05 for both). CONCLUSION: Patients treated with TMVR, as compared with SMVR, were older and had more comorbidities, but had a lower incidence of inpatient complications, shorter LOS, and better discharge disposition. Therefore, TMVR may be a safer option than SMVR in older patients and those with a higher burden of comorbidities.

Effect of Cigarette Smoking on Risk for Adverse Events in Patients With Heart Failure and Preserved Ejection Fraction.

Smoking is an important risk factor in the development of heart failure with preserved ejection (HFpEF), and previous reports have identified smoking as a significant predictor of death in this population. However, the relation between smoking and heart failure-specific outcomes has not been examined in patients with HFpEF. This analysis included 1,717 patients (mean age = 71 ± 10 years; 50% men; 78% white) with HFpEF enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial from the Americas. Smoking was ascertained by self-reported history and categorized as never, former, or current. Multivariable Cox regression was used to examine the risk of hospitalization for heart failure, death, and cardiovascular death across smoking categories. There were 116 current smokers (7%), 871 former smokers (51%), and 729 never smokers (42%) in this analysis. Current smoking was associated with an increased risk of hospitalization for heart failure (never: hazard ratio [HR] 1.0; former: HR 1.25, 95% confidence interval [CI] 0.99 to 1.57; current: HR 1.68, 95% CI 1.08 to 2.61), death (never: HR 1.0; former: HR 1.02, 95% CI 0.81 to 1.29; current: HR 1.82, 95% CI 1.19 to 2.78), and cardiovascular death (never: HR 1.0; former: HR 1.00, 95% CI 0.74 to 1.35; current: HR 1.85, 95% CI 1.09 to 3.24) compared with former or never smokers in a multivariable model adjusted for cardiovascular risk factors. A similar increased risk of hospitalization for heart failure (former: HR 1.0; current: HR 1.54, 95% CI 1.01, 2.36), death (former: HR 1.0; current: HR 1.81, 95% CI 1.19, 2.75), and cardiovascular death (former: HR 1.0; current: HR 1.76, 95% CI 1.04, 2.98) was observed for current smokers when we limited the analysis to those with a history of smoking. In conclusion, current smoking is associated with an increased risk for adverse outcomes in HFpEF, including hospitalization for heart failure. Smoking cessation strategies possibly have a role to reduce the risk for adverse cardiovascular outcomes in patients with HFpEF.

Urban-rural differences in mortality for atrial fibrillation hospitalizations in the United States.

BACKGROUND: Cardiovascular outcomes vary between urban and rural hospitals, with worse outcomes in rural settings. OBJECTIVE: The purpose of this study was to examine whether in-hospital mortality for hospitalization for atrial fibrillation (AF) varied between urban and rural hospitals. METHODS: A cross-sectional examination of patients who were hospitalized for AF was performed in the National Inpatient Sample between 2012 and 2014 to compare in-hospital mortality in patients admitted to urban vs rural hospitals. Patients with a principal International Classification of Diseases, Ninth Revision discharge diagnosis of AF were included. Hospitals were classified as urban or rural on the basis of core-based statistical areas. In-hospital mortality was defined as death due to any cause during hospitalization. RESULTS: A total of 248,731 (mean age 69 years; 78% white; 48% women) admissions for AF were identified. Of these, 218,946 (88%) were from urban hospitals and 29,785 (12%) were from rural hospitals. Patients admitted to rural hospitals had a 17% increased risk of death as compared with those admitted to urban hospitals in a multivariable model, which accounted for differences in patient characteristics and potential confounders (odds ratio 1.17; 95% confidence interval 1.04-1.32). Similar results were obtained in a propensity score-matched analysis and in subgroup analyses by sex, race, and region. CONCLUSION: In-hospital mortality of AF is higher in rural hospitals than in urban hospitals. Further research is needed to understand this finding and to develop targeted strategies to reduce mortality in patients admitted for AF in rural hospitals.

Echocardiographic predictors of atrial fibrillation in patients with heart failure with preserved ejection fraction.

AIMS: To determine if markers of diastolic dysfunction are associated with atrial fibrillation (AF) development among patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We examined the association of several echocardiographic measures of diastolic dysfunction with incident AF in 573 patients (mean age = 68 ± 9.5 years; 48% men; 79% white) with HFpEF from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT) who were free of baseline AF. Echocardiograms were analysed at a core laboratory. Incident AF cases were identified by follow-up study electrocardiograms and review of relevant medical records through May of 2013. Over a median follow-up of 3 years, 40 patients developed AF (incidence rate = 2.2 per 100 person years). Increasing values of the E/A ratio [per 0.1 increase: hazard ratio (HR) = 1.11, 95% confidence interval (CI) = 1.06-1.17], left atrial volume (per 5 mL increase: HR = 1.13, 95% CI = 1.03-1.23), and left atrial area (per 5 cm2 increase: HR = 1.51, 95% CI = 1.03-2.22) were associated with greater risk of AF. The risk of AF decreased with increasing peak A wave velocities (per 10 cm/s increase: HR = 0.83, 95% CI = 0.72-0.96). The risk of AF was not materially altered when peak A wave velocity was further adjusted for left atrial volume (HR = 0.83, 95% CI = 0.71-0.96) and area (HR = 0.83, 95% CI = 0.71-0.96). However, the associations of left atrial volume (HR = 1.10, 95% CI = 0.99-1.22) and area (HR = 1.48, 95% CI = 0.96-2.28) were no longer significant when accounting for peak A wave velocity. CONCLUSION: Diastolic parameters of left atrial function possibly are more important markers of AF risk than left atrial dilation in HFpEF.

Gender Differences in the Risk of Adverse Outcomes in Patients With Atrial Fibrillation and Heart Failure With Preserved Ejection Fraction.

Atrial fibrillation (AF) is associated with an increased risk for adverse events in patients with heart failure with preserved ejection fraction (HFpEF), but it is currently unknown if gender differences in these outcomes exist. To explore this hypothesis, we examined gender differences in the associations of AF with adverse outcomes in 3,385 (mean age 69 ± 9.6 years, 49% male, 89% white) patients with HFpEF from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial. Baseline AF cases were identified by self-reported history, medical record review, and baseline electrocardiogram data. Outcomes were adjudicated by a clinical end point committee and included the following: hospitalization, hospitalization for heart failure, stroke, death, and cardiovascular death. Cox regression was used to examine the risk of each outcome associated with AF. Over a median follow-up of 3.4 years, AF was associated with an increased risk for hospitalization (hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.34 to 1.66), hospitalization for heart failure (HR 1.49, 95% CI 1.23 to 1.81), stroke (HR 2.10, 95% CI 1.43 to 2.09), death (HR 1.22, 95% CI 1.02 to 1.47), and cardiovascular death (HR 1.31, 95% CI 1.04 to 1.65). The association between AF and hospitalization was stronger in women (HR 1.63, 95% CI 1.40 to 1.91) than men (HR 1.37, 95% CI 1.18 to 1.58; p-interaction = 0.032). Although significant interactions were not observed for the other outcomes, we appreciated that the risk estimates were higher for women compared with men. In conclusion, AF increases the risk for adverse cardiovascular outcomes in patients with HFpEF, and the presence of this arrhythmia in women possibly is associated with a greater risk for adverse events than men.

The clinical utility of normal findings on noninvasive cardiac assessment in the prediction of atrial fibrillation.

BACKGROUND: The absence of abnormalities on noninvasive cardiac assessment possibly confers a reduced risk of atrial fibrillation (AF) despite the presence of traditional risk factors. HYPOTHESIS: Normal findings on noninvasive cardiac assessment are associated with a lower risk of AF development. METHODS: We examined the clinical utility of normal findings on routine noninvasive cardiac assessment in 5331 participants (85% white; 57% women) from the Cardiovascular Health Study who were free of baseline AF. The combination of a normal electrocardiogram (ECG) + normal echocardiogram was assessed for the development of AF events. A normal ECG was defined as the absence of major or minor Minnesota code abnormalities. A normal echocardiogram was defined as the absence of contractile dysfunction, wall motion abnormalities, or abnormal left ventricular mass. Cox regression was used to compute the 10-year risk of developing AF. RESULTS: During the 10-year study period, a total of 951 (18%) AF events were detected. A normal ECG (multivariable hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.69-0.92) and normal echocardiogram (multivariable HR: 0.75, 95% CI: 0.65-0.87) were associated with a reduced risk of AF in isolation. This association improved in those with normal ECG + normal echocardiogram (multivariable HR: 0.66, 95% CI: 0.55-0.79) compared with participants who had abnormal ECG + abnormal echocardiogram (referent). CONCLUSIONS: Normal findings on routine noninvasive cardiac assessment identify persons in whom the risk of AF is low. Further studies are needed to explore the utility of this profile regarding the decision to implement certain risk factor modification strategies in older adults to reduce AF burden.

Utility of Normal Findings on Electrocardiogram and Echocardiogram in Subjects ≥65 Years.

The lack of abnormalities found on noninvasive cardiac testing possibly improves cardiovascular disease (CVD) risk stratification efforts and conveys reduced risk despite the presence of traditional risk factors. This analysis included 3,805 (95% white and 61% women) participants from the Cardiovascular Health Study (CHS) without baseline CVD. The combination of a normal electrocardiogram (ECG) and echocardiogram was assessed for the development of CVD. A normal ECG was defined as the absence of major or minor Minnesota code abnormalities. A normal echocardiogram was defined as the absence of contractile dysfunction, wall motion abnormalities, or abnormal left ventricular mass. Cox regression was used to compute the 10-year risk of developing coronary heart disease, stroke, and heart failure events. There were 1,555 participants (41%) with normal findings on both measures. After accounting for traditional CVD risk factors, a protective benefit was observed for all outcomes among participants who had normal ECG and echocardiographic findings (coronary heart disease: hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.46, 0.69; stroke: HR 0.57, 95% CI 0.43, 0.76; heart failure: HR 0.36, 95% CI 0.29, 0.41). The addition of this normal profile resulted in significant net reclassification improvement of the Framingham risk score for heart failure (net reclassification improvement 4.3%, 95% CI 1.0, 8.0). In conclusion, normal findings on routine noninvasive cardiac assessment identify subjects in whom CVD risk is low.

Biomarkers and the prediction of atrial fibrillation: state of the art.

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice, and it places a substantial burden on the health care system. Despite improvements in our understanding of AF pathophysiology, we have yet to develop targeted preventive therapies. Recently, numerous biological markers have been identified to aid in the prediction of future AF events. Subclinical markers of atrial stress, inflammation, endothelial dysfunction, kidney dysfunction, and atherosclerosis have been linked to AF. The connection between these markers and AF is the identification of subclinical states in which AF propagation is likely to occur, as these conditions are associated with abnormal atrial remodeling and fibrosis. Additionally, several risk scores have been developed to aid in the identification of at-risk patients. The practicing clinician should be aware of these subclinical markers, as several of these markers improve the predictive abilities of current AF risk scores. Knowledge of these subclinical markers also provides clinicians with a better understanding of AF risk factors, and the opportunity to reduce the occurrence of AF by incorporating well-known cardiovascular disease risk factor modification strategies. In this review, we highlight several novel biological markers that have improved our understanding of AF pathophysiology and appraise the utility of these markers to improve our ability to predict future AF events.

Rapid identification of oxidation-induced conformational changes by kinetic analysis.

Protein oxidation by reactive oxygen species is known to result in changes in the structure and function of the oxidized protein. Many proteins can tolerate multiple oxidation events before altering their conformation, while others suffer gross changes in conformation after a single oxidation event. Additionally, reactive oxygen species have been used in conjunction with mass spectrometry to map the accessible surface of proteins, often after verification that the oxidations do not alter the conformation. However, detection of oxidation-induced conformational changes by detailed kinetic oxidation analysis of individual proteolytic peptides or non-mass spectrometric analysis is labor-intensive and often requires significant amounts of sample. In this work, we describe a methodology to detect oxidation-induced conformational changes in proteins via direct analysis of the intact protein. The kinetics of addition of oxygen to unmodified protein are compared with the kinetics of addition of oxygen to the mono-oxidized protein. These changes in the rate of oxidation of the oxidized versus the non-oxidized protein are strongly correlated with increases in the random coil content as measured by the molar ellipticity at 198 nm. This methodology requires only small amounts of protein, and can be done rapidly without additional sample handling or derivatization.