Association of the V122I Hereditary Transthyretin Amyloidosis Genetic Variant With Heart Failure Among Individuals of African or Hispanic/Latino Ancestry.

Importance: Hereditary transthyretin (TTR) amyloid cardiomyopathy (hATTR-CM) due to the TTR V122I variant is an autosomal-dominant disorder that causes heart failure in elderly individuals of African ancestry. The clinical associations of carrying the variant, its effect in other African ancestry populations including Hispanic/Latino individuals, and the rates of achieving a clinical diagnosis in carriers are unknown. Objective: To assess the association between the TTR V122I variant and heart failure and identify rates of hATTR-CM diagnosis among carriers with heart failure. Design, Setting, and Participants: Cross-sectional analysis of carriers and noncarriers of TTR V122I of African ancestry aged 50 years or older enrolled in the Penn Medicine Biobank between 2008 and 2017 using electronic health record data from 1996 to 2017. Case-control study in participants of African and Hispanic/Latino ancestry with and without heart failure in the Mount Sinai BioMe Biobank enrolled between 2007 and 2015 using electronic health record data from 2007 to 2018. Exposures: TTR V122I carrier status. Main Outcomes and Measures: The primary outcome was prevalent heart failure. The rate of diagnosis with hATTR-CM among TTR V122I carriers with heart failure was measured. Results: The cross-sectional cohort included 3724 individuals of African ancestry with a median age of 64 years (interquartile range, 57-71); 1755 (47%) were male, 2896 (78%) had a diagnosis of hypertension, and 753 (20%) had a history of myocardial infarction or coronary revascularization. There were 116 TTR V122I carriers (3.1%); 1121 participants (30%) had heart failure. The case-control study consisted of 2307 individuals of African ancestry and 3663 Hispanic/Latino individuals; the median age was 73 years (interquartile range, 68-80), 2271 (38%) were male, 4709 (79%) had a diagnosis of hypertension, and 1008 (17%) had a history of myocardial infarction or coronary revascularization. There were 1376 cases of heart failure. TTR V122I was associated with higher rates of heart failure (cross-sectional cohort: n = 51/116 TTR V122I carriers [44%], n = 1070/3608 noncarriers [30%], adjusted odds ratio, 1.7 [95% CI, 1.2-2.4], P = .006; case-control study: n = 36/1376 heart failure cases [2.6%], n = 82/4594 controls [1.8%], adjusted odds ratio, 1.8 [95% CI, 1.2-2.7], P = .008). Ten of 92 TTR V122I carriers with heart failure (11%) were diagnosed as having hATTR-CM; the median time from onset of symptoms to clinical diagnosis was 3 years. Conclusions and Relevance: Among individuals of African or Hispanic/Latino ancestry enrolled in 2 academic medical center-based biobanks, the TTR V122I genetic variant was significantly associated with heart failure.

Coronary calcium scoring for long-term mortality prediction in patients with and without a family history of coronary disease.

OBJECTIVE: Minimal data are available regarding the long-term mortality risk of subclinical atherosclerosis using coronary artery calcium (CAC) scoring among patients with a family history (FH) of coronary artery disease (CAD). The aim of the present analysis was to assess the prognostic utility of CAC scoring among cohorts of young and older patients with and without a FH of CAD. METHODS: A total of 9715 consecutive asymptomatic patients, free of known CAD, underwent CAC scoring for cardiovascular risk assessment. The primary end point was all-cause mortality, with a median follow-up of 14.6 years. Unadjusted and risk-factor adjusted Cox proportional hazard modelling was employed. We calculated the area under the curve (AUC) from receiver operating characteristics analysis. RESULTS: 15-year all-cause mortality rates ranged from 4.7% to 25.0% for FH patients and from 5.0% to 38.0% for non-FH patients with CAC scores of 0 to >400 (p<0.0001). Effect modification by age altered the mortality risk of CAC among FH patients. For patients aged >60 years with FH of CAD, there was a significant improvement in the AUC with CAC over CAD risk factors (AUC: 0.539 vs 0.725, p<0.001). No such improvement was observed in FH patients aged <60 years (AUC: 0.636 vs 0.626, p=0.67). CONCLUSION: CAC effectively stratified mortality risk of patients with and without FH of CAD. However, for younger and lower-risk FH cohorts, CAC screening did not provide additive prognostic information beyond that of the traditional cardiac risk factors.

Influence of sex on risk stratification with stress myocardial perfusion Rb-82 positron emission tomography: Results from the PET (Positron Emission Tomography) Prognosis Multicenter Registry.

OBJECTIVES: The aim of the current analysis was to compare sex differences in the prognostic accuracy of stress myocardial perfusion rubidum-82 (Rb-82) positron emission tomography (PET). BACKGROUND: The diagnostic evaluation of women presenting with suspected cardiac symptoms is challenging with reported reduced accuracy, attenuation artifact, and more recent concerns regarding radiation safety. Stress myocardial perfusion Rb-82 PET is a diagnostic alternative with improved image quality and radiation dosimetry. Currently, the prognostic accuracy of stress Rb-82 PET in women has not been established. METHODS: A total of 6,037 women and men were enrolled in the PET Prognosis Multicenter Registry. Patients were followed for the occurrence of coronary artery disease (CAD) mortality, with a median follow-up of 2.2 years. Cox proportional hazards modeling was used to estimate CAD mortality. The net re-classification improvement index (NRI) was calculated. RESULTS: The 5-year CAD mortality was 3.7% for women and 6.0% for men (p < 0.0001). Unadjusted CAD mortality ranged from 0.9% to 12.9% for women (p < 0.0001) and from 1.5% to 17.4% for men (p < 0.0001) for 0% to ≥15% abnormal myocardium at stress. In multivariable models, the percentage of abnormal stress myocardium was independently predictive of CAD mortality in women and men. An interaction term of sex by the percentage of abnormal stress myocardium was nonsignificant (p = 0.39). The categorical NRI when Rb-82 PET data was added to a clinical risk model was 0.12 for women and 0.17 for men. Only 2 cardiac deaths were reported in women <55 years of age; accordingly the percentage of abnormal myocardium at stress was of borderline significance (p = 0.063), but it was highly significant for women ≥55 years of age (p < 0.0001), with an increased NRI of 0.21 (95% confidence interval: 0.09 to 0.34), including 17% of CAD deaths and 3.9% of CAD survivors that were correctly re-classified in this older female subset. CONCLUSIONS: Stress Rb-82 PET provides significant and clinically meaningful effective risk stratification of women and men, supporting this modality as an alternative to comparative imaging modalities. Rb-82 PET findings were particularly helpful at identifying high-risk, older women.

Virologic suppression in nevirapine-exposed HIV-infected infants initiating antiretroviral therapy in rural Uganda.

We measured virologic suppression among 34 nevirapine (NVP)-exposed HIV-infected children with median age of 8.6 months (range: 3.2-19.9) initiating NVP-based antiretroviral therapy (ART) in rural Uganda. In Kaplan-Meier analysis, the cumulative probability of virologic suppression, defined as having two consecutive HIV-1 RNA <400 copies ml(-1) by 18 months was 56%. In multivariate Cox proportional hazard modeling, the following pre-ART measurements were independently associated with an increased probability of viral suppression: increasing age [hazard ratio (HR) =1.28 per 1 month increase in age, p = 0.002], lower viral load (HR = 3.54 for HIV RNA > 7 50 000 copies ml(-1), p = 0.03) and high CD4% (HR = 6.0 for CD4% > 25, p = 0.003). These results lend additional support to the 2010 World Health Organization recommendations that protease inhibitors be used to treat NVP-exposed children, but that NVP-based ART should be initiated before the decline of CD4% to optimize outcomes in NVP-exposed children when protease inhibitors are not available.