Standardization and clinical applications of retinal imaging biomarkers for cardiovascular disease: a Roadmap from an NHLBI workshop.

The accessibility of the retina with the use of non-invasive and relatively low-cost ophthalmic imaging techniques and analytics provides a unique opportunity to improve the detection, diagnosis and monitoring of systemic diseases. The National Heart, Lung, and Blood Institute conducted a workshop in October 2022 to examine this concept. On the basis of the discussions at that workshop, this Roadmap describes current knowledge gaps and new research opportunities to evaluate the relationships between the eye (in particular, retinal biomarkers) and the risk of cardiovascular diseases, including coronary artery disease, heart failure, stroke, hypertension and vascular dementia. Identified gaps include the need to simplify and standardize the capture of high-quality images of the eye by non-ophthalmic health workers and to conduct longitudinal studies using multidisciplinary networks of diverse at-risk populations with improved implementation and methods to protect participant and dataset privacy. Other gaps include improving the measurement of structural and functional retinal biomarkers, determining the relationship between microvascular and macrovascular risk factors, improving multimodal imaging 'pipelines', and integrating advanced imaging with 'omics', lifestyle factors, primary care data and radiological reports, by using artificial intelligence technology to improve the identification of individual-level risk. Future research on retinal microvascular disease and retinal biomarkers might additionally provide insights into the temporal development of microvascular disease across other systemic vascular beds.

Comprehensive nutrient consumption estimation and metabolic profiling during ketogenic diet and relationship with myocardial glucose uptake on FDG-PET.

AIMS: The ketogenic diet (KD) is standard-of-care to achieve myocardial glucose suppression (MGS) for assessing inflammation using fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET). As KD protocols remain highly variable between centres (including estimation of nutrient intake by dietary logs for adequacy of dietary preparation), we aimed to assess the predictive utility of nutrient intake in achieving MGS. METHODS AND RESULTS: Nineteen healthy participants underwent short-term KD, with FDG-PET performed after 1 and 3 days of KD (goal carbohydrate intake <20 g/day). Nutrient consumption was estimated from dietary logs using nutrition research software. The area under receiver operating characteristics (AUROC) of macronutrients (carbohydrate, fat, and protein intake) for predicting MGS was analysed. The association between 133 nutrients and 4 biomarkers [beta-hydroxybutyrate (BHB), non-esterified fatty acids, insulin, and glucagon] with myocardial glucose uptake was assessed using mixed effects regression with false discovery rate (FDR) correction. Median (25th-75th percentile) age was 29 (25-34) years, 47% were women, and 42% were non-white. Median (25th-75th percentile) carbohydrate intake (g) was 18.7 (13.1-30.7), 16.9 (10.4-28.7), and 21.1 (16.6-29.0) on Days 1-3. No macronutrient intake (carbohydrate, fat, or protein) predicted MGS (c-statistic 0.45, 0.53, 0.47, respectively). Of 133 nutrients and 4 biomarkers, only BHB was associated with myocardial glucose uptake after FDR correction (corrected P-value 0.003). CONCLUSIONS: During highly supervised, short-term KD, approximately half of patients meet strict carbohydrate goals. Yet, in healthy volunteers, dietary review does not provide reassurance for adequacy of myocardial preparation since no clear thresholds for carbohydrate or fat intake reliably predict MGS.

Serum metabolomic signatures of plant-based diets and incident chronic kidney disease.

BACKGROUND: Greater adherence to plant-based diets is associated with a lower risk of incident chronic kidney disease (CKD). Metabolomics can help identify blood biomarkers of plant-based diets and enhance understanding of underlying mechanisms. OBJECTIVES: Using untargeted metabolomics, we aimed to identify metabolites associated with 4 plant-based diet indices (PDIs) (overall PDI, provegetarian diet, healthful PDI, and unhealthful PDI) and incident CKD in 2 subgroups within the Atherosclerosis Risk in Communities study. METHODS: We calculated 4 PDIs based on participants' responses on an FFQ. We used multivariable linear regression to examine the association between 4 PDIs and 374 individual metabolites, adjusting for confounders. We used Cox proportional hazards regression to evaluate associations between PDI-related metabolites and incident CKD. Estimates were meta-analyzed across 2 subgroups (n1 = 1762; n2 = 1960). We calculated C-statistics to assess whether metabolites improved the prediction of those in the highest quintile compared to the lower 4 quintiles of PDIs, and whether PDI- and CKD-related metabolites predicted incident CKD beyond the CKD prediction model. RESULTS: We identified 82 significant PDI-metabolite associations (overall PDI = 27; provegetarian = 17; healthful PDI = 20; unhealthful PDI = 18); 11 metabolites overlapped across the overall PDI, provegetarian diet, and healthful PDI. The addition of metabolites improved prediction of those in the highest quintile as opposed to the lower 4 quintiles of PDIs compared with participant characteristics alone (range of differences in C-statistics = 0.026-0.104; P value ≤ 0.001 for all tests). Six PDI-related metabolites (glycerate, 1,5-anhydroglucitol, γ-glutamylalanine, γ-glutamylglutamate, γ-glutamylleucine, γ-glutamylvaline), involved in glycolysis, gluconeogenesis, pyruvate metabolism, and γ-glutamyl peptide metabolism, were significantly associated with incident CKD and improved prediction of incident CKD beyond the CKD prediction model (difference in C-statistics for 6 metabolites = 0.005; P value = 0.006). CONCLUSIONS: In a community-based study of US adults, we identified metabolites that were related to plant-based diets and predicted incident CKD. These metabolites highlight pathways through which plant-based diets are associated with incident CKD.

Obesity Duration, Severity, and Distribution Trajectories and Cardiovascular Disease Risk in the Atherosclerosis Risk in Communities Study.

Background Research examining the role of obesity in cardiovascular disease (CVD) often fails to adequately consider heterogeneity in obesity severity, distribution, and duration. Methods and Results We here use multivariate latent class mixed models in the biracial Atherosclerosis Risk in Communities study (N=14 514; mean age=54 years; 55% female) to associate obesity subclasses (derived from body mass index, waist circumference, self-reported weight at age 25, tricep skinfold, and calf circumference across up to four triennial visits) with total mortality, incident CVD, and CVD risk factors. We identified four obesity subclasses, summarized by their body mass index and waist circumference slope as decline (4.1%), stable/slow decline (67.8%), moderate increase (24.6%), and rapid increase (3.6%) subclasses. Compared with participants in the stable/slow decline subclass, the decline subclass was associated with elevated mortality (hazard ratio [HR] 1.45, 95% CI 1.31, 1.60, P<0.0001) and with heart failure (HR 1.41, 95% CI 1.22, 1.63, P<0.0001), stroke (HR 1.53, 95% CI 1.22, 1.92, P=0.0002), and coronary heart disease (HR 1.36, 95% CI 1.14, 1.63, P=0.0008), adjusting for baseline body mass index and CVD risk factor profile. The moderate increase latent class was not associated with any significant differences in CVD risk as compared to the stable/slow decline latent class and was associated with a lower overall risk of mortality (HR 0.85, 95% CI 0.80, 0.90, P<0.0001), despite higher body mass index at baseline. The rapid increase latent class was associated with a higher risk of heart failure versus the stable/slow decline latent class (HR 1.34, 95% CI 1.10, 1.62, P=0.004). Conclusions Consideration of heterogeneity and longitudinal changes in obesity measures is needed in clinical care for a more precision-oriented view of CVD risk.

COVID-19 illness in relation to sleep and burnout.

BACKGROUND: Sleep habits and burnout have been shown to be associated with increase in infectious diseases, but it is unknown if these factors are associated with risk of COVID-19. We assessed whether sleep and self-reported burnout may be risk factors for COVID-19 among high-risk healthcare workers (HCWs). METHODS: From 17 July to 25 September 2020, a web-based survey was administered to HCWs in six countries (France, Germany, Italy, Spain, UK, USA) with a high frequency of workplace exposure. Participants provided information on demographics, sleep (number of sleep hours at night, daytime napping hours, sleep problems), burnout from work and COVID-19 exposures. We used multivariable linear and logistic regression models to evaluate the associations between sleep, burnout and COVID-19. RESULTS: Among 2884 exposed HCWs, there were 568 COVID-19 cases and 2316 controls. After adjusting for confounders, 1-hour longer sleep duration at night was associated with 12% lower odds of COVID-19 (p=0.003). Daytime napping hours was associated with 6% higher odds, but the association varied by countries, with a non-significant inverse association in Spain. Compared with having no sleep problems, having three sleep problems was associated with 88% greater odds of COVID-19. Reporting burnout 'every day' was associated with greater odds of COVID-19 (OR: 2.60, 95% CI 1.57 to 4.31, p trend across categories=0.001), longer duration (OR: 2.98, 95% CI 1.10 to 8.05, p trend=0.02) and severity (OR: 3.26, 95% CI 1.25 to 8.48, p trend=0.02) compared with reporting no burnout. These associations remained significant after adjusting for frequency of COVID-19 exposures. CONCLUSIONS: In six countries, longer sleep duration was associated with lower odds of COVID-19, but the association with daytime nap may not be consistent across countries. Greater sleep problems and high level of burnout were robustly associated with greater odds of COVID-19. Sleep and burnout may be risk factors for COVID-19 in high-risk HCWs.

Plant-based diets, pescatarian diets and COVID-19 severity: a population-based case-control study in six countries.

BACKGROUND: Several studies have hypothesised that dietary habits may play an important role in COVID-19 infection, severity of symptoms, and duration of illness. However, no previous studies have investigated the association between dietary patterns and COVID-19. METHODS: Healthcare workers (HCWs) from six countries (France, Germany, Italy, Spain, UK, USA) with substantial exposure to COVID-19 patients completed a web-based survey from 17 July to 25 September 2020. Participants provided information on demographic characteristics, dietary information, and COVID-19 outcomes. We used multivariable logistic regression models to evaluate the association between self-reported diets and COVID-19 infection, severity, and duration. RESULTS: There were 568 COVID-19 cases and 2316 controls. Among the 568 cases, 138 individuals had moderate-to-severe COVID-19 severity whereas 430 individuals had very mild to mild COVID-19 severity. After adjusting for important confounders, participants who reported following 'plant-based diets' and 'plant-based diets or pescatarian diets' had 73% (OR 0.27, 95% CI 0.10 to 0.81) and 59% (OR 0.41, 95% CI 0.17 to 0.99) lower odds of moderate-to-severe COVID-19 severity, respectively, compared with participants who did not follow these diets. Compared with participants who reported following 'plant-based diets', those who reported following 'low carbohydrate, high protein diets' had greater odds of moderate-to-severe COVID-19 (OR 3.86, 95% CI 1.13 to 13.24). No association was observed between self-reported diets and COVID-19 infection or duration. CONCLUSION: In six countries, plant-based diets or pescatarian diets were associated with lower odds of moderate-to-severe COVID-19. These dietary patterns may be considered for protection against severe COVID-19.

Access to personal protective equipment in exposed healthcare workers and COVID-19 illness, severity, symptoms and duration: a population-based case-control study in six countries.

BACKGROUND: Despite the widespread implementation of personal protective equipment (PPE) in the COVID-19 pandemic, there are surprisingly few studies of its impact. To assess the risk, severity and duration of COVID-19 in relation to access to PPE in at-risk healthcare workers (HCWs). METHODS: From 17 July to 25 September 2020, at-risk physicians and nurses registered as a provider in the Survey Healthcare Globus network in six countries (the UK, Germany, France, Italy, Spain and USA) were identified based on adult medical specialties with frequent and close contact with patients with COVID-19. Exposed HCWs completed a detailed questionnaire including demographics, medical, social and lifestyle factors. COVID-19 cases were defined as COVID-19 symptoms (fever, cough, fatigue, loss of taste or smell) and asymptomatic COVID-19 test positive cases. RESULTS: Among 2884 exposed HCWs (94% medical doctors and 6% nurses or physician assistants), there were 514 reports of COVID-19 illness and 54 asymptomatic COVID-19 test positive cases. COVID-19 risk was significantly associated with close contact with COVID-19 cases both inside and outside the workplace, number of work shifts and hours worked per week. Limited access to PPE compared with access to a fresh mask, gown and gloves and face shield with each patient encounter was associated with a 2.2-fold to 22-fold increased risk of reporting COVID-19 symptoms (p<0.0001), a pattern consistent across all six countries. Further, limited access to PPE was associated with symptom duration greater than 2 weeks and the presence of moderate to severe symptoms such as difficulty breathing, abnormal chest X-ray, low oxygen saturations, respiratory distress and acute lung injury. CONCLUSION: In six countries, less access to PPE was strongly associated with both increased risk of reporting COVID-19 illness as well as more prolonged and severe disease course in frontline HCWs.

Serum Metabolites Associated with Healthy Diets in African Americans and European Americans.

BACKGROUND: High diet quality is associated with a lower risk of chronic diseases. Metabolomics can be used to identify objective biomarkers of diet quality. OBJECTIVES: We used metabolomics to identify serum metabolites associated with 4 diet indices and the components within these indices in 2 samples from African Americans and European Americans. METHODS: We studied cross-sectional associations between known metabolites and Healthy Eating Index (HEI)-2015, Alternative Healthy Eating Index (AHEI)-2010, the Dietary Approaches to Stop Hypertension Trial (DASH) diet, alternate Mediterranean diet (aMED), and their components using untargeted metabolomics in 2 samples (n1 = 1,806, n2 = 2,056) of the Atherosclerosis Risk in Communities study (aged 45-64 y at baseline). Dietary intakes were assessed using an FFQ. We used multivariable linear regression models to examine associations between diet indices and serum metabolites in each sample, adjusting for participant characteristics. Metabolites significantly associated with diet indices were meta-analyzed across 2 samples. C-statistics were calculated to examine if these candidate biomarkers improved prediction of individuals in the highest compared with lowest quintile of diet scores beyond participant characteristics. RESULTS: Seventeen unique metabolites (HEI: n = 6; AHEI: n = 5; DASH: n = 14; aMED: n = 2) were significantly associated with higher diet scores after Bonferroni correction in sample 1 and sample 2. Six of 17 significant metabolites [glycerate, N-methylproline, stachydrine, threonate, pyridoxate, 3-(4-hydroxyphenyl)lactate)] were associated with ≥1 dietary pattern. Candidate biomarkers of HEI, AHEI, and DASH distinguished individuals with highest compared with lowest quintile of diet scores beyond participant characteristics in samples 1 and 2 (P value for difference in C-statistics <0.02 for all 3 diet indices). Candidate biomarkers of aMED did not improve C-statistics beyond participant characteristics (P value = 0.930). CONCLUSIONS: A considerable overlap of metabolites associated with HEI, AHEI, DASH, and aMED reflects the similar food components and similar metabolic pathways involved in the metabolism of healthy diets in African Americans and European Americans.

The association of retinal vessel calibres with heart failure and long-term alterations in cardiac structure and function: the Atherosclerosis Risk in Communities (ARIC) Study.

AIMS: Narrower retinal arterioles and wider retinal venules have been associated with macrovascular forms of cardiovascular disease (CVD). However, whether they are predictive of the development of heart failure (HF) independent of atherosclerotic CVD is unclear. We aimed to describe long-term associations of retinal vessel calibres with incident HF, in those with and without prevalent macrovascular disease, and how they relate to cardiac structure and function. METHODS AND RESULTS: This analysis included Atherosclerosis Risk in Communities Study participants who underwent retinal photography between 1993 and 1995. HF outcomes were followed in these participants until the end of 2013. Returning participants underwent echocardiography between 2011 and 2013. Participants with retinal vessel measurements who were free of CVD at baseline (n = 10 692) were followed for a mean of 16 years (baseline mean age 60 ± 6 years). Wider central retinal venular equivalent (CRVE) and narrower central retinal arteriolar equivalent (CRAE), adjusted for age, gender, and race, were significantly linearly associated with incident HF; however, a non-linear association was detected with CRVE and incident HF (P-value for overall trend < 0.001; P-value for non-linearity = 0.002). After adjustment with clinical risk factors, CRVE association with incident HF remained significant (P-value for overall trend = 0.025). Adjusted for age, gender, and race, CRVE widening and CRAE narrowing were associated with larger left ventricular size, higher prevalence of left ventricular hypertrophy, and worse measures of diastolic and systolic function. CONCLUSION: Retinal vessel calibre imaging, which characterizes retinal microvasculature, is a simple, non-invasive test that predicts incident HF and adverse cardiac structure/function 18 years in the future, thereby providing insight into systemic cardiovascular health.

Impact of Malnutrition Using Geriatric Nutritional Risk Index in Heart Failure With Preserved Ejection Fraction.

OBJECTIVES: This study sought to investigate the relationship between malnutrition and adverse cardiovascular (CV) events in heart failure with preserved ejection fraction (HFpEF). BACKGROUND: Malnutrition is associated with poor prognosis in a wide range of illnesses, however, the prognostic impact of malnutrition in HFpEF patients is not well known. METHODS: Baseline malnutrition risk was determined in 1,677 patients with HFpEF enrolled in the Americas regions of the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial, according to 3 categories of the geriatric nutritional risk index (GNRI) as previously validated: moderate to severe, GNRI of <92; low, GNRI of 92 to <98; and absence of risk, GNRI of ≥98. The relationships between malnutrition risk and the primary composite outcome of CV events (CV death, heart failure hospitalization, or resuscitated sudden death) and all-cause death were examined. RESULTS: Approximately one-third of patients were at risk for malnutrition (moderate to severe: 11%; low: 25%; and absence of risk: 64%). Over a median of 2.9-years' follow-up, compared to those with absent risk for malnutrition, moderate to severe risk was associated with significantly increased risk for the primary outcome, CV death and all-cause death (hazard ratio [HR]: 1.34; 95% confidence interval [CI]: 1.02 to 1.76; HR: 2.06; 95% CI: 1.40 to 3.03; and HR: 1.79; 95% CI: 1.33 to 2.42, respectively) after multivariate adjustment for age, sex, history of CV diseases, and laboratory biomarkers. CONCLUSIONS: Patients with HFpEF are at an elevated risk for malnutrition, which was associated with an increased risk for CV events in this population.

HFE H63D Polymorphism and the Risk for Systemic Hypertension, Myocardial Remodeling, and Adverse Cardiovascular Events in the ARIC Study.

H63D has been identified as a novel locus associated with the development of hypertension. The quantitative risks for hypertension, cardiac remodeling, and adverse events are not well studied. We analyzed white participants from the ARIC study (Atherosclerosis Risk in Communities) with H63D genotyping (N=10 902). We related genotype status to prevalence of hypertension at each of 5 study visits and risk for adverse cardiovascular events. Among visit 5 participants (N=4507), we related genotype status to echocardiographic features. Frequencies of wild type (WT)/WT, H63D/WT, and H63D/H63D were 73%, 24.6%, and 2.4%. The average age at baseline was 54.9±5.7 years and 47% were men. Participants carrying the H63D variant had higher systolic blood pressure ( P=0.004), diastolic blood pressure (0.012), and more frequently had hypertension ( P<0.001). Compared with WT/WT, H63D/WT and H63D/H63D participants had a 2% to 4% and 4% to 7% absolute increase in hypertension risk at each visit, respectively. The population attributable risk of H63D for hypertension among individuals aged 45 to 64 was 3.2% (95% CI, 1.3-5.1%) and 1.3% (95% CI, 0.0-2.4%) among individuals >65 years. After 25 years of follow-up, there was no relationship between genotype status and any outcome ( P>0.05). H63D/WT and H63D/H63D genotypes were associated with small differences in cardiac remodeling. In conclusion, the HFE H63D variant confers an increased risk for hypertension per allele and, given its frequency, accounts for a significant number of cases of hypertension. However, there was no increased risk for adverse cardiovascular events or substantial left ventricular remodeling.

Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk.

BACKGROUND: Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized. OBJECTIVES: The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. METHODS: Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed. RESULTS: Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)-Asn51Ser, Ala411Thr, and His615Gln-had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (ß-coefficient: -8.0; 95% confidence interval [CI]: -12.7 to -3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (ß = -16.3; 95% CI: -36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (ß = -3.2; 95% CI: -6.4 to -0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90). CONCLUSIONS: Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions.

Dietary carbohydrate intake and mortality: a prospective cohort study and meta-analysis.

BACKGROUND: Low carbohydrate diets, which restrict carbohydrate in favour of increased protein or fat intake, or both, are a popular weight-loss strategy. However, the long-term effect of carbohydrate restriction on mortality is controversial and could depend on whether dietary carbohydrate is replaced by plant-based or animal-based fat and protein. We aimed to investigate the association between carbohydrate intake and mortality. METHODS: We studied 15 428 adults aged 45-64 years, in four US communities, who completed a dietary questionnaire at enrolment in the Atherosclerosis Risk in Communities (ARIC) study (between 1987 and 1989), and who did not report extreme caloric intake (<600 kcal or >4200 kcal per day for men and <500 kcal or >3600 kcal per day for women). The primary outcome was all-cause mortality. We investigated the association between the percentage of energy from carbohydrate intake and all-cause mortality, accounting for possible non-linear relationships in this cohort. We further examined this association, combining ARIC data with data for carbohydrate intake reported from seven multinational prospective studies in a meta-analysis. Finally, we assessed whether the substitution of animal or plant sources of fat and protein for carbohydrate affected mortality. FINDINGS: During a median follow-up of 25 years there were 6283 deaths in the ARIC cohort, and there were 40 181 deaths across all cohort studies. In the ARIC cohort, after multivariable adjustment, there was a U-shaped association between the percentage of energy consumed from carbohydrate (mean 48·9%, SD 9·4) and mortality: a percentage of 50-55% energy from carbohydrate was associated with the lowest risk of mortality. In the meta-analysis of all cohorts (432 179 participants), both low carbohydrate consumption (<40%) and high carbohydrate consumption (>70%) conferred greater mortality risk than did moderate intake, which was consistent with a U-shaped association (pooled hazard ratio 1·20, 95% CI 1·09-1·32 for low carbohydrate consumption; 1·23, 1·11-1·36 for high carbohydrate consumption). However, results varied by the source of macronutrients: mortality increased when carbohydrates were exchanged for animal-derived fat or protein (1·18, 1·08-1·29) and mortality decreased when the substitutions were plant-based (0·82, 0·78-0·87). INTERPRETATION: Both high and low percentages of carbohydrate diets were associated with increased mortality, with minimal risk observed at 50-55% carbohydrate intake. Low carbohydrate dietary patterns favouring animal-derived protein and fat sources, from sources such as lamb, beef, pork, and chicken, were associated with higher mortality, whereas those that favoured plant-derived protein and fat intake, from sources such as vegetables, nuts, peanut butter, and whole-grain breads, were associated with lower mortality, suggesting that the source of food notably modifies the association between carbohydrate intake and mortality. FUNDING: National Institutes of Health.

Diagnostic and prognostic value of myocardial blood flow quantification as non-invasive indicator of cardiac allograft vasculopathy.

Aims: Cardiac allograft vasculopathy (CAV) is a leading cause of death in orthotopic heart transplant (OHT) survivors. Effective non-invasive screening methods are needed. Our aim was to investigate the added diagnostic and prognostic value of myocardial blood flow (MBF) to standard myocardial perfusion imaging (MPI) with positron emission tomography (PET) for CAV detection. Methods and results: We studied 94 OHT recipients (prognostic cohort), including 66 who underwent invasive coronary angiography and PET within 1 year (diagnostic cohort). The ISHLT classification was used as standard definition for CAV. Positron emission tomography evaluation included semiquantitative MPI, quantitative MBF (mL/min/g), and left ventricular ejection fraction (LVEF). A PET CAV severity score (on a scale of 0-3) was modelled on the ISHLT criteria. Patients were followed for a median of 2.3 years for the occurrence of major adverse events (death, re-transplantation, acute coronary syndrome, and hospitalization for heart failure). Sensitivity, specificity, positive, and negative predictive value of semiquantitative PET perfusion alone for detecting moderate-severe CAV were 83% [52-98], 82% [69-91], 50% [27-73], and 96% [85-99], respectively {receiver operating characteristic (ROC area: 0.82 [0.70-0.95])}. These values improved to 83% [52-98], 93% [82-98], 71% [42-92], and 96% [97-99], respectively, when LVEF and stress MBF were added (ROC area: 0.88 [0.76-0.99]; P = 0.01). There were 20 major adverse events during follow-up. The annualized event rate was 5%, 9%, and 25% in patients with normal, mildly, and moderate-to-severely abnormal PET CAV grading (P < 0.001), respectively. Conclusion: Multiparametric cardiac PET evaluation including quantification of MBF provides improved detection and gradation of CAV severity over standard myocardial perfusion assessment and is predictive of major adverse events.

Left Atrial structure and function in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy.

BACKGROUND: Impaired left atrial (LA) function is an early marker of cardiac dysfunction and predictor of adverse cardiac events. Herein, we assess LA structure and function in hypertrophy in hypertrophic cardiomyopathy (HCM) sarcomere mutation carriers with and without left ventricular hypertrophy (LVH). METHOD: Seventy-three participants of the HCMNet study who underwent cardiovascular magnetic resonance (CMR) imaging were studied, including mutation carriers with overt HCM (n = 34), preclinical mutation carriers without HCM (n = 24) and healthy, familial controls (n = 15). RESULTS: LA volumes were similar between preclinical, control and overt HCM cohorts after covariate adjustment. However, there was evidence of impaired LA function with decreased LA total emptying function in both preclinical (64 ± 8%) and overt HCM (59 ± 10%), compared with controls (70 ± 7%; p = 0.002 and p = 0.005, respectively). LA passive emptying function was also decreased in overt HCM (35 ± 11%) compared with controls (47 ± 10%; p = 0.006). Both LAtotal emptying function and LA passive emptying function were inversely correlated with the extent of late gadolinium enhancement (LGE; p = 0.005 and p < 0.05, respectively), LV mass (p = 0.02 and p < 0.001) and interventricular septal thickness (p < 0.001 for both) and serum NT-proBNP levels (p < 0.001 for both). CONCLUSION: LA dysfunction is detectable by CMR in preclinical HCM mutation carriers despite non-distinguishable LV wall thickness and LA volume. LA function appears most impaired in subjects with overt HCM and a greater extent of LV fibrosis.

Integrated Noninvasive Physiological Assessment of Coronary Circulatory Function and Impact on Cardiovascular Mortality in Patients With Stable Coronary Artery Disease.

BACKGROUND: It is suggested that the integration of maximal myocardial blood flow (MBF) and coronary flow reserve (CFR), termed coronary flow capacity, allows for comprehensive evaluation of patients with known or suspected stable coronary artery disease. Because management decisions are predicated on clinical risk, we sought to determine the independent and integrated value of maximal MBF and CFR for predicting cardiovascular death. METHODS: MBF and CFR were quantified in 4029 consecutive patients (median age 66 years, 50.5% women) referred for rest/stress myocardial perfusion positron emission tomography scans from January 2006 to December 2013. The primary outcome was cardiovascular mortality. Maximal MBF <1.8 mL·g-1·min-1 and CFR<2 were considered impaired. Four patient groups were identified based on the concordant or discordant impairment of maximal MBF or CFR. Association of maximal MBF and CFR with cardiovascular death was assessed using Cox and Poisson regression analyses. RESULTS: A total of 392 (9.7%) cardiovascular deaths occurred over a median follow-up of 5.6 years. CFR was a stronger predictor of cardiovascular mortality than maximal MBF beyond traditional cardiovascular risk factors, left ventricular ejection fraction, myocardial scar and ischemia, rate-pressure product, type of radiotracer or stress agent used, and revascularization after scan (adjusted hazard ratio, 1.79; 95% confidence interval [CI], 1.38-2.31; P<0.001 per unit decrease in CFR after adjustment for maximal MBF and clinical covariates; and adjusted hazard ratio, 1.03; 95% CI, 0.84-1.27; P=0.8 per unit decrease in maximal MBF after adjustment for CFR and clinical covariates). In univariable analyses, patients with concordant impairment of CFR and maximal MBF had high cardiovascular mortality of 3.3% (95% CI, 2.9-3.7) per year. Patients with impaired CFR but preserved maximal MBF had an intermediate cardiovascular mortality of 1.7% (95% CI, 1.3-2.1) per year. These patients were predominantly women (70%). Patients with preserved CFR but impaired maximal MBF had low cardiovascular mortality of 0.9% (95% CI, 0.6-1.6) per year. Patients with concordantly preserved CFR and maximal MBF had the lowest cardiovascular mortality of 0.4% (95 CI, 0.3-0.6) per year. In multivariable analysis, the cardiovascular mortality risk gradient across the 4 concordant or discordant categories was independently driven by impaired CFR irrespective of impairment in maximal MBF. CONCLUSIONS: CFR is a stronger predictor of cardiovascular mortality than maximal MBF. Concordant and discordant categories based on integrating CFR and maximal MBF identify unique prognostic phenotypes of patients with known or suspected coronary artery disease.

Human Papillomavirus Status and the Risk of Cerebrovascular Events Following Radiation Therapy for Head and Neck Cancer.

BACKGROUND: Radiation therapy (RT) is a standard treatment for head and neck cancer; however, it is associated with inflammation, accelerated atherosclerosis, and cerebrovascular events (CVEs; stroke or transient ischemic attack). Human papillomavirus (HPV) is found in nearly half of head and neck cancers and is associated with inflammation and atherosclerosis. Whether HPV confers an increased risk of CVEs after RT is unknown. METHODS AND RESULTS: Using an institutional database, we identified all consecutive patients treated with RT from 2002 to 2012 for head and neck cancer who were tested for HPV. The outcome of interest was the composite of ischemic stroke and transient ischemic attack, and the association between HPV and CVEs was assessed using Cox proportional hazard models, competing risk analysis, and inverse probability weighting. Overall, 326 participants who underwent RT for head and neck cancer were tested for HPV (age 59±12 years, 75% were male, 9% had diabetes mellitus, 45% had hypertension, and 61% were smokers), of which 191 (59%) were tumor HPV positive. Traditional risk factors for CVEs were similar between HPV-positive and -negative patients. Over a median follow-up of 3.4 years, there were 18 ischemic strokes and 5 transient ischemic attacks (event rate of 1.8% per year). The annual event rate was higher in the HPV-positive patients compared with the HPV-negative patients (2.6% versus 0.9%, P=0.002). In a multivariable model, HPV-positive status was associated with a >4 times increased risk of CVEs (hazard ratio: 4.4; 95% confidence interval, 1.5-13.2; P=0.008). CONCLUSIONS: In this study, HPV-positive status is associated with an increased risk of stroke or transient ischemic attack following RT for head and neck cancer.

An NPPB Promoter Polymorphism Associated With Elevated N-Terminal pro-B-Type Natriuretic Peptide and Lower Blood Pressure, Hypertension, and Mortality.

BACKGROUND: Elevated B-type natriuretic peptide (BNP) levels are associated with heart failure and increased mortality in the general population. We investigated rs198389, a functional variant in the promoter region of the BNP gene (NPPB), in patients from the Atherosclerosis Risk in Communities Study to investigate associations with N-terminal pro-BNP (NT-proBNP) levels and outcomes. METHODS AND RESULTS: A total of 11 361 black and white patients with rs198389 genotyping attended visit 1 (aged 45-64 years; 1987-1989), with follow-up visits occurring every 3 years (visit 2-visit 4, 1990-1999), followed by visit 5 (2011-2013). NT-proBNP levels were measured at visits 2, 4, and 5. At visit 2, the GG genotype (frequency 18%) was associated with a 41% higher mean plasma level of NT-proBNP compared with the AA genotype (frequency 34%), with intermediate values observed in AGs (P=4.2×10-52). The GG genotype was associated with reduced systolic blood pressure (-1.6 mm Hg, P=0.006), diastolic blood pressure (-1 mm Hg, P=0.003), antihypertension medication use (odds ratio, 0.85; 95% CI, 0.74-0.97 [P=0.02]), and hypertension (odds ratio, 0.81; 95% CI, 0.72-0.92 [P=0.002]) compared with the AA genotype with intermediate values in AGs. These relationships persisted throughout subsequent visits. After a median follow-up of 23 years, there were 4031 deaths. With and without covariate adjustment, the GG genotype was associated with modestly lower mortality (hazard ratio, 0.86; 95% CI, 0.78-0.95), primarily reflective of cardiovascular death (hazard ratio, 0.75; 95% CI, 0.61-0.92), and increased residual lifespan of 8 months from 50 years of age (P=0.02) versus AAs. CONCLUSIONS: The rs198389 G allele in the NPPB promoter is associated with elevated levels of NT-proBNP throughout adult life, reduced blood pressure, hypertension and cardiovascular mortality, and increased lifespan.