Samer S. Najjar

Newly identified loci that influence lipid concentrations and risk of coronary artery disease

To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.

Elevated Aortic Pulse Wave Velocity, a Marker of Arterial Stiffness, Predicts Cardiovascular Events in Well-Functioning Older Adults

Background—Aging results in vascular stiffening and an increase in the velocity of the pressure wave as it travels down the aorta. Increased aortic pulse wave velocity (aPWV) has been associated with mortality in clinical but not general populations. The objective of this investigation was to determine whether aPWV is associated with total and cardiovascular (CV) mortality and CV events in a community-dwelling sample of older adults. Methods and Results—aPWV was measured at baseline in 2488 participants from the Health, Aging and Body Composition (Health ABC) study. Vital status, cause of death and coronary heart disease (CHD), stroke, and congestive heart failure were determined from medical records. Over 4.6 years, 265 deaths occurred, 111 as a result of cardiovascular causes. There were 341 CHD events, 94 stroke events, and 181 cases of congestive heart failure. Results are presented by quartiles because of a threshold effect between the first and second aPWV quartiles. Higher aPWV was associated with both total mortality (relative risk, 1.5, 1.6, and 1.7 for aPWV quartiles 2, 3, and 4 versus 1; P=0.019) and cardiovascular mortality (relative risk, 2.1, 3.0, and 2.3 for quartiles 2, 3, and 4 versus 1; P=0.004). aPWV quartile was also significantly associated with CHD (P=0.007) and stroke (P=0.001). These associations remained after adjustment for age, gender, race, systolic blood pressure, known CV disease, and other variables related to events. Conclusions—Among generally healthy, community-dwelling older adults, aPWV, a marker of arterial stiffness, is associated with higher CV mortality, CHD, and stroke.

Arterial Aging: Is It an Immutable Cardiovascular Risk Factor?

Age is the dominant risk factor for cardiovascular diseases. However, until recently, convincing mechanistic or molecular explanations for the increased cardiovascular risks conferred by aging have been elusive. Aging is associated with alterations in a number of structural and functional properties of large arteries, including diameter, wall thickness, wall stiffness, and endothelial function. Emerging evidence indicates that these age-associated changes are also accelerated in the presence of cardiovascular diseases, and that these changes are themselves risk factors for the appearance or progression of these diseases. In this review, the evidence demonstrating that arterial aging is accelerated in cardiovascular diseases and that accelerated arterial aging is a risk factor for adverse cardiovascular outcomes is briefly reviewed, and selected advances in vascular biology that provide insights into the mechanisms that may underlie the increased risks conferred by arterial aging are summarized. Remarkably, a host of biochemical, enzymatic, and cellular alterations that are operative in accelerated arterial aging have also been implicated in the pathogenesis and progression of arterial diseases. These vascular alterations are thus putative candidates that could be targeted by interventions aimed at attenuating arterial aging, similar to the lifestyle and pharmacological interventions that have already been proven effective. Therefore, the notion that aging is a chronological process and that its risky components cannot be modulated is no longer tenable. It is our hope that a greater appreciation of the links between arterial aging and cardiovascular diseases will stimulate further investigation into strategies aimed at preventing or retarding arterial aging.

Common variants at ten loci modulate the QT interval duration in the QTSCD Study

The QT interval, a measure of cardiac repolarization, predisposes to ventricular arrhythmias and sudden cardiac death (SCD) when prolonged or shortened. A common variant in NOS1AP is known to influence repolarization. We analyze genome-wide data from five population-based cohorts (ARIC, KORA, SardiNIA, GenNOVA and HNR) with a total of 15,842 individuals of European ancestry, to confirm the NOS1AP association and identify nine additional loci at P < 5 × 10−8. Four loci map near the monogenic long-QT syndrome genes KCNQ1, KCNH2, SCN5A and KCNJ2. Two other loci include ATP1B1 and PLN, genes with established electrophysiological function, whereas three map to RNF207, near LITAF and within NDRG4-GINS3-SETD6-CNOT1, respectively, all of which have not previously been implicated in cardiac electrophysiology. These results, together with an accompanying paper from the QTGEN consortium, identify new candidate genes for ventricular arrhythmias and SCD.

Genome-wide association study of PR interval

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 × 10−8. At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

Pulse Wave Velocity Is an Independent Predictor of the Longitudinal Increase in Systolic Blood Pressure and of Incident Hypertension in the Baltimore Longitudinal Study of Aging

OBJECTIVES This study sought to evaluate whether pulse wave velocity (PWV), a noninvasive index of arterial stiffness, is a predictor of the longitudinal changes in systolic blood pressure (SBP) and of incident hypertension. BACKGROUND Although arterial stiffness is believed to underlie, in part, the age-associated changes in SBP, particularly at older ages, few longitudinal studies in humans have examined the relationship between arterial stiffness and blood pressure. METHODS Pulse wave velocity was measured at baseline in 449 normotensive or untreated hypertensive volunteers (age 53 +/- 17 years). Repeated measurements of blood pressure were performed during an average follow-up of 4.9 +/- 2.5 years. RESULTS After adjusting for covariates including age, body mass index, and mean arterial pressure, linear mixed effects regression models showed that PWV was an independent determinant of the longitudinal increase in SBP (p = 0.003 for the interaction term with time). In a subset of 306 subjects who were normotensive at baseline, hypertension developed in 105 (34%) during a median follow-up of 4.3 years (range 2 to 12 years). By stepwise Cox proportional hazards models, PWV was an independent predictor of incident hypertension (hazard ratio 1.10 per 1 m/s increase in PWV, 95% confidence interval 1.00 to 1.30, p = 0.03) in individuals with a follow-up duration greater than the median. CONCLUSIONS Pulse wave velocity is an independent predictor of the longitudinal increase in SBP and of incident hypertension. This suggests that PWV could help identify normotensive individuals who should be targeted for the implementation of interventions aimed at preventing or delaying the progression of subclinical arterial stiffening and the onset of hypertension.

Recommendations for Improving and Standardizing Vascular Research on Arterial Stiffness: A Scientific Statement From the American Heart Association.

Much has been published in the past 20 years on the use of measurements of arterial stiffness in animal and human research studies. This summary statement was commissioned by the American Heart Association to address issues concerning the nomenclature, methodologies, utility, limitations, and gaps in knowledge in this rapidly evolving field. The following represents an executive version of the larger online-only Data Supplement and is intended to give the reader a sense of why arterial stiffness is important, how it is measured, the situations in which it has been useful, its limitations, and questions that remain to be addressed in this field. Throughout the document, pulse-wave velocity (PWV; measured in meters per second) and variations such as carotid-femoral PWV (cfPWV; measured in meters per second) are used. PWV without modification is used in the general sense of arterial stiffness. The addition of lowercase modifiers such as “cf” is used when speaking of specific segments of the arterial circulation. The ability to measure arterial stiffness has been present for many years, but the measurement was invasive in the early times. The improvement in technologies to enable repeated, minimal-risk, reproducible measures of this aspect of circulatory physiology led to its incorporation into longitudinal cohort studies spanning a variety of clinical populations, including those at extreme cardiovascular risk (patients on dialysis), those with comorbidities such as diabetes mellitus (DM) and hypertension, healthy elders, and general populations. In the ≈3 decades of clinical use of PWV measures in humans, we have learned much about the importance of this parameter. PWV has proven to have independent predictive utility when evaluated in conjunction with standard risk factors for death and cardiovascular disease (CVD). However, the field of arterial stiffness investigation, which has exploded over the past 20 years, has proliferated without logistical guidance for clinical and …

Wave reflection and arterial stiffness in the prediction of 15-year all-cause and cardiovascular mortalities: a community-based study.

The value of increased arterial wave reflection, usually assessed by the transit time–dependent augmentation index and augmented pressure (Pa), in the prediction of cardiovascular events may have been underestimated. We investigated whether the transit time–independent measures of reflected wave magnitude predict cardiovascular outcomes independent of arterial stiffness indexed by carotid-femoral pulse wave velocity. A total of 1272 participants (47% women; mean age: 52±13 years; range: 30 to 79 years) from a community-based survey were studied. Carotid pressure waveforms derived by tonometry were decomposed into their forward wave amplitudes, backward wave amplitudes (Pb), and a reflection index (=[Pb/(forward wave amplitude+Pb)]), in addition to augmentation index, Pa, and reflected wave transit time. During a median follow-up of 15 years, 225 deaths occurred (17.6%), including 64 cardiovascular origins (5%). In univariate Cox proportional hazard regression analysis, pulse wave velocity, Pa, and Pb predicted all-cause and cardiovascular mortality in both men and women, whereas augmentation index, reflected wave transit time, and reflection index were predictive only in men. In multivariate analysis accounting for age, height, and heart rate, Pb predicted cardiovascular mortality in both men and women, whereas Pa was predictive only in men. Per 1-SD increment (6 mm Hg), Pb predicted 15-year cardiovascular mortality independent of brachial but not central pressure, pulse wave velocity, augmentation index, Pa, and conventional cardiovascular risk factors with hazard ratios of ≈1.60 (all P<0.05). In conclusion, Pb, a transit time–independent measure of reflected wave magnitude, predicted long-term cardiovascular mortality in men and women independent of arterial stiffness.

The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts.

High serum uric acid levels elevate pro-inflammatory–state gout crystal arthropathy and place individuals at high risk for cardiovascular morbidity and mortality. Genome-wide scans in the genetically isolated Sardinian population identified variants associated with serum uric acid levels as a quantitative trait. They mapped within GLUT9, a Chromosome 4 glucose transporter gene predominantly expressed in liver and kidney. SNP rs6855911 showed the strongest association (p = 1.84 × 10−16), along with eight others (p = 7.75 × 10−16 to 6.05 × 10−11). Individuals homozygous for the rare allele of rs6855911 (minor allele frequency = 0.26) had 0.6 mg/dl less uric acid than those homozygous for the common allele; the results were replicated in an unrelated cohort from Tuscany. Our results suggest that polymorphisms in GLUT9 could affect glucose metabolism and uric acid synthesis and/or renal reabsorption, influencing serum uric acid levels over a wide range of values.

An analysis of pump thrombus events in patients in the HeartWare ADVANCE bridge to transplant and continued access protocol trial

BACKGROUND The HeartWare left ventricular assist device (HVAD, HeartWare Inc, Framingham, MA) is the first implantable centrifugal continuous-flow pump approved for use as a bridge to transplantation. An infrequent but serious adverse event of LVAD support is thrombus ingestion or formation in the pump. In this study, we analyze the incidence of pump thrombus, evaluate the comparative effectiveness of various treatment strategies, and examine factors pre-disposing to the development of pump thrombus. METHODS The analysis included 382 patients who underwent implantation of the HVAD as part of the HeartWare Bridge to Transplant (BTT) and subsequent Continued Access Protocol (CAP) trial. Descriptive statistics and group comparisons were generated to analyze baseline characteristics, incidence of pump thrombus, and treatment outcomes. A multivariate analysis was performed to assess significant risk factors for developing pump thrombus. RESULTS There were 34 pump thrombus events observed in 31 patients (8.1% of the cohort) for a rate of 0.08 events per patient-year. The incidence of pump thrombus did not differ between BTT and CAP. Medical management of pump thrombus was attempted in 30 cases, and was successful in 15 (50%). A total of 16 patients underwent pump exchange, and 2 underwent urgent transplantation. Five patients with a pump thrombus died after medical therapy failed, 4 of whom also underwent a pump exchange. Survival at 1 year in patients with and without a pump thrombus was 69.4% and 85.5%, respectively (p = 0.21). A multivariable analysis revealed that significant risk factors for pump thrombus included a mean arterial pressure > 90 mm Hg, aspirin dose ≤ 81 mg, international normalized ratio ≤ 2, and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile level of ≥ 3 at implant. CONCLUSIONS Pump thrombus is a clinically important adverse event in patients receiving an HVAD, occurring at a rate of 0.08 events per patient-year. Significant risk factors for pump thrombosis include elevated blood pressure and sub-optimal anti-coagulation and anti-platelet therapies. This suggests that pump thrombus event rates could be reduced through careful adherence to patient management guidelines.