HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.

Pre-Liver Transplant Transthoracic Echocardiogram Findings and 6-Month Post-Transplant Outcomes: A Case-Control Analysis.

BACKGROUND Cardiopulmonary (CP) outcomes remain a leading cause of morbidity and mortality following liver transplantation (LT). The optimal CP risk stratification of LT candidates remains unclear. The aim of this study was to evaluate the association of pre-LT transthoracic echocardiogram (TTE) findings and 6-month post-LT outcomes. MATERIAL AND METHODS This retrospective review analyzed adults who underwent LT, comparing those who died within 6 months of LT (cases; n=38) with age- and sex-matched patients who survived >6 months (controls; n=38). Cases were categorized by cause of death (COD) defined as either a primary CP process (n=20) or a non-CP process (n=18). Data were analyzed using logistic regression and survival analysis was performed using Kaplan-Meier curves. RESULTS There was a higher odds of death within 6 months of LT with ≥ mild mitral regurgitation (OR 3.44, p=0.03) or an incomplete assessment of right ventricular systolic function (RVSF) (OR 24, p=0.004). On subgroup analysis, these findings only persisted in patients with a CP COD. Patients with CP COD were older (61 vs. 54.5, p=0.04), had longer intervals between TTE and LT (122 vs. 29 days, p=0.05), less complete assessments of RVSF (p=0.009), and lower RV fractional area change (p=0.04) compared to patients with non-CP COD. CONCLUSIONS Multiple TTE parameters were associated with patients who died within 6 months of LT, and in particular patients with a CP COD. Our findings suggest that pre-LT TTEs can convey useful CP risk stratification information and emphasizes the importance of adequately assessing these parameters prior to LT.

Genetic associations with valvular calcification and aortic stenosis.

BACKGROUND: Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. METHODS: We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. RESULTS: One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently. CONCLUSIONS: Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).

Waiting for the National Cholesterol Education Program Adult Treatment Panel IV Guidelines, and in the meantime, some challenges and recommendations.

The National Cholesterol Education Program Adult Treatment Panel (ATP) has provided education and guidance for decades on the management of hypercholesterolemia. Its third report (ATP III) was published 10 years ago, with a white paper update in 2004. There is a need for translation of more recent evidence into a revised guideline. To help address the significant challenges facing the ATP IV writing group, this statement aims to provide balanced recommendations that build on ATP III. The authors aim for simplicity to increase the likelihood of implementation in clinical practice. To move from ATP III to ATP IV, the authors recommend the following: (1) assess risk more accurately, (2) simplify the starting algorithm, (3) prioritize statin therapy, (4) relax the follow-up interval for repeat lipid testing, (5) designate <70 mg/dl as an "ideal" low-density lipoprotein cholesterol target, (6) endorse targets beyond low-density lipoprotein cholesterol, (7) refine therapeutic target levels to the equivalent population percentile, (8) remove misleading descriptors such as "borderline high," and (9) make lifestyle messages simpler. In conclusion, the solutions offered in this statement represent ways to translate the totality of published reports into enhanced hyperlipidemia guidelines to better combat the devastating impact of hyperlipidemia on cardiovascular health.

Acute changes in N-terminal pro-B-type natriuretic peptide during hospitalization and risk of readmission and mortality in patients with heart failure.

The level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a predictor of adverse events in patients with heart failure. We examined the relation between acute changes in NT-proBNP during a single hospitalization and subsequent mortality and readmission. The data from a cohort of 241 consecutive patients aged ≥ 25 years who had been admitted to an urban tertiary care hospital with a primary diagnosis of heart failure were analyzed. Creatinine and NT-proBNP were measured at admission and at discharge of the first admission. The patient demographics, co-morbidities, and length of stay were collected. The patients were prospectively grouped into 2 categories according to the acute changes in NT-proBNP: a decrease of ≥ 50% or <50% from admission to discharge. The primary composite outcome was readmission or death within 1 year of the first hospital admission. The unadjusted hazard ratio of readmission/death was 1.40 (95% confidence interval 0.97 to 2.01; p = 0.07) for those with a < 50% decrease in NT-proBNP compared to their counterparts with a ≥ 50% decrease. After adjustment for age, gender, race, and admission creatinine and NT-proBNP, the risk of readmission/death was 57% greater for those with a < 50% decrease (hazard ratio 1.57, 95% confidence interval 1.08 to 2.28; p = 0.02). An adjustment for co-morbidity, length of stay, and left ventricular ejection fraction did not significantly change this relation. Reductions in NT-proBNP of < 50% during an acute hospitalization for heart failure might be associated with an increased hazard of readmission/death, independent of age, gender, race, creatinine, admission NT-proBNP, co-morbidities, left ventricular ejection fraction, and length of stay. In conclusion, patients with a < 50% reduction in NT-proBNP might benefit from more intensive medical treatment, monitoring, and follow-up.

Associations between genetic variants in the ACE, AGT, AGTR1 and AGTR2 genes and renal function in the Multi-ethnic Study of Atherosclerosis.

BACKGROUND/AIMS: Some studies suggest that polymorphisms in angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II type I receptor (AGTR1) and angiotensin II type II receptor (AGTR2) genes may contribute to renal function variation. METHODS: Genotyping for single nucleotide polymorphisms (SNPs) in these candidate genes was performed in 2,847 participants from four racial/ethnic groups (African American, Chinese, White and Hispanic) without known cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. SNP and haplotype analyses were performed to determine associations between genotypes and cross-sectional renal function measurements, including urine albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) using serum creatinine and cystatin C. RESULTS: Twenty-four ACE SNPs, 10 AGT SNPs, 15 AGTR1 SNPs and 6 AGTR2 SNPs were typed successfully. After adjusting for ancestry, age and gender, 3 SNPs (AGT M235T, AGT rs2148582 and AGTR1 rs2131127) showed associations with an empiric p value <0.05 with the same phenotype in multiple racial/ethnic groups, suggesting replication. The AGT M235T SNP has been shown previously to be associated with diabetic and hypertensive nephropathy. CONCLUSIONS: These data suggest that genetic polymorphisms in the renin-angiotensin system are associated with renal phenotypes in the general population, but that many associations differ across racial/ethnic groups.

Usefulness of cystatin C and prognosis following admission for acute heart failure.

Cystatin C is a novel marker of renal function that has been found to predict adverse cardiovascular outcomes in ambulatory patients. The aim of this study was to investigate whether this biomarker predicts the length of hospitalization and adverse outcomes in patients hospitalized for heart failure. Two hundred forty consecutive patients aged > or =25 admitted to Johns Hopkins Hospital with exacerbations of heart failure were prospectively enrolled. Cystatin C levels were measured on admission. Patients were followed for 1 year. The primary outcome measure was the length of hospitalization. Secondary outcomes included all-cause mortality and readmission for heart failure. Cystatin C showed no significant association with the length of hospitalization. Patients in the highest quartile (quartile 4) of cystatin C level were at increased risk for death (hazard ratio 2.07 for quartile 4 vs quartiles 1 to 3, p = 0.01) and death or rehospitalization (hazard ratio 1.61 for quartile 4 vs quartiles 1 to 3, p = 0.01). The association between cystatin C and the combined end point of death or rehospitalization during 1-year follow-up remained significant after adjusting for age, race, gender, co-morbidities, and creatinine. Cystatin C was more predictive of these end points than creatinine, and the combination of cystatin C and creatinine was more predictive than either variable alone. In conclusion, cystatin C may be useful in addition to creatinine for predicting outcomes after admission for acute heart failure exacerbations.

Coronary artery calcification and inflammation according to various metabolic syndrome definitions.

A number of metabolic syndrome (MS) definitions exist, and one's cardiovascular disease risk may depend on the definition used. The authors compared the association of subclinical atherosclerosis (coronary artery calcification [CAC] score >0] and inflammation (white blood cell [WBC] count greater than or equal to the highest quartile) with 3 definitions of MS (those of the National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III], the American Heart Association/National Heart, Lung and Blood Institute [AHA/NHLBI], and the International Diabetes Federation [IDF]) in 458 asymptomatic men (mean age, 46+/-7 years). MS was present in 28%, 29%, and 34% according to NCEP ATP III, AHA/NHLBI, and IDF criteria, respectively. CAC was observed in 40% and high WBC count in 24%. After adjustment for age, smoking, and low-density lipoprotein cholesterol, the odds ratios for CAC scores >0 with MS by NCEP ATP III, AHA/NHLBI, and IDF definitions were 1.67 (95% confidence interval [CI], 1.02-2.72), 1.67 (95% CI, 1.03-2.70), and 1.63 (95% CI, 1.03-2.57), respectively. The multivariate odds ratios for high WBC count with MS by NCEP ATP III, AHA/NHLBI, and IDF definitions were 1.69 (95% CI, 1.04-2.73), 1.84 (95% CI, 1.14-2.95), and 1.66 (95% CI, 1.05-2.62), respectively. MS is associated with increased subclinical atherosclerosis and inflammation irrespective of various definitions.

The use of high-sensitivity assays for C-reactive protein in clinical practice.

High-sensitivity assays that accurately measure levels of the inflammatory biomarker C-reactive protein have been proposed for use in assessments of risk for cardiovascular disease (CVD). A growing body of evidence supports recommendations for these tests in selected asymptomatic individuals deemed to be at intermediate risk of CVD according to traditional risk-factor assessments and who do not already warrant chronic treatment with aspirin and statin therapy. Data suggests that these high-sensitivity assays should be used in combination with measurements of LDL-cholesterol levels to assist risk stratification of selected patients for prevention of CVD.

The metabolic syndrome adds incremental value to the Framingham risk score in identifying asymptomatic individuals with higher degrees of inflammation.

Recent studies have shown that elevated white blood cell (WBC) counts independently predict adverse cardiovascular disease (CVD) outcomes. The metabolic syndrome (MS) is known to be associated with a higher degree of inflammation and increased CVD risk. It is unclear, however, whether MS provides incremental information to the Framingham risk score (FRS). The authors studied 458 asymptomatic men, of whom 112 had MS. WBC count was used as a marker of inflammation. The odds ratio (OR) for presence of WBCs in the highest quartile vs the lower 3 quartiles was 2.2; 95% confidence interval (CI), 1.39-3.40 for MS. After further adjustment for the FRS, the relationship remained significant (OR, 1.97; 95% CI, 1.25-3.13). The ability to identify higher levels of WBCs with MS was especially important in the low-risk men (OR, 2.66; 95% CI, 1.39-5.07). The study findings suggest that MS adds value to the FRS in identifying those with higher degrees of inflammation, especially among those classified as low-risk by the FRS.

Residual risk in statin-treated patients: future therapeutic options.

Statin therapy for aggressive low-density lipoprotein cholesterol (LDL-C) reduction reduces cardiovascular morbidity and mortality. However, even on maximal statin therapy, high-risk patients have substantial residual risk of coronary heart disease (CHD). Certain subgroups, such as individuals with diabetes mellitus, low high-density lipoprotein cholesterol (HDL-C), metabolic syndrome, or other comorbidities, have a particularly high residual risk. Patients at high risk for future CHD events often require multiple aggressive risk-reduction therapies (eg, antiplatelet agents, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, beta-blockade, cholesterol and/or diabetes management, and lifestyle interventions) to further lower their overall cardiovascular risk. For cholesterol management, combination therapy may be required to attain optimal levels of LDL-C, HDL-C, and non-HDL-C.

Combined effect of high low-density lipoprotein cholesterol and metabolic syndrome on subclinical coronary atherosclerosis in white men without clinical evidence of myocardial ischemia.

High low-density lipoprotein (LDL) cholesterol and the presence of metabolic syndrome (MS) are established risk factors for clinical and subclinical cardiovascular disease (CVD). However, the relative contribution to CVD risk of MS and high LDL cholesterol is not well defined. Therefore, the aim was assess the relative risk for the presence of coronary artery calcification (CAC) with metabolic syndrome (MS) compared with that of moderate or high LDL cholesterol. A total of 440 consecutive asymptomatic men (mean age 46 +/- 7 years, range 29 to 65) presenting for CVD risk stratification were studied. MS was defined using National Cholesterol Education Program Adult Treatment Panel III criteria (n = 112; 24%). Moderate LDL cholesterol was defined as 130 to 159 mg/dl, and high LDL cholesterol as >/=160 mg/dl (n = 76; 17%). Overall, CAC was observed in 190 men (40%). The prevalence of CAC >0 was lowest in MS-negative men with LDL cholesterol <130 (35%) or 130 to 159 mg/dl (34%) and highest in MS-positive men with LDL cholesterol >/=160 mg/dl (80%). MS-positive men with LDL cholesterol of 130 to 159 mg/dl had CAC prevalence similar to that of MS-negative men with LDL cholesterol >/=160 mg/dl (54% vs 57%, respectively). This relation persisted with additional adjustment for age, smoking status, and cholesterol-lowering medication. In logistic regression analyses, the odds ratio for CAC >0 was highest in MS-positive men combined with high LDL cholesterol. In conclusion, these results suggest that the risk of CAC in asymptomatic men with moderate or high LDL cholesterol is magnified in persons with MS.

C-reactive protein in cardiovascular risk assessment: a review of the evidence.

C-reactive protein (CRP) is an inflammatory biomarker that is strongly associated with coronary heart disease, inflammation, and the metabolic syndrome. Large-scale prospective cohort trials have shown that measurement of CRP may add predictive accuracy to the Framingham risk score, but interpretation of these data are conflicting. In the primary prevention setting, CRP can be used to reclassify patients in low or intermediate Framingham risk score groups to a higher risk category, thus making them eligible for more intensive pharmacologic interventions.

Chest pain in a young basketball player.

A 32-year-old man was elbowed in the chest while fighting for a rebound in a recreational basketball game. He fell to the ground and his chest ached from the blow. Four days later he developed more severe chest pressure with dyspnea and came to the hospital. His chest wall was tender and his pulse slow, but the remainder of his physical examination was normal. Electrocardiogram showed sinus bradycardia, first-degree atrioventricular (AV) block, and occasional isorhythmic AV dissociation, but no ischemic ST-T changes. Cardiac troponin I rose to 1.74 ng/mL (normal <0.50). The patient therefore underwent coronary angiography, showing spiral dissection of the right coronary artery with extensive thrombus filling the distal portion of the vessel. Stenting was unsuccessful in restoring flow. This case highlights the potential dangers of blunt chest trauma in recreational sports and shows how angiography can distinguish myocardial contusion from coronary artery dissection.

Role of atherosclerosis assessment and other novel markers in the metabolic syndrome.

The metabolic syndrome is a constellation of cardiovascular disease risk factors predisposing to future cardiovascular disease events as well as the development of type 2 diabetes mellitus. This syndrome is closely linked to both subclinical atherosclerosis and vascular inflammation. The extent of vascular inflammation can be estimated by a number of biomarkers, such as high-sensitivity C-reactive protein, that are associated with the presence of the metabolic syndrome. Evaluating for the presence of subclinical atherosclerosis and inflammatory biomarkers may help to risk stratify patients with the metabolic syndrome.

The association of subclinical coronary atherosclerosis with abdominal and total obesity in asymptomatic men.

The present study assesses and compares the association of waist circumference and body mass index with presence and severity of coronary artery calcium in asymptomatic men. The study population consisted of 451 asymptomatic men free of known coronary heart disease. The subjects were broadly divided into tertiles by waist circumference (< or =92 cm; 92.5-100 cm; > or =101 cm) and body mass index (< or =25.5 kg/m2; 25.6-28.4 kg/m2; > or =28.5 kg/m2), respectively. The risk of coronary artery calcium was two-fold higher among those with a waist circumference in the highest tertile (> or =101 cm) compared with men with waist circumference < or =92 cm. The relationship was found to be independent of body mass index, age, and conventional coronary heart disease risk factors. No significant association of body mass index with coronary artery calcium was observed. Our results are consistent with evidence that measures of central obesity, compared with body mass index, are more strongly related to clinical as well as subclinical coronary heart disease end points.

Metabolic syndrome, subclinical coronary atherosclerosis, and cardiovascular risk.

The metabolic syndrome is a constellation of cardiovascular disease risk factors, and it is associated with the presence of advanced subclinical coronary atherosclerosis. The presence of the metabolic syndrome appears to provide incremental predictive value on top of the Framingham risk score in predicting future cardiovascular events. Traditional risk-prediction formulas fail to account for a significant portion of coronary heart disease morbidity and mortality. The metabolic syndrome may be particularly useful in predicting risk among individuals classified as low or intermediate risk by Framingham risk score.