Bone mineral density and long-term progression of aortic valve and mitral annular calcification: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: Bone and mineral metabolism has been implicated in the pathophysiology of cardiac valve calcification. Whether bone demineralization, a common aging-related disorder, promotes calcific valve disease remains uncertain. We tested the hypothesis that low bone mineral density (BMD) is associated with greater incidence/progression of cardiac valve calcification in the Multi-Ethnic Study of Atherosclerosis. METHODS: Using linear mixed-effects models, we related baseline measurement of BMD of the thoracic vertebrae by computed tomography (CT) in 6768 participants to serial CT assessments of aortic valve calcification (AVC) and mitral annular calcification (MAC) obtained over a >10-year period. RESULTS: After multivariable adjustment, lower BMD (per SD decrement) was associated with accelerated increase in AVC over time in women (0.76 [95% CI 0.42,1.09] Agatston -units [AU]/year) and men (1.41 [95% CI 0.48,2.33] AU/year), as well as for MAC in women (3.22 [95% CI 1.16,5.28] AU/year) and men (3.59 [95% CI 2.09,5.09] AU/year). Significant effect modification was observed, with more pronounced BMD-related acceleration of AVC and MAC progression in older or white participants of one or both sexes, as well as by estimated glomerular filtration rate, though the latter differed by sex for AVC and MAC. CONCLUSIONS: In this multi-ethnic cohort, low thoracic BMD was significantly, but modestly, associated with increased AVC and MAC progression. This suggests that altered bone mineral metabolism does not have a major impact on calcific valve disease in the general population, but the possibility of a more meaningful influence in higher-risk individuals with osteoporosis will require further investigation.

Electrocardiogram interpretation in college athletes: Local institution versus sports cardiology center interpretation.

BACKGROUND: Electrocardiogram (ECG) screening in athletes enhances the detection of conditions associated with sudden cardiac death (SCD), but concerns remain for false positive results when conducted outside of specialized centers. This study compared ECG interpretation in college athletes between local physicians and a sports cardiology center (SCC). METHODS: Screening ECGs in athletes from eight Pacific-12 Conference institutions performed between 2010 and 2016 were included. Local interpretation was compared to SCC interpretation using both the Seattle Criteria (SCC-SC) and the International Criteria (SCC-IC). RESULTS: A total of 2445 athlete ECGs (mean age 18.5 years; 57.1% male; 63.2% Caucasian and 15.3% African American) were reviewed. The proportion of ECGs classified as abnormal was similar between local and SCC-SC interpretation (3.5% vs. 3.4%, respectively; p = .94), but was lower by SCC-IC interpretation (1.5%, p < .001). ECG abnormalities interpreted as normal by local physicians but as abnormal by SCC-SC (n = 33) and SCC-IC (n = 16) standards included: pathological Q waves (n = 15 SCC-SC; n = 3 SCC-IC), T-wave inversions (n = 8 both), and ST-depressions (n = 3 both). There was a 97.5% ECG interpretation agreement and substantial interobserver reliability (k = 0.611, p < .001) between local and SCC-SC interpretation in athletes screened starting one year after publication of the Seattle Criteria (n = 1388). Both local and SCC physicians correctly identified six abnormal ECGs associated with conditions at risk of SCD. CONCLUSIONS: ECG interpretation by local physicians at college universities had similar accuracy compared to a specialized SCC with a low overall abnormal rate, similar sensitivity, and substantial interobserver reliability. Uniform application of current ECG interpretation standards is recommended to further improve accuracy.

Comparison of cardiovascular screening in college athletes by history and physical examination with and without an electrocardiogram: Efficacy and cost.

BACKGROUND: Preparticipation screening for conditions associated with sudden cardiac death (SCD) is required in college athletes. Previous cost analyses used theoretical models based on variable assumptions, but no study used real-life outcomes. OBJECTIVE: The purpose of this study was to compare disease prevalence, positive findings, and costs of 2 different screening strategies: history and physical examination alone (H&P) or with an electrocardiogram (H&P+ECG). METHODS: De-identified preparticipation data (2009-2017) from Pacific-12 Conference institutions were abstracted for cardiovascular history questions, cardiovascular physical examination, and ECG result. Secondary testing, cardiac diagnoses, return to play outcomes, and complications from testing were recorded. The costs of screening and secondary testing were based on the Centers for Medicare & Medicaid Services Physician Fee Schedule. RESULTS: A total of 8602 records (4955 H&P, 3647 H&P+ECG) were included. Eleven conditions associated with SCD were detected (2 H&P only, 9 H&P+ECG). The prevalence of cardiovascular conditions associated with SCD discovered with H&P alone was 0.04% (1/2454) compared to 0.24% (1/410) when ECG was added (P = .01) (odds ratio 5.17; 95% confidence interval 1.28-20.85; P = .02). Cost of screening and secondary testing with H&P alone was $130 per athlete and in the ECG-added group was $152 per athlete. The cost per diagnosis was $312,407 in the H&P group and $61,712 in the ECG-added group. There were no adverse outcomes from secondary testing or treatment. CONCLUSION: H&P with the addition of ECG is 6 times more likely to detect a cardiovascular condition associated with SCD than without. The addition of ECG improves the cost efficiency per diagnosis by 5-fold and should be considered at college institutions with appropriate resources.

Performance of the American Heart Association ( AHA ) 14-Point Evaluation Versus Electrocardiography for the Cardiovascular Screening of High School Athletes: A Prospective Study.

Background Preparticipation cardiovascular screening in athletes is fully endorsed by major medical societies, yet the most effective screening protocol remains debated. We prospectively compared the performance of the American Heart Association ( AHA ) 14-point screening evaluation and a resting ECG for cardiovascular screening of high school athletes. Methods and Results Competitive athletes participating in organized high school or premier/select level sports underwent cardiovascular screening using the AHA 14-point history and physical examination, and an ECG interpreted with the Seattle Criteria. A limited echocardiogram was performed for all screening abnormalities. The primary outcome measure was identification of a cardiovascular disorder associated with sudden cardiac death. From October 2014 to June 2017, 3620 high school athletes (median age, 16 years; range 13-19; 46.2% female; 78.6% white, 8.0% black) were screened. One or more positive responses to the AHA 14-point questionnaire were present in 814 (22.5%) athletes. The most common history responses included chest pain (8.1%), family history of inheritable conditions (7.3%), and shortness of breath (6.4%). Abnormal physical examination was present in 356 (9.8%) athletes, and 103 (2.8%) athletes had an abnormal ECG . Sixteen (0.4%) athletes had conditions associated with sudden cardiac death. The sensitivity (18.8%), specificity (68.0%), and positive predictive value (0.3%) of the AHA 14-point evaluation was substantially lower than the sensitivity (87.5%), specificity (97.5%), and positive predictive value (13.6%) of ECG . Conclusions The AHA 14-point evaluation performs poorly compared with ECG for cardiovascular screening of high school athletes. The use of consensus-derived history questionnaires as the primary tool for cardiovascular screening in athletes should be reevaluated.

Prevalence of Unexplained Left Ventricular Hypertrophy by Cardiac Magnetic Resonance Imaging in MESA.

Background Hypertrophic cardiomyopathy is defined as unexplained left ventricular ( LV ) hypertrophy (wall thickness ≥15 mm) and is prevalent in 0.2% of adults (1:500) in population-based studies using echocardiography. Cardiac magnetic resonance imaging ( MRI ) allows for more accurate wall thickness measurement across the entire ventricle than echocardiography. The prevalence of unexplained LV hypertrophy by cardiac MRI is unknown. MESA (Multi-Ethnic Study of Atherosclerosis) recruited individuals without overt cardiovascular disease 45 to 84 years of age. Methods and Results We studied 4972 individuals who underwent measurement of regional LV wall thickness by cardiac MRI as part of the MESA baseline exam. American Heart Association criteria were used to define LV segments. We excluded participants with hypertension, LV dilation (≥95% predicted end-diastolic volume) or dysfunction (ejection fraction ≤50%), moderate-to-severe left-sided valve lesions by cardiac MRI , severe aortic valve calcification by cardiac computed tomography (aortic valve Agatston calcium score >1200 in women or >2000 in men), obesity (body mass index >35 kg/m2), diabetes mellitus, and current smoking. Sixty-seven participants (aged 64±10 years, 9% female) had unexplained LV hypertrophy (wall thickness ≥15 mm in at least 2 adjacent LV segments), representing 1.4% (1 in 74) participants, 2.6% of men and 0.2% of women. Prevalence was similar across categories of race/ethnicity. Hypertrophy was focal in 17 (25.4%), intermediate in 44 (65.7%), and diffuse in 5 (7.5%) participants. Conclusions The prevalence of unexplained LV hypertrophy in a population-based cohort using cardiac MRI was 1.4%. This may have implications for the diagnosis of patients with hypertrophic cardiomyopathy and will require further study.

Association of Triglyceride-Related Genetic Variants With Mitral Annular Calcification.

BACKGROUND: Mitral annular calcium (MAC), commonly identified by cardiac imaging, is associated with cardiovascular events and predisposes to the development of clinically important mitral valve regurgitation and mitral valve stenosis. However, its biological determinants remain largely unknown. OBJECTIVES: The authors sought to evaluate whether a genetic predisposition to elevations in plasma lipids is associated with the presence of MAC. METHODS: The authors used 3 separate Mendelian randomization techniques to evaluate the associations of lipid genetic risk scores (GRS) with MAC in 3 large patient cohorts: the Framingham Health Study, MESA (Multiethnic European Study of Atherosclerosis), and the AGE-RS (Age, Gene/Environment Susceptibility-Reykjavik Study). The authors provided cross-ethnicity replication in the MESA Hispanic-American participants. RESULTS: MAC was present in 1,149 participants (20.4%). In pooled analyses across all 3 cohorts, a triglyceride GRS was significantly associated with the presence of MAC (odds ratio [OR] per triglyceride GRS unit: 1.73; 95% confidence interval [CI]: 1.24 to 2.41; p = 0.0013). Neither low- nor high-density lipoprotein cholesterol GRS was significantly associated with MAC. Results were consistent in cross-ethnicity analyses among the MESA Hispanic-Americans cohort (OR per triglyceride GRS unit: 2.04; 95% CI: 1.03 to 4.03; p = 0.04). In joint meta-analysis across all included cohorts, the triglyceride GRS was associated with MAC (OR per triglyceride GRS unit: 1.79; 95% CI: 1.32 to 2.41; p = 0.0001). The results were robust to several sensitivity analyses that limit both known and unknown forms of genetic pleiotropy. CONCLUSIONS: Genetic predisposition to elevated triglyceride levels was associated with the presence of MAC, a risk factor for clinically significant mitral valve disease, suggesting a causal association. Whether reducing triglyceride levels can lower the incidence of clinically significant mitral valve disease requires further study.

Relationship of bone mineral density with valvular and annular calcification in community-dwelling older people: The Cardiovascular Health Study.

Associations between bone mineral density and aortic valvular, aortic annular, and mitral annular calcification were investigated in a cross-sectional analysis of a population-based cohort of 1497 older adults. Although there was no association between continuous bone mineral density and outcomes, a significant association between osteoporosis and aortic valvular calcification in men was found. INTRODUCTION: The process of cardiac calcification bears a resemblance to skeletal bone metabolism and its regulation. Experimental studies suggest that bone mineral density (BMD) and valvular calcification may be reciprocally related, but epidemiologic data are sparse. METHODS: We tested the hypothesis that BMD of the total hip and femoral neck measured by dual-energy X-ray absorptiometry (DXA) is inversely associated with prevalence of three echocardiographic measures of cardiac calcification in a cross-sectional analysis of 1497 older adults from the Cardiovascular Health Study. The adjusted association of BMD with aortic valve calcification (AVC), aortic annular calcification (AAC), and mitral annular calcification (MAC) was assessed with relative risk (RR) regression. RESULTS: Mean (SD) age was 76.2 (4.8) years; 58% were women. Cardiac calcification was highly prevalent in women and men: AVC, 59.5 and 71.0%; AAC 45.1 and 46.7%; MAC 42.8 and 39.5%, respectively. After limited and full adjustment for potential confounders, no statistically significant associations were detected between continuous BMD at either site and the three measures of calcification. Assessment of WHO BMD categories revealed a significant association between osteoporosis at the total hip and AVC in men (adjusted RR compared with normal BMD = 1.24 (1.01-1.53)). In graded sensitivity analyses, there were apparent inverse associations between femoral neck BMD and AVC with stenosis in men, and femoral neck BMD and moderate/severe MAC in women, but these were not significant. CONCLUSION: These findings support further investigation of the sex-specific relationships between low BMD and cardiac calcification, and whether processes linking the two could be targeted for therapeutic ends.

International criteria for electrocardiographic interpretation in athletes: Consensus statement.

Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport. A variety of mostly hereditary, structural or electrical cardiac disorders are associated with SCD in young athletes, the majority of which can be identified or suggested by abnormalities on a resting 12-lead electrocardiogram (ECG). Whether used for diagnostic or screening purposes, physicians responsible for the cardiovascular care of athletes should be knowledgeable and competent in ECG interpretation in athletes. However, in most countries a shortage of physician expertise limits wider application of the ECG in the care of the athlete. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from distinctly abnormal findings suggestive of underlying pathology. Since the original 2010 European Society of Cardiology recommendations for ECG interpretation in athletes, ECG standards have evolved quickly, advanced by a growing body of scientific data and investigations that both examine proposed criteria sets and establish new evidence to guide refinements. On 26-27 February 2015, an international group of experts in sports cardiology, inherited cardiac disease, and sports medicine convened in Seattle, Washington (USA), to update contemporary standards for ECG interpretation in athletes. The objective of the meeting was to define and revise ECG interpretation standards based on new and emerging research and to develop a clear guide to the proper evaluation of ECG abnormalities in athletes. This statement represents an international consensus for ECG interpretation in athletes and provides expert opinion-based recommendations linking specific ECG abnormalities and the secondary evaluation for conditions associated with SCD.

Cardiac Magnetic Resonance Imaging Versus Transthoracic Echocardiography for Prediction of Outcomes in Chronic Aortic or Mitral Regurgitation.

In subjects with aortic regurgitation (AR) or mitral regurgitation (MR), transthoracic echocardiography (TTE) is recommended for surveillance. Few prospective studies have directly compared the ability of TTE and cardiac magnetic resonance (CMR) to predict clinical outcomes in AR and MR. We hypothesized that, given its higher reproducibility, CMR would predict the need for valve surgery or heart failure (HF) hospitalization better than TTE. Quantitative TTE and CMR were performed on the same day for 51 subjects: 29 with chronic AR and 22 with chronic, primary MR for quantification of valve regurgitation. Baseline measurements of valve regurgitation were compared to the combined primary end point of new HF and valve surgery using receiver operating characteristics, simple logistic regression, and Kaplan-Meier survival analyses. The primary end point occurred in 5 AR subjects (all surgery) and 8 MR subjects (7 surgery, 1 HF) after a mean follow-up of 4.4 ± 1.5 years. For AR, CMR-derived regurgitant volume >50 ml identified those at high risk with 50% undergoing valve surgery versus 0% for those with regurgitant volume ≤50 ml and was more strongly associated with outcomes than regurgitant volume by TTE (p <0.05). For MR, 6.8% of those with regurgitant volume by TTE ≤30 ml developed the primary end point versus 70% in those with regurgitant volume >30 ml. Regurgitant volume by CMR showed no significant separation of survival curves for MR. In conclusion, regurgitant volume by CMR was more predictive of outcomes than by TTE in subjects with AR. In MR, the 2 methods performed similarly.

Scan, plan, print, practice, perform: Development and use of a patient-specific 3-dimensional printed model in adult cardiac surgery.

OBJECTIVE: Static 3-dimensional printing is used for operative planning in cases that involve difficult anatomy. An interactive 3D print allowing deliberate surgical practice would represent an advance. METHODS: Two patients with hypertrophic cardiomyopathy had 3-dimensional prints constructed preoperatively. Stereolithography files were generated by segmentation of chest computed tomographic scans. Prints were made with hydrogel material, yielding tissue-like models that can be surgically manipulated. Septal myectomy of the print was performed preoperatively in the simulation laboratory. Volumetric measures of print and patient resected specimens were compared. An assessment tool was developed and used to rate the utility of this process. Clinical and echocardiographic data were reviewed. RESULTS: There was congruence between volumes of print and patient resection specimens (patient 1, 3.5 cm3 and 3.0 cm3, respectively; patient 2, 4.0 cm3 and 4.0 cm3, respectively). The prints were rated useful (3.5 and 3.6 on a 5-point Likert scale) for preoperative visualization, planning, and practice. Intraoperative echocardiographic assessment showed adequate relief of left ventricular outflow tract obstruction (patient 1, 80 mm Hg to 18 mm Hg; patient 2, 96 mm Hg to 9 mm Hg). Both patients reported symptomatic improvement (New York Heart Association functional class III to class I). CONCLUSIONS: Three-dimensional printing of interactive hypertrophic cardiomyopathy heart models allows for patient-specific preoperative simulation. Resection volume relationships were congruous on both specimens and suggest evidence of construct validity. This model also holds educational promise for simulation of a low-volume, high-risk operation that is traditionally difficult to teach.

Incidence and Etiology of Sudden Cardiac Arrest and Death in High School Athletes in the United States.

OBJECTIVE: To determine the incidence and etiology of sudden cardiac arrest and death (SCA/D) in US high school athletes. PATIENTS AND METHODS: A prospective media database of SCA/D was queried for cases aged 14 to 18 years from 7 states over 6 school years (September 1, 2007, to August 30, 2013). Event details were investigated to determine participation on a high school athletic team, sex, sport, and occurrence during school-sponsored activity or exertion. National sports participation numbers were used and a conversion factor was applied to account for multisport athletes. Autopsy reports were reviewed and cause of death was adjudicated by an expert panel. RESULTS: A total of 16,390,409 million athlete-seasons representing 6,974,640 athlete-years (AY) were examined, encompassing 36% of the total US high school athlete population. A total of 104 cases of SCA/D were identified (35 SCA with survival and 69 sudden cardiac deaths [SCDs]). The rate of SCD was 1:101,082 AY and of SCA/D 1:67,064 AY. Eighty-eight percent (92) of events occurred in male athletes. The rate of SCA/D in male athletes was 1:44,832 AY and in female athletes 1:237,510 AY (incidence rate ratio, 5.3; 95% CI, 2.9-10.6; P<.001). Men's basketball was the highest risk sport with an SCA/D incidence of 1:37,087 AY followed by men's football at 1:86,494 AY. Men's basketball and football athletes accounted for 57% (39) of deaths. Eighty percent of SCDs (55 of 69) were exertional and 55% (38 of 69) occurred while playing for a school-sponsored team. Autopsy reports were obtained in 73% (50) of cases. The most common findings of autopsy were idiopathic left ventricular hypertrophy or possible cardiomyopathy (13 of 50 [26%]), autopsy-negative sudden unexplained death (9 of 50 [18%]), hypertrophic cardiomyopathy (7 of 50 [14%]), and myocarditis (7 of 50 [14%]). CONCLUSION: The rate of SCA/D in male high school athletes was 1:44,832 AY, with almost half due to possible or confirmed cardiomyopathy disease. It is likely that many cases were not identified because of reliance on media reports, and these numbers represent a minimum estimate.

Electrocardiographic Screening in National Collegiate Athletic Association Athletes.

The most effective protocol for cardiovascular screening of competitive athletes remains highly controversial. This study was a prospective, multicenter trial of cardiovascular screening at 35 National Collegiate Athletic Association institutions. Screening included a standardized history and physical examination (PE) as recommended by the American Heart Association and a 12-lead electrocardiogram (ECG) at rest. Centralized electrocardiographic interpretation was provided using the Seattle criteria. Athletes with screening abnormalities underwent additional evaluation directed by the host institution medical team. Primary outcomes included the proportion of total and false-positive screens; the sensitivity, specificity, and positive predictive value of history, PE, and ECG; and the prevalence of serious cardiovascular disorders associated with severe morbidity or sudden cardiac death. From August 2012 to June 2014, 5,258 athletes from 17 intercollegiate sports were screened: 55% men (mean age 20.1 years), 73% Caucasian, 16% African-American, and 11% other/mixed race. At least 1 positive cardiac symptom or family history response was reported by 1,750 athletes (33.3%). PE was abnormal in 108 athletes (2.1%), and electrocardiographic abnormalities were present in 192 athletes (3.7%). Thirteen athletes (0.25%) were identified with serious cardiac conditions including hypertrophic cardiomyopathy (1), large atrial septal defect with right ventricular dilation (1), and ventricular pre-excitation (11). The false-positive rate for history was 33.3%, PE 2.0%, and ECG 3.4%. The sensitivity/specificity/positive predictive value for history was 15.4%/66.9%/0.1%, PE 7.7%/98.2%/0.9%, and ECG 100%/96.6%/6.8%. In conclusion, electrocardiographic screening in National Collegiate Athletic Association athletes has a low false-positive rate and provides superior accuracy compared with a standardized history and PE to detect athletes with potentially dangerous cardiovascular conditions.

Association of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis.

IMPORTANCE: Plasma low-density lipoprotein cholesterol (LDL-C) has been associated with aortic stenosis in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression. OBJECTIVE: To evaluate whether genetic data are consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease. DESIGN, SETTING, AND PARTICIPANTS: Using a Mendelian randomization study design, we evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids, were associated with aortic valve disease. We included community-based cohorts participating in the CHARGE consortium (n = 6942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n = 1295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n = 2527), Age Gene/Environment Study-Reykjavik (2000-2012; n = 3120), and the Malmö Diet and Cancer Study (MDCS, 1991-2010; n = 28,461). MAIN OUTCOMES AND MEASURES: Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS. RESULTS: The prevalence of aortic valve calcium across the 3 CHARGE cohorts was 32% (n = 2245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1000 participants (n = 473) and aortic valve replacement for aortic stenosis occurred in 7 per 1000 (n = 205). Plasma LDL-C, but not HDL-C or TG, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% CI, 1.04-1.57; P = .02; aortic stenosis incidence: 1.3% and 2.4% in lowest and highest LDL-C quartiles, respectively). The LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P = .007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P = .02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P = .03) and aortic stenosis (P = .009). In instrumental variable analysis, LDL-C was associated with an increase in the risk of incident aortic stenosis (HR per mmol/L, 1.51; 95% CI, 1.07-2.14; P = .02). CONCLUSIONS AND RELEVANCE: Genetic predisposition to elevated LDL-C was associated with presence of aortic valve calcium and incidence of aortic stenosis, providing evidence supportive of a causal association between LDL-C and aortic valve disease. Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation.

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.).

Aortic valve calcium independently predicts coronary and cardiovascular events in a primary prevention population.

OBJECTIVES: This study sought to test whether aortic valve calcium (AVC) is independently associated with coronary and cardiovascular events in a primary-prevention population. BACKGROUND: Aortic sclerosis is associated with increased cardiovascular morbidity and mortality among the elderly, but the mechanisms underlying this association remain controversial. Also, it is unknown whether this association extends to younger individuals. METHODS: We performed a prospective analysis of 6,685 participants in MESA (Multi-Ethnic Study of Atherosclerosis). All subjects, ages 45 to 84 years and free of clinical cardiovascular disease at baseline, underwent computed tomography for AVC and coronary artery calcium scoring. The primary, pre-specified combined endpoint of cardiovascular events included myocardial infarctions, fatal and nonfatal strokes, resuscitated cardiac arrest, and cardiovascular death, whereas a secondary combined endpoint of coronary events excluded strokes. The association between AVC and clinical events was assessed using Cox proportional hazards regression with incremental adjustments for demographics, cardiovascular risk factors, inflammatory biomarkers, and subclinical coronary atherosclerosis. RESULTS: Over a median follow-up of 5.8 years (interquartile range: 5.6 to 5.9 years), adjusting for demographics and cardiovascular risk factors, subjects with AVC (n = 894, 13.4%) had higher risks of cardiovascular (hazard ratio [HR]: 1.50; 95% confidence interval [CI]: 1.10 to 2.03) and coronary (HR: 1.72; 95% CI: 1.19 to 2.49) events compared with those without AVC. Adjustments for inflammatory biomarkers did not alter these associations, but adjustment for coronary artery calcium substantially attenuated both cardiovascular (HR: 1.32; 95% CI: 0.98 to 1.78) and coronary (HR: 1.41; 95% CI: 0.98 to 2.02) event risk. AVC remained predictive of cardiovascular mortality even after full adjustment (HR: 2.51; 95% CI: 1.22 to 5.21). CONCLUSIONS: In this MESA cohort, free of clinical cardiovascular disease, AVC predicts cardiovascular and coronary event risk independent of traditional risk factors and inflammatory biomarkers, likely due to the strong correlation between AVC and subclinical atherosclerosis. The association of AVC with excess cardiovascular mortality beyond coronary atherosclerosis risk merits further investigation. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487).

Incidence and progression of aortic valve calcium in the Multi-ethnic Study of Atherosclerosis (MESA).

Aortic valve calcium (AVC) is common among older adults and shares epidemiologic and histopathologic similarities to atherosclerosis. However, prospective studies have failed to identify meaningful risk associations with incident ("new") AVC or its progression. In the present study, AVC was quantified from serial computed tomographic images from 5,880 participants (aged 45 to 84 years) in the Multi-Ethnic Study of Atherosclerosis, using the Agatston method. Multivariate backward selection modeling was used to identify the risk factors for incident AVC and AVC progression. During a mean follow-up of 2.4 +/- 0.9 years, 210 subjects (4.1%) developed incident AVC. The incidence rate (mean 1.7%/year) increased significantly with age (p <0.001). The risk factors for incident AVC included age, male gender, body mass index, current smoking, and the use of lipid-lowering and antihypertensive medications. Among those with AVC at baseline, the median rate of AVC progression was 2 Agatston units/year (interquartile range -21 to 37). The baseline Agatston score was a strong, independent predictor of progression, especially among those with high calcium scores at baseline. In conclusion, in this ethnically diverse, preclinical cohort, the rate of incident AVC increased significantly with age. The incident AVC risk was associated with several traditional cardiovascular risk factors, specifically age, male gender, body mass index, current smoking, and the use of both antihypertensive and lipid-lowering medications. AVC progression risk was associated with male gender and the baseline Agatston score. Additional research is needed to determine whether age- and stage-specific mechanisms underlie the risk of AVC progression.

Age-modification of lipoprotein, lipid, and lipoprotein ratio-associated risk for coronary artery calcium (from the Multi-Ethnic Study of Atherosclerosis [MESA]).

Although abnormal lipoproteins and lipoprotein ratios are powerful risk factors for clinical cardiovascular events, these associations are stronger in younger than in older subjects. Whether age modifies the relation of lipoproteins and lipoprotein ratios to the relative risk of subclinical cardiovascular disease (CVD), as assessed by coronary artery calcium (CAC) scores, has not been examined in a contemporary, multiethnic cohort. We performed multivariate relative risk regression analyses to determine the relative risks for associations of lipoproteins and lipoprotein ratios with prevalent CAC in participants in Multi-Ethnic Study of Atherosclerosis (MESA). The participants were community-dwelling adults aged 45 to 84 years without clinically apparent CVD at baseline. We excluded those taking lipid-lowering therapy (15%) and stratified the results by decades of age. A total of 5,092 participants met the inclusion criteria. In the fully adjusted models, per SD of low-density lipoprotein, the age-stratified, adjusted relative risk for CAC was 1.17 (95% confidence interval [CI] 1.07 to 1.28) for those aged 45 to 84 years but was 1.05 (95% CI 1.01 to 1.10) for those aged 75 to 84 years (p-interaction = 0.12). The relative risk per SD of total/high-density lipoprotein cholesterol ratio was 1.20 (95% CI 1.12 to 1.29) for those aged 45 to 54 years but only 1.04 (95% CI 1.00 to 1.09) for those aged 75 to 84 years (p-interaction <0.001). The lipoproteins levels and lipoprotein ratios were associated with increased relative risks for CAC across all age categories. However, these associations were markedly attenuated by age. In conclusion, abnormal lipoprotein levels in middle age are a powerful risk factor for early atherosclerosis, as manifested by prevalent CAC.

Interaction of age with lipoproteins as predictors of aortic valve calcification in the multi-ethnic study of atherosclerosis.

BACKGROUND: Previous epidemiologic studies have shown that low-density lipoprotein is an independent risk factor for prevalent aortic valve calcification (AVC); however, to our knowledge, the interactions between plasma lipoprotein concentrations and age on the relative risks (RRs) for AVC prevalence and severity have not been examined in a large, racially and ethnically diverse cohort. METHODS: Using stepwise RR regression, the relationships of baseline fasting lipid levels and lipoprotein levels to baseline prevalence and severity of AVC were determined in 5801 non-statin-using participants in the Multi-Ethnic Study of Atherosclerosis (MESA). RESULTS: In age-stratified, adjusted analyses, the low-density lipoprotein-associated RRs (95% confidence intervals) for prevalent AVC were higher for younger compared with older participants (age 45-54 years, 1.69 [1.19-2.39]; age 55-64 years, 1.48 [1.24-1.76]; age 65-74 years, 1.09 [0.95-1.25]; and age 75-84 years, 1.16 [0.99-1.36]; P interaction = .04]. There was a similar, significant interaction of age with total cholesterol-associated RR for prevalent AVC (P interaction = .04). In contrast, total- to high-density lipoprotein cholesterol ratio RRs were similar across all age strata (P interaction = .68). At multivariate analyses, no lipoprotein parameter was associated with AVC severity. CONCLUSIONS: In this racially and ethnically diverse, preclinical cohort, low-density lipoprotein was a risk factor for AVC only in participants younger than 65 years, whereas the total cholesterol/high-density lipoprotein cholesterol ratio was associated with a modest increased risk of AVC across all ages. These findings may have important implications for the efficacy of and targets for dyslipidemia therapies in calcific aortic valve disease.