Palopegteriparatide Treatment Improves Renal Function in Adults with Chronic Hypoparathyroidism: 1-Year Results from the Phase 3 PaTHway Trial.

INTRODUCTION: Individuals with chronic hypoparathyroidism managed with conventional therapy (active vitamin D and calcium) have an increased risk for renal dysfunction versus age- and sex-matched controls. Treatments that replace the physiologic effects of parathyroid hormone (PTH) while reducing the need for conventional therapy may help prevent a decline in renal function in this population. This post hoc analysis examined the impact of palopegteriparatide treatment on renal function in adults with chronic hypoparathyroidism. METHODS: PaTHway is a phase 3 trial of palopegteriparatide in adults with chronic hypoparathyroidism that included a randomized, double-blind, placebo-controlled 26-week period followed by an ongoing 156-week open-label extension (OLE) period. Changes in renal function over 52 weeks (26 weeks blinded + 26 weeks OLE) were assessed using estimated glomerular filtration rate (eGFR). A subgroup analysis was performed with participants stratified by baseline eGFR < 60 or ≥ 60 mL/min/1.73 m2. RESULTS: At week 52, over 95% (78/82) of participants remained enrolled in the OLE and of those, 86% maintained normocalcemia and 95% achieved independence from conventional therapy (no active vitamin D and ≤ 600 mg/day of calcium), with none requiring active vitamin D. Treatment with palopegteriparatide over 52 weeks resulted in a mean (SD) increase in eGFR of 9.3 (11.7) mL/min/1.73 m2 from baseline (P < 0.0001) and 43% of participants had an increase ≥ 10 mL/min/1.73 m2. In participants with baseline eGFR < 60 mL/min/1.73 m2, 52 weeks of treatment with palopegteriparatide resulted in a mean (SD) increase of 11.5 (11.3) mL/min/1.73 m2 (P < 0.001). One case of nephrolithiasis was reported for a participant in the placebo group during blinded treatment; none were reported through week 52 with palopegteriparatide. CONCLUSION: In this post hoc analysis of the PaTHway trial, palopegteriparatide treatment was associated with significantly improved eGFR at week 52 in addition to previously reported maintenance and normalization of serum and urine biochemistries. Further investigation of palopegteriparatide for the preservation of renal function in hypoparathyroidism is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT04701203.

Chronic hypoparathyroidism is caused by inadequate parathyroid hormone (PTH) levels. Hypoparathyroidism is managed with conventional therapy (active vitamin D and calcium), but over time the disease itself and conventional therapy can increase the risk of medical complications including kidney problems. This study looked at how a new treatment for chronic hypoparathyroidism, palopegteriparatide (approved in the European Union under the brand name YORVIPATH^®), affects kidney function in adults in the PaTHway clinical trial. Participants were randomly assigned to receive palopegteriparatide or a placebo injection once daily along with conventional therapy. For both groups, clinicians used a protocol to eliminate conventional therapy while maintaining normal blood calcium levels. After 26 weeks, participants on placebo switched to palopegteriparatide. Ninety-five percent of participants were still enrolled in the PaTHway trial after 52 weeks. Of those, 86% had normal blood calcium levels and 95% did not need conventional therapy (not taking vitamin D and not taking therapeutic doses of calcium [> 600 mg/day]). After 52 weeks of treatment with palopegteriparatide, significant improvements were seen in a measure of kidney function called estimated glomerular filtration rate (eGFR). Improvements in eGFR from the beginning of the trial to week 52 were considered clinically meaningful for over 57% of participants. In participants with impaired kidney function at the beginning of the trial, eGFR improvements were even greater, and 74% of participants had a clinically meaningful improvement. These results suggest that palopegteriparatide treatment may be beneficial for kidney function in adults with chronic hypoparathyroidism, especially those with impaired kidney function.

Efficacy and Safety of Parathyroid Hormone Replacement With TransCon PTH in Hypoparathyroidism: 26-Week Results From the Phase 3 PaTHway Trial.

Conventional therapy for hypoparathyroidism consisting of active vitamin D and calcium aims to alleviate hypocalcemia but fails to restore normal parathyroid hormone (PTH) physiology. PTH replacement therapy is the ideal physiologic treatment for hypoparathyroidism. The double-blind, placebo-controlled, 26-week, phase 3 PaTHway trial assessed the efficacy and safety of PTH replacement therapy for hypoparathyroidism individuals with the investigational drug TransCon PTH (palopegteriparatide). Participants (n = 84) were randomized 3:1 to once-daily TransCon PTH (initially 18 µg/d) or placebo, both co-administered with conventional therapy. The study drug and conventional therapy were titrated according to a dosing algorithm guided by serum calcium. The composite primary efficacy endpoint was the proportion of participants at week 26 who achieved normal albumin-adjusted serum calcium levels (8.3-10.6 mg/dL), independence from conventional therapy (requiring no active vitamin D and ≤600 mg/d of calcium), and no increase in study drug over 4 weeks before week 26. Other outcomes of interest included health-related quality of life measured by the 36-Item Short Form Survey (SF-36), hypoparathyroidism-related symptoms, functioning, and well-being measured by the Hypoparathyroidism Patient Experience Scale (HPES), and urinary calcium excretion. At week 26, 79% (48/61) of participants treated with TransCon PTH versus 5% (1/21) wiplacebo met the composite primary efficacy endpoint (p < 0.0001). TransCon PTH treatment demonstrated a significant improvement in all key secondary endpoint HPES domain scores (all p < 0.01) and the SF-36 Physical Functioning subscale score (p = 0.0347) compared with placebo. Additionally, 93% (57/61) of participants treated with TransCon PTH achieved independence from conventional therapy. TransCon PTH treatment normalized mean 24-hour urine calcium. Overall, 82% (50/61) treated with TransCon PTH and 100% (21/21) wiplacebo experienced adverse events; most were mild (46%) or moderate (46%). No study drug-related withdrawals occurred. In conclusion, TransCon PTH maintained normocalcemia while permitting independence from conventional therapy and was well-tolerated in individuals with hypoparathyroidism. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Coronary CT Angiography and Carotid MRI Improve Phenotyping of Disease Extent Compared with ACC/AHA Risk Score Alone.

PURPOSE: To determine the relationship between the American College of Cardiology/American Heart Association (ACC/AHA) risk score and plaque phenotype of the coronary and carotid arteries assessed directly using CT angiography and MRI. MATERIALS AND METHODS: Asymptomatic subjects eligible for statin therapy by risk score were enrolled in a prospective study of disease burden using coronary artery calcium (CAC) scoring, coronary CT angiography, and MRI of the carotid arteries. Quartiles were calculated for noncalcified plaque, CAC, and average carotid wall volume and were compared with ACC/AHA risk quartiles. RESULTS: Two hundred three subjects were studied (60% men; mean age, 65 years). There were weak correlations between risk and carotid wall volume (Kendall tau = 0.29), noncalcified plaque (tau = 0.16), and CAC (tau = 0.33). ACC/AHA risk alone misclassified plaque extent compared with measurement by carotid wall volume, CAC, and noncalcified plaque in 22.1%, 24.1%, and 29.6% of subjects, respectively. On average, 13% of the subjects were underclassified, and 12.5% were overclassified. CONCLUSION: Approximately 25% of subjects had large discrepancies between ACC/AHA risk and plaque burden at imaging. These results suggest that clinical risk score models alone do not fully reflect the amount of atherosclerotic disease present.© RSNA, 2020See also the commentary by Truong and Villines in this issue.

Metabolically Healthy Obesity, Transition to Metabolic Syndrome, and Cardiovascular Risk.

BACKGROUND: Debate over the cardiometabolic risk associated with metabolically healthy obesity (MHO) continues. Many studies have investigated this relationship by examining MHO at baseline with longitudinal follow-up, with inconsistent results. OBJECTIVES: The authors hypothesized that MHO at baseline is transient and that transition to metabolic syndrome (MetS) and duration of MetS explains heterogeneity in incident cardiovascular disease (CVD) and all-cause mortality. METHODS: Among 6,809 participants of the MESA (Multi-Ethnic Study of Atherosclerosis) the authors used Cox proportional hazards and logistic regression models to investigate the joint association of obesity (≥30 kg/m2) and MetS (International Diabetes Federation consensus definition) with CVD and mortality across a median of 12.2 years. We tested for interaction and conducted sensitivity analyses for a number of conditions. RESULTS: Compared with metabolically healthy normal weight, baseline MHO was not significantly associated with incident CVD; however, almost one-half of those participants developed MetS during follow-up (unstable MHO). Those who had unstable MHO had increased odds of CVD (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.14 to 2.25), compared with those with stable MHO or healthy normal weight. Dose response for duration of MetS was significantly and linearly associated with CVD (1 visit with MetS OR: 1.62; 95% CI: 1.27 to 2.07; 2 visits, OR: 1.92; 95% CI: 1.48 to 2.49; 3+ visits, OR: 2.33; 95% CI: 1.89 to 2.87; p value for trend <0.001) and MetS mediated approximately 62% (44% to 100%) of the relationship between obesity at any point during follow-up and CVD. CONCLUSIONS: Metabolically healthy obesity is not a stable or reliable indicator of future risk for CVD. Weight loss and lifestyle management for CVD risk factors should be recommended to all individuals with obesity.

Three-Dimensional Volumetric Assessment of Diastolic Function by Cardiac Magnetic Resonance Imaging: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND:: Cardiac Magnetic Resonance is in need of a simple and robust method for diastolic function assessment that can be done with routine protocol sequences. OBJECTIVE:: To develop and validate a three-dimensional (3D) model-based volumetric assessment of diastolic function using cardiac magnetic resonance (CMR) imaging and compare the results obtained with the model with those obtained by echocardiography. METHODS:: The study participants provided written informed consent and were included if having undergone both echocardiography and cine steady-state free precession (SSFP) CMR on the same day. Guide points at the septal and lateral mitral annulus were used to define the early longitudinal relaxation rate (E'), while a time-volume curve from the 3D model was used to assess diastolic filling parameters. We determined the correlation between 3D CMR and echocardiography and the accuracy of CMR in classifying the diastolic function grade. RESULTS:: The study included 102 subjects. The E/A ratio by CMR was positively associated with the E/A ratio by echocardiography (r = 0.71, p < 0.0001). The early diastolic relaxation velocity by tissue Doppler and longitudinal relaxation rate for the lateral mitral annulus displacement were positively associated (p = 0.007), as were the ratio between Doppler E/e' and CMR E/E' (p = 0.01). CMR-determined normalized peak E (NE) and deceleration time (DT) were able to predict diastolic dysfunction (areas under the curve [AUCs] = 0.70 and 0.72, respectively). In addition, the lateral E/E' ratio showed good utility in identifying diastolic dysfunction (AUC = 0.80). Overall, echocardiography and CMR interobserver and intraobserver agreements were excellent (intraclass correlation coefficient range 0.72 - 0.97). CONCLUSION:: 3D modeling of standard cine CMR images was able to identify study subjects with reduced diastolic function and showed good reproducibility, suggesting a potential for a routine diastolic function assessment by CMR. FUNDAMENTO:: A ressonância magnética cardíaca necessita de um método simples e robusto para a avaliação da função diastólica que pode ser feito com sequências protocolares de rotina. OBJETIVO:: Desenvolver e validar a avaliação volumétrica da função diastólica através de um modelo tridimensional (3D) com utilização de imagens de ressonância magnética cardíaca (RMC) e comparar os resultados obtidos com este modelo com os obtidos por ecocardiografia. MÉTODOS:: Os participantes do estudo assinaram um termo de consentimento e foram incluídos se tivessem sido submetidos no mesmo dia tanto à ecocardiografia quanto à cine RMC com precessão livre no estado estacionário (steady-state free precession, SSFP). Pontos-guia foram utilizados no anel mitral septal e lateral para definir a velocidade de estiramento no início da diástole (E'), enquanto curvas de volume-tempo do modelo 3D foram utilizadas para avaliar os parâmetros de enchimento diastólico. Foram determinadas a correlação entre a RMC 3D e a ecocardiografia, além da acurácia da RMC em classificar o grau de função diastólica. RESULTADOS:: Ao todo, 102 sujeitos foram incluídos no estudo. A razão E/A pela RMC esteve positivamente associada com a razão E/A obtida pela ecocardiografia (r = 0,71, p < 0,0001). Estiveram positivamente associadas a velocidade de relaxamento diastólico inicial ao Doppler tecidual e a velocidade de relaxamento longitudinal de deslocamento do anel mitral lateral (p = 0,007), bem como a razão entre E/e' por Doppler e E/E' pela RMC (p = 0,01). A velocidade normalizada de pico de enchimento (EM) determinada pela RMC e o tempo de desaceleração (TD) foram capazes de predizer a disfunção diastólica (áreas sob a curva [AUCs] = 0,70 e 0,72, respectivamente). Além disso, a razão E/E' lateral mostrou boa utilidade para a identificação da disfunção diastólica (AUC = 0,80). No geral, a ecocardiografia e a RMC apresentaram excelente concordância interobservador e intraobservador (coeficiente de correlação intraclasse 0,72 - 0,97). CONCLUSÃO:: Uma modelagem 3D de imagens padrões de cine RMC foi capaz de identificar os indivíduos do estudo com função diastólica reduzida e mostrou uma boa reprodutibilidade, sugerindo ter potencial na avaliação rotineira da função diastólica por RMC.

Three-Dimensional Volumetric Assessment of Diastolic Function by Cardiac Magnetic Resonance Imaging: The Multi-Ethnic Study of Atherosclerosis (MESA) / Avaliação Volumétrica Tridimensional da Função Diastólica Por Ressonância Magnética Cardíaca: Multi-Ethnic Study Of Atherosclerosis (MESA)

Abstract Background: Cardiac Magnetic Resonance is in need of a simple and robust method for diastolic function assessment that can be done with routine protocol sequences. Objective: To develop and validate a three-dimensional (3D) model-based volumetric assessment of diastolic function using cardiac magnetic resonance (CMR) imaging and compare the results obtained with the model with those obtained by echocardiography. Methods: The study participants provided written informed consent and were included if having undergone both echocardiography and cine steady-state free precession (SSFP) CMR on the same day. Guide points at the septal and lateral mitral annulus were used to define the early longitudinal relaxation rate (E'), while a time-volume curve from the 3D model was used to assess diastolic filling parameters. We determined the correlation between 3D CMR and echocardiography and the accuracy of CMR in classifying the diastolic function grade. Results: The study included 102 subjects. The E/A ratio by CMR was positively associated with the E/A ratio by echocardiography (r = 0.71, p < 0.0001). The early diastolic relaxation velocity by tissue Doppler and longitudinal relaxation rate for the lateral mitral annulus displacement were positively associated (p = 0.007), as were the ratio between Doppler E/e' and CMR E/E' (p = 0.01). CMR-determined normalized peak E (NE) and deceleration time (DT) were able to predict diastolic dysfunction (areas under the curve [AUCs] = 0.70 and 0.72, respectively). In addition, the lateral E/E' ratio showed good utility in identifying diastolic dysfunction (AUC = 0.80). Overall, echocardiography and CMR interobserver and intraobserver agreements were excellent (intraclass correlation coefficient range 0.72 - 0.97). Conclusion: 3D modeling of standard cine CMR images was able to identify study subjects with reduced diastolic function and showed good reproducibility, suggesting a potential for a routine diastolic function assessment by CMR.

Resumo Fundamento: A ressonância magnética cardíaca necessita de um método simples e robusto para a avaliação da função diastólica que pode ser feito com sequências protocolares de rotina. Objetivo: Desenvolver e validar a avaliação volumétrica da função diastólica através de um modelo tridimensional (3D) com utilização de imagens de ressonância magnética cardíaca (RMC) e comparar os resultados obtidos com este modelo com os obtidos por ecocardiografia. Métodos: Os participantes do estudo assinaram um termo de consentimento e foram incluídos se tivessem sido submetidos no mesmo dia tanto à ecocardiografia quanto à cine RMC com precessão livre no estado estacionário (steady-state free precession, SSFP). Pontos-guia foram utilizados no anel mitral septal e lateral para definir a velocidade de estiramento no início da diástole (E'), enquanto curvas de volume-tempo do modelo 3D foram utilizadas para avaliar os parâmetros de enchimento diastólico. Foram determinadas a correlação entre a RMC 3D e a ecocardiografia, além da acurácia da RMC em classificar o grau de função diastólica. Resultados: Ao todo, 102 sujeitos foram incluídos no estudo. A razão E/A pela RMC esteve positivamente associada com a razão E/A obtida pela ecocardiografia (r = 0,71, p < 0,0001). Estiveram positivamente associadas a velocidade de relaxamento diastólico inicial ao Doppler tecidual e a velocidade de relaxamento longitudinal de deslocamento do anel mitral lateral (p = 0,007), bem como a razão entre E/e' por Doppler e E/E' pela RMC (p = 0,01). A velocidade normalizada de pico de enchimento (EM) determinada pela RMC e o tempo de desaceleração (TD) foram capazes de predizer a disfunção diastólica (áreas sob a curva [AUCs] = 0,70 e 0,72, respectivamente). Além disso, a razão E/E' lateral mostrou boa utilidade para a identificação da disfunção diastólica (AUC = 0,80). No geral, a ecocardiografia e a RMC apresentaram excelente concordância interobservador e intraobservador (coeficiente de correlação intraclasse 0,72 - 0,97). Conclusão: Uma modelagem 3D de imagens padrões de cine RMC foi capaz de identificar os indivíduos do estudo com função diastólica reduzida e mostrou uma boa reprodutibilidade, sugerindo ter potencial na avaliação rotineira da função diastólica por RMC.

Obesity Is Associated With Progression of Atherosclerosis During Statin Treatment.

BACKGROUND: This study aimed to determine the relationship of statin therapy and cardiovascular risk factors to changes in atherosclerosis in the carotid artery. METHODS AND RESULTS: Carotid magnetic resonance imaging was used to evaluate 106 hyperlipidemic participants at baseline and after 12 months of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) treatment. Multivariable logistic regression was used to determine factors associated with progression (change in carotid wall volume >0) or regression (change ≤0) of carotid atherosclerosis. Computed tomography coronary calcium scores were obtained at baseline for all participants. The median age was 65 years (interquartile range 60-69 years), and 63% of the participants were male. Body mass index >30, elevated C-reactive protein, and hypertension were associated with increased carotid wall volume (obesity: odds ratio for progression 4.6, 95% CI 1.8-12.4, P<0.01; C-reactive protein: odds ratio for progression 2.56, 95% CI 1.17-5.73, P=0.02; hypertension: odds ratio 2.4, 95% CI 1.1-5.3, P<0.05). Higher statin dose was associated with regression of carotid wall volume (P<0.05). In multivariable analysis, obesity remained associated with progression (P<0.01), whereas statin use remained associated with regression (P<0.05). Change in atheroma volume in obese participants was +4.8% versus -4.2% in nonobese participants (P<0.05) despite greater low-density lipoprotein cholesterol reduction in obese participants. CONCLUSIONS: In a population with hyperlipidemia, obese patients showed atheroma progression despite optimized statin therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01212900.

Utility of Nontraditional Risk Markers in Atherosclerotic Cardiovascular Disease Risk Assessment.

BACKGROUND: The improvement in discrimination gained by adding nontraditional cardiovascular risk markers cited in the 2013 American College of Cardiology/American Heart Association cholesterol guidelines to the atherosclerotic cardiovascular disease (ASCVD) risk estimator (pooled cohort equation [PCE]) is untested. OBJECTIVES: This study assessed the predictive accuracy and improvement in reclassification gained by the addition of the coronary artery calcium (CAC) score, the ankle-brachial index (ABI), high-sensitivity C-reactive protein (hsCRP) levels, and family history (FH) of ASCVD to the PCE in participants of MESA (Multi-Ethnic Study of Atherosclerosis). METHODS: The PCE was calibrated (cPCE) and used for this analysis. The Cox proportional hazards survival model, Harrell's C statistics, and net reclassification improvement analyses were used. ASCVD was defined as myocardial infarction, coronary heart disease-related death, or fatal or nonfatal stroke. RESULTS: Of 6,814 MESA participants not prescribed statins at baseline, 5,185 had complete data and were included in this analysis. Their mean age was 61 years; 53.1% were women, 9.8% had diabetes, and 13.6% were current smokers. After 10 years of follow-up, 320 (6.2%) ASCVD events occurred. CAC score, ABI, and FH were independent predictors of ASCVD events in the multivariable Cox models. CAC score modestly improved the Harrell's C statistic (0.74 vs. 0.76; p = 0.04); ABI, hsCRP levels, and FH produced no improvement in Harrell's C statistic when added to the cPCE. CONCLUSIONS: CAC score, ABI, and FH were independent predictors of ASCVD events. CAC score modestly improved the discriminative ability of the cPCE compared with other nontraditional risk markers.

Role of Coronary Artery Calcium Score of Zero and Other Negative Risk Markers for Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Limited attention has been paid to negative cardiovascular disease (CVD) risk markers despite their potential to improve medical decision making. We compared 13 negative risk markers using diagnostic likelihood ratios (DLRs), which model the change in risk for an individual after the result of an additional test. METHODS AND RESULTS: We examined 6814 participants from the Multi-Ethnic Study of Atherosclerosis. Coronary artery calcium score of 0, carotid intima-media thickness <25th percentile, absence of carotid plaque, brachial flow-mediated dilation >5% change, ankle-brachial index >0.9 and <1.3, high-sensitivity C-reactive protein <2 mg/L, homocysteine <10 µmol/L, N-terminal pro-brain natriuretic peptide <100 pg/mL, no microalbuminuria, no family history of coronary heart disease (any/premature), absence of metabolic syndrome, and healthy lifestyle were compared for all and hard coronary heart disease and all CVD events over the 10-year follow-up. Models were adjusted for traditional CVD risk factors. Among all negative risk markers, coronary artery calcium score of 0 was the strongest, with an adjusted mean DLR of 0.41 (SD, 0.12) for all coronary heart disease and 0.54 (SD, 0.12) for CVD, followed by carotid intima-media thickness <25th percentile (DLR, 0.65 [SD, 0.04] and 0.75 [SD, 0.04], respectively). High-sensitivity C-reactive protein <2 mg/L and normal ankle-brachial index had DLRs >0.80. Among clinical features, absence of any family history of coronary heart disease was the strongest (DLRs, 0.76 [SD, 0.07] and 0.81 [SD, 0.06], respectively). Net reclassification improvement analyses yielded similar findings, with coronary artery calcium score of 0 resulting in the largest, most accurate downward risk reclassification. CONCLUSIONS: Negative results of atherosclerosis-imaging tests, particularly coronary artery calcium score of 0, resulted in the greatest downward shift in estimated CVD risk. These results may help guide discussions on the identification of individuals less likely to receive net benefit from lifelong preventive pharmacotherapy.

Implications of Coronary Artery Calcium Testing Among Statin Candidates According to American College of Cardiology/American Heart Association Cholesterol Management Guidelines: MESA (Multi-Ethnic Study of Atherosclerosis).

BACKGROUND: The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guidelines have significantly broadened the scope of candidates eligible for statin therapy. OBJECTIVES: This study evaluated the implications of the absence of coronary artery calcium (CAC) in reclassifying patients from a risk stratum in which statins are recommended to one in which they are not. METHODS: MESA (Multi-Ethnic Study of Atherosclerosis) is a longitudinal study of 6,814 men and women 45 to 84 years of age without clinical atherosclerotic cardiovascular disease (ASCVD) risk at enrollment. We excluded 1,100 participants (16%) on lipid-lowering medication, 87 (1.3%) without low-density lipoprotein levels, 26 (0.4%) with missing risk factors for calculation of 10-year risk of ASCVD, 633 (9%) >75 years of age, and 209 (3%) with low-density lipoprotein <70 mg/dl from the analysis. RESULTS: The study population consisted of 4,758 participants (age 59 ± 9 years; 47% males). A total of 247 (5.2%) ASCVD and 155 (3.3%) hard coronary heart disease events occurred over a median (interquartile range) follow-up of 10.3 (9.7 to 10.8) years. The new ACC/AHA guidelines recommended 2,377 (50%) MESA participants for moderate- to high-intensity statins; the majority (77%) was eligible because of a 10-year estimated ASCVD risk ≥7.5%. Of those recommended statins, 41% had CAC = 0 and had 5.2 ASCVD events/1,000 person-years. Among 589 participants (12%) considered for moderate-intensity statin, 338 (57%) had a CAC = 0, with an ASCVD event rate of 1.5 per 1,000 person-years. Of participants eligible (recommended or considered) for statins, 44% (1,316 of 2,966) had CAC = 0 at baseline and an observed 10-year ASCVD event rate of 4.2 per 1,000 person-years. CONCLUSIONS: Significant ASCVD risk heterogeneity exists among those eligible for statins according to the new guidelines. The absence of CAC reclassifies approximately one-half of candidates as not eligible for statin therapy.

Can Antihypertensive Treatment Restore the Risk of Cardiovascular Disease to Ideal Levels?: The Coronary Artery Risk Development in Young Adults (CARDIA) Study and the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: It is unclear whether antihypertensive treatment can restore cardiovascular disease risk to the risk level of persons with ideal blood pressure (BP) levels. METHODS AND RESULTS: Data from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Coronary Artery Risk Development in Young Adults (CARDIA) study were analyzed. Outcomes were compared among participants without or with antihypertensive treatment at 3 BP levels: <120/<80 mm Hg, systolic BP 120 to 139 mm Hg or diastolic BP 80 to 89 mm Hg (120 to 129/≤80 mm Hg for participants with diabetes), and systolic BP ≥140 or diastolic BP ≥90 mm Hg (systolic BP ≥130 or diastolic BP ≥80 mm Hg for participants with diabetes). Among MESA participants aged ≥50 years at baseline, those with BP <120/<80 mm Hg on treatment had higher left ventricular mass index, prevalence of estimated glomerular filtration rate <60 mL/min per 1.73 m(2), prevalence of coronary calcium score >100, and twice the incident cardiovascular disease rate over 9.5 years of follow-up than those with BP <120/<80 mm Hg without treatment. In CARDIA at year 25, persons with BP <120/<80 mm Hg with treatment had much longer exposure to higher BP and higher risk of end-organ damage and subclinical atherosclerosis than those with BP <120/<80 mm Hg without treatment. An exploratory analysis suggested that when cumulative systolic BP was high (eg, >3000 mm Hg-years in 25 years), the increase in left ventricular mass index accelerated. CONCLUSIONS: The data suggest that based on the current approach, antihypertensive treatment cannot restore cardiovascular disease risk to ideal levels. Emphasis should be placed on primordial prevention of BP increases to further reduce cardiovascular disease morbidity and mortality.

Utility of Nontraditional Risk Markers in Individuals Ineligible for Statin Therapy According to the 2013 American College of Cardiology/American Heart Association Cholesterol Guidelines.

BACKGROUND: In the general population, the majority of cardiovascular events occur in people at the low to moderate end of population risk distribution. The 2013 American College of Cardiology/American Heart Association guideline on the treatment of blood cholesterol recommends consideration of statin therapy for adults with an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥7.5% based on traditional risk factors. Whether use of nontraditional risk markers can improve risk assessment in those below this threshold for statin therapy is unclear. METHODS AND RESULTS: Using data from the Multi-Ethnic Study of Atherosclerosis (MESA), a population sample free of clinical CVD at baseline, we calibrated the Pooled Cohort Equations (cPCE). ASCVD was defined as myocardial infarction, coronary heart disease death, or fatal or nonfatal stroke. Adults with an initial cPCE <7.5% and elevated levels of additional risk markers (abnormal test) whose new calculated risk was ≥7.5% were considered statin eligible: low-density lipoprotein cholesterol ≥160 mg/dL; family history of ASCVD; high-sensitivity C-reactive protein ≥2 mg/dL; coronary artery calcium score ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity; and ankle-brachial index <0.9. We compared the absolute and relative ASCVD risks among those with versus without elevated posttest estimated risk. We calculated the number needed to screen to identify 1 person with abnormal test for each risk marker, defined as the number of participants with baseline cPCE risk <7.5% divided by the number with an abnormal test reclassified as statin eligible. Of 5185 participants not taking statins with complete data (age, 45-84 years), 4185 had a cPCE risk <7.5%. During 10 years of follow-up, 57% of the ASCVD events (183 of 320) occurred among adults with a cPCE risk <7.5%. When people with diabetes mellitus were excluded, the coronary artery calcium criterion reclassified 6.8% upward, with an event rate of 13.3%, absolute risk of 10%, relative risk of 4.0 (95% confidence interval [CI], 2.8-5.7), and number needed to screen of 14.7. The corresponding numbers for family history of ASCVD were 4.6%, 15.1%, 12%, 4.3 (95% CI, 3.0-6.4), and 21.8; for high-sensitivity C-reactive protein criteria, 2.6%, 10%, 6%, 2.6 (95% CI, 1.4-4.8), and 39.2; for ankle-brachial index criteria, 0.6%, 9%, 5%, 2.3 (95% CI, 0.6-8.6), and 176.5; and for low-density lipoprotein cholesterol criteria, 0.5%, 5%, 1%, 1.2 (95% CI, 0.2-8.4), and 193.3, respectively. Of the 3882 with <7.5% cPCE risk, 431 (11.1%) were reclassified to ≥7.5% (statin eligible) by at least 1 of the additional risk marker criteria. CONCLUSIONS: In this generally low-risk population sample, a large proportion of ASCVD events occurred among adults with a 10-year cPCE risk <7.5%. We found that the coronary artery calcium score, high-sensitivity C-reactive protein, family history of ASCVD, and ankle-brachial index recommendations by the American College of Cardiology/American Heart Association cholesterol guidelines (Class IIB) identify small subgroups of asymptomatic population with a 10-year cPCE risk <7.5% but with observed ASCVD event rates >7.5% who may warrant statin therapy considerations.

Coronary Plaque Burden at Coronary CT Angiography in Asymptomatic Men and Women.

Purpose To assess the relationship between total, calcified, and noncalcified coronary plaque burdens throughout the entire coronary vasculature at coronary computed tomographic (CT) angiography in relationship to cardiovascular risk factors in asymptomatic individuals with low-to-moderate risk. Materials and Methods This HIPAA-compliant study had institutional review board approval, and written informed consent was obtained. Two hundred two subjects were recruited to an ongoing prospective study designed to evaluate the effect of HMG-CoA reductase inhibitors on atherosclerosis. Eligible subjects were asymptomatic individuals older than 55 years who were eligible for statin therapy. Coronary CT angiography was performed by using a 320-detector row scanner. Coronary wall thickness and plaque were evaluated in all epicardial coronary arteries greater than 2 mm in diameter. Images were analyzed by using dedicated software involving an adaptive lumen attenuation algorithm. Total plaque index (calcified plus noncalcified plaque) was defined as plaque volume divided by vessel length. Multivariable regression analysis was performed to determine the relationship between risk factors and plaque indexes. Results The mean age of the subjects was 65.5 years ± 6.9 (standard deviation) (36% women), and the median coronary artery calcium (CAC) score was 73 (interquartile range, 1-434). The total coronary plaque index was higher in men than in women (42.06 mm(2) ± 9.22 vs 34.33 mm(2) ± 8.35; P < .001). In multivariable analysis controlling for all risk factors, total plaque index remained higher in men than in women (by 5.01 mm(2); P = .03) and in those with higher simvastatin doses (by 0.44 mm(2)/10 mg simvastatin dose equivalent; P = .02). Noncalcified plaque index was positively correlated with systolic blood pressure (ß = 0.80 mm(2)/10 mm Hg; P = .03), diabetes (ß = 4.47 mm(2); P = .03), and low-density lipoprotein (LDL) cholesterol level (ß = 0.04 mm(2)/mg/dL; P = .02); the association with LDL cholesterol level remained significant (P = .02) after additional adjustment for the CAC score. Conclusion LDL cholesterol level, systolic blood pressure, and diabetes were associated with noncalcified plaque burden at coronary CT angiography in asymptomatic individuals with low-to-moderate risk. (©) RSNA, 2015 Online supplemental material is available for this article.

Abnormal Myocardial Function Is Related to Myocardial Steatosis and Diffuse Myocardial Fibrosis in HIV-Infected Adults.

BACKGROUND: Impaired cardiac function persists in the era of effective human immunodeficiency virus (HIV) therapy, although the etiology is unclear. We used magnetic resonance imaging (MRI) to measure intramyocardial lipid levels and fibrosis as possible contributors to HIV-associated myocardial dysfunction. METHODS: A cross-sectional study of 95 HIV-infected and 30 matched-healthy adults, without known cardiovascular disease (CVD) was completed. Intramyocardial lipid levels, myocardial fibrosis, and cardiac function (measured on the basis of strain) were quantified by MRI. RESULTS: Systolic function was significantly decreased in HIV-infected subjects as compared to controls (mean radial strain [±SD], 21.7 ± 8.6% vs 30.5 ± 14.2%; P = .004). Intramyocardial lipid level and fibrosis index were both increased in HIV-infected subjects as compared to controls (P ≤ .04 for both) and correlated with the degree of myocardial dysfunction measured by strain parameters. Intramyocardial lipid levels correlated positively with antiretroviral therapy duration and visceral adiposity. Further, impaired myocardial function was strongly correlated with increased monocyte chemoattractant protein 1 levels (r = 0.396, P = .0002) and lipopolysaccharide binding protein levels (r = 0.25, P = .02). CONCLUSIONS: HIV-infected adults have reduced myocardial function as compared to controls in the absence of known CVD. Decreased cardiac function was associated with abnormal myocardial tissue composition characterized by increased lipid levels and diffuse myocardial fibrosis. Metabolic alterations related to antiretroviral therapy and chronic inflammation may be important targets for optimizing long-term cardiovascular health in HIV-infected individuals.

Determination and distribution of left ventricular size as measured by noncontrast CT in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Left ventricular (LV) volume and mass have prognostic relevance. Overall size of the left ventricle as it appears in noncontrast CT is a composite of the ventricular volume and myocardial mass. We describe a method to estimate the LV size using a single cross-section in noncontrast CT and determined normal ranges on the basis of a large population cohort. METHODS: The Multi-Ethnic Study of Atherosclerosis with 6814 participants from 4 ethnicities who were free of known cardiovascular disease and enrolled between 2000 and 2002 form the basis of our analysis. LV size was calculated from a single cross-sectional slice obtained by either nonenhanced electron beam or multidetector CT. LV size was adjusted to body surface area to obtain the LV size index, which was adjusted for age, sex, race or ethnicity, hypertension, hyperlipidemia, and diabetes. RESULTS: There were significant differences in LV size index by race which were further influenced by age and sex. Higher values were noted in men in all ethnic groups across all age groups. Similarly, LV size index uniformly decreased with age across all ethnic and sex categories. Caucasians had the lowest and African Americans had the highest LV size index across all age and sex categories. In multivariate regression analyses adjusted for age, sex, race or ethnicity, hypertension, hyperlipidemia, smoking, and diabetes mellitus, the significant differences were noted between male vs female (median difference, 17.5 cc/m(2); P < .001), ethnic groups (Caucasian, reference group; Asian, 3.7 cc/m(2); African American, 8.3 cc/m(2); and Hispanic, 5.6 cc/m(2); P < .001), and age groups (45-54 years, reference group; 55-64 years, -5.2 cc/m(2); 65-74 years, -11.4 cc/m(2); and 74-84 years, -12.5 cc/m(2)). CONCLUSIONS: This study provides normative values for LV size as determined from a single, nonenhanced CT cross-section and indexed to body surface area, and it demonstrates that the LV size index varies by age, sex, and ethnic background.

Lipoprotein particles and incident type 2 diabetes in the multi-ethnic study of atherosclerosis.

OBJECTIVE: In the Multi-Ethnic Study of Atherosclerosis (MESA), we evaluated associations of baseline levels of a lipoprotein-based insulin resistance (IR) index (LP-IR), IR-related lipoprotein particles, mean particle sizes, and lipids, with incident type 2 diabetes, independent of confounders, glucose, insulin, and HOMA-IR. RESEARCH DESIGN AND METHODS: Among 5,314 adults aged 45-84 years without baseline diabetes or cardiovascular disease, 656 cases of diabetes were identified during a mean follow-up of 7.7 years. Lipoprotein particle concentrations, size, and LP-IR were determined by nuclear magnetic resonance spectroscopy of stored baseline plasma. Potential effect modification, by race/ethnicity, sex, baseline use of lipid-lowering medications or hormone therapy, or glucose strata (<90, 90-99, and ≥ 100 mg/dL), was also evaluated. RESULTS: Higher levels of LP-IR, large VLDL particles (VLDL-P), small LDL particles, triglycerides (TG), and TG-to-HDL cholesterol (HDL-C) ratio and lower levels of large HDL particles, smaller HDL and LDL size, and larger VLDL size were significantly associated with incident diabetes adjusted for confounders and glucose or insulin. These also were similar by race/ethnicity, sex, and treatment group. Associations were similar for LP-IR, large VLDL-P, mean VLDL size, TG, and TG-to-HDL-C ratio; they persisted for LP-IR, large VLDL-P, or mean VLDL size adjusted for HOMA-IR or TG-to-HDL-C ratio and glucose but not for the TG-to-HDL-C ratio adjusted for LP-IR or for HOMA-IR or insulin if adjusted for LP-IR and glucose. CONCLUSIONS: Among ethnically diverse men and women, LP-IR, large VLDL-P, large VLDL size, TG, and TG-to-HDL-C ratio were associated with incident diabetes independent of established risk factors, glucose, insulin, or HOMA-IR, as well as the use of lipid-lowering medications or hormone therapy.

Association of albumin-creatinine ratio and cystatin C with change in ankle-brachial index: the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Low ankle-brachial index (ABI) is a reflection of atherosclerotic disease, and high ABI is an indicator of calcified vessels. The associations of albuminuria and cystatin C level with incidence of either low or high ABI are unknown. STUDY DESIGN: Prospective longitudinal cohort study. SETTING & PARTICIPANTS: MESA (Multi-Ethnic Study of Atherosclerosis) enrolled community-dwelling adults (N=6,814) aged 45-84 years who were free of clinical cardiovascular disease at baseline. PREDICTORS: Baseline albumin-creatinine ratio (ACR) and serum cystatin C level. OUTCOMES: Development of low (<0.90), and high (>1.40) ABI using multinomial regression among persons with ABI of 0.90-1.40 at baseline. RESULTS: During 9.8 years of follow-up, 221 and 89 participants progressed to low and high ABIs, respectively. Baseline ACR and cystatin C level were higher among progressors compared with nonprogressors. In multivariable analyses, doubling of ACR was associated with increased risk of progression to low (OR, 1.08; 95% CI, 0.99-1.20) and high (OR, 1.16; 95% CI, 1.01-1.32) ABIs. Compared to the lowest quintile, the highest quintile of ACR had a significantly increased risk of progression to low (OR, 1.79; 95% CI, 1.03-3.12) and high (OR, 2.76; 95% CI, 1.32-5.77) ABIs. Higher cystatin C levels were associated with progression to low (OR per 1-SD greater, 1.12; 95% CI, 1.00-1.26) but not high (OR per 1-SD greater, 1.01; 95% CI, 0.81-1.25) ABI, but the highest quintile of cystatin C was not associated independently with either outcome. LIMITATIONS: Single measure of albuminuria and low number of progressors to high ABI. CONCLUSIONS: In adults free of clinical cardiovascular disease, albuminuria was a strong independent risk factor for the development of both high and low ABIs, important and different measures of peripheral artery disease.

Assessment of atherosclerosis in chronic granulomatous disease.

BACKGROUND: Patients with chronic granulomatous disease (CGD) experience immunodeficiency because of defects in the phagocyte NADPH oxidase and the concomitant reduction in reactive oxygen intermediates. This may result in a reduction in atherosclerotic injury. METHODS AND RESULTS: We prospectively assessed the prevalence of cardiovascular risk factors, biomarkers of inflammation and neutrophil activation, and the presence of magnetic resonance imaging and computed tomography quantified subclinical atherosclerosis in the carotid and coronary arteries of 41 patients with CGD and 25 healthy controls in the same age range. Univariable and multivariable associations among risk factors, inflammatory markers, and atherosclerosis burden were assessed. Patients with CGD had significant elevations in traditional risk factors and inflammatory markers compared with control subjects, including hypertension, high-sensitivity C-reactive protein, oxidized low-density lipoprotein, and low high-density lipoprotein. Despite this, patients with CGD had a 22% lower internal carotid artery wall volume compared with control subjects (361.3±76.4 mm(3) versus 463.5±104.7 mm(3); P<0.001). This difference was comparable in p47(phox)- and gp91(phox)-deficient subtypes of CGD and independent of risk factors in multivariate regression analysis. In contrast, the prevalence of coronary arterial calcification was similar between patients with CGD and control subjects (14.6%, CGD; 6.3%, controls; P=0.39). CONCLUSIONS: The observation by magnetic resonance imaging and computerized tomography of reduced carotid but not coronary artery atherosclerosis in patients with CGD despite the high prevalence of traditional risk factors raises questions about the role of NADPH oxidase in the pathogenesis of clinically significant atherosclerosis. Additional high-resolution studies in multiple vascular beds are required to address the therapeutic potential of NADPH oxidase inhibition in cardiovascular diseases. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01063309.

Association of parity with carotid diameter and distensibility: multi-ethnic study of atherosclerosis.

Pregnancy and childbirth are associated with hemodynamic changes and vascular remodeling. It is not known whether parity is associated with later adverse vascular properties such as larger arterial diameter, wall thickness, and lower distensibility. We used baseline data from 3283 women free of cardiovascular disease aged 45 to 84 years enrolled in the population-based Multi-Ethnic Study of Atherosclerosis. Participants self-reported parity status. Ultrasound-derived carotid artery lumen diameters and brachial artery blood pressures were measured at peak-systole and end-diastole. Common carotid intima-media thickness was also measured. Regression models to determine the association of carotid distensibility coefficient, lumen diameter, and carotid intima-media thickness with parity were adjusted for age, race, height, weight, diabetes mellitus, current smoking, blood pressure medication use, and total and high-density lipoprotein cholesterol levels. The prevalence of nulliparity was 18%. In adjusted models, carotid distensibility coefficient was 0.09×10−5 Pa−1 lower (P=0.009) in parous versus nulliparous women. Among parous women, there was a nonlinear association with the greatest carotid distensibility coefficient seen in women with 2 live births and significantly lower distensibility seen in primiparas (P=0.04) or with higher parity >2 (P=0.005). No such pattern of association with parity was found for lumen diameter or carotid intima-media thickness. Parity is associated with lower carotid artery distensibility, suggesting arterial remodeling that lasts beyond childbirth. These long-term effects on the vasculature may explain the association of parity with cardiovascular events later in life.

Mediation of cardiovascular risk factor effects through subclinical vascular disease: the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVE: It is unclear to what extent subclinical cardiovascular disease (CVD) such as coronary artery calcium (CAC), carotid intima-media thickness (CIMT), and brachial flow-mediated dilation (FMD) are mediators of the known associations between traditional cardiovascular risk factors and incident CVD events. We assessed the portion of the effects of risk factors on incident CVD events that are mediated through CAC, CIMT, and FMD. APPROACH AND RESULTS: Six thousand three hundred fifty-five of 6814 Multi-Ethnic Study of Atherosclerosis participants were included. Nonlinear implementation of structural equation modeling (STATA mediation package) was used to assess whether CAC, CIMT, or FMD are mediators of the association between traditional risk factors and incident CVD event. Mean age was 62 years, with 47% men, 12% diabetics, and 13% current smokers. After a mean follow-up of 7.5 years, there were 539 CVD adjudicated events. CAC showed the highest mediation while FMD showed the least. Age had the highest percent of total effect mediated via CAC for CVD outcomes, whereas current cigarette smoking had the least percent of total effect mediated via CAC (percent [95% confidence interval]: 80.2 [58.8-126.7] versus 10.6 [6.1-38.5], respectively). Body mass index showed the highest percent of total effect mediated via CIMT (17.7 [11.6-38.9]); only a negligible amount of the association between traditional risk factors and CVD was mediated via FMD. CONCLUSIONS: Many of the risk factors for incident CVD (other than age, sex, and body mass index) showed a modest level of mediation via CAC, CIMT, and FMD, suggesting that current subclinical CVD markers may not be optimal intermediaries for gauging upstream risk factor modification.