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Derivation of a Coronary Age Calculator Using Traditional Risk Factors and Coronary Artery Calcium: The Multi-Ethnic Study of Atherosclerosis.
Blaha, MJ, Naazie, IN, Cainzos-Achirica, M, Dardari, ZA, DeFilippis, AP, McClelland, RL, Mirbolouk, M, Orimoloye, OA, Dzaye, O, Nasir, K, et al
Journal of the American Heart Association. 2021;(6):e019351
Abstract
Background The optimal method for communicating coronary heart disease (CHD) risk to individual patients is not yet clear. Recent research supports the concept of "coronary age" for more effective risk communication. We defined an individual's coronary age as the age at which an average healthy individual would have an equivalent estimated CHD risk as that calculated for the index individual, building on our previously validated MESA (Multi-Ethnic Study of Atherosclerosis) 10-year CHD Risk Score equations with and without coronary artery calcium (CAC). Methods and Results We derived a coronary age by (1) calculating the MESA 10-year CHD risk; (2) mathematically setting this equal to an equation describing risk of an average healthy MESA participant, as a function of age; and (3) solving for age. The risk discrimination of the resultant coronary age was compared with that of chronological age, the MESA CHD Risk Score, and CAC alone. Approximately 95% of coronary age values ranged from 30 years less to 30 years higher than chronological age. Although the mean chronological age of individuals experiencing CHD events compared with those free of events was 67.4 versus 61.8 years, the difference in coronary age including CAC was larger (80.6 versus 62.8 years). Coronary age with CAC had identical predictive ability to that of MESA CHD Risk Score and outperformed chronological age and CAC alone. Conclusions The newly derived coronary age is a convenient transformation of MESA CHD Risk, retaining very good risk discrimination. This easy-to-communicate tool will be available for patients and clinicians, potentially facilitating risk communication in routine care.
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Genetically Determined Serum Calcium Levels and Markers of Ventricular Repolarization: A Mendelian Randomization Study in the UK Biobank.
Young, WJ, Warren, HR, Mook-Kanamori, DO, Ramírez, J, van Duijvenboden, S, Orini, M, Tinker, A, van Heemst, D, Lambiase, PD, Jukema, JW, et al
Circulation. Genomic and precision medicine. 2021;(3):e003231
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BACKGROUND ECG markers of ventricular depolarization and repolarization are associated with an increased risk of arrhythmia and sudden cardiac death. Our prior work indicated lower serum calcium concentrations are associated with longer QT and JT intervals in the general population. Here, we investigate whether serum calcium is a causal risk factor for changes in ECG measures using Mendelian randomization (MR). METHODS Independent lead variants from a newly performed genome-wide association study for serum calcium in >300 000 European-ancestry participants from UK Biobank were used as instrumental variables. Two-sample MR analyses were performed to approximate the causal effect of serum calcium on QT, JT, and QRS intervals using an inverse-weighted method in 76 226 participants not contributing to the serum calcium genome-wide association study. Sensitivity analyses including MR-Egger, weighted-median estimator, and MR pleiotropy residual sum and outlier were performed to test for the presence of horizontal pleiotropy. RESULTS Two hundred five independent lead calcium-associated variants were used as instrumental variables for MR. A decrease of 0.1 mmol/L serum calcium was associated with longer QT (3.01 ms [95% CI, 2.03 to 3.99]) and JT (2.89 ms [1.91 to 3.87]) intervals. A weak association was observed for QRS duration (secondary analyses only). Results were concordant in all sensitivity analyses. CONCLUSIONS These analyses support a causal effect of serum calcium levels on ventricular repolarization, in a middle-aged population of European-ancestry where serum calcium concentrations are likely stable and chronic. Modulation of calcium concentration may, therefore, directly influence cardiovascular disease risk.
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Association of Statin Treatment With Progression of Coronary Atherosclerotic Plaque Composition.
van Rosendael, AR, van den Hoogen, IJ, Gianni, U, Ma, X, Tantawy, SW, Bax, AM, Lu, Y, Andreini, D, Al-Mallah, MH, Budoff, MJ, et al
JAMA cardiology. 2021;(11):1257-1266
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IMPORTANCE The density of atherosclerotic plaque forms the basis for categorizing calcified and noncalcified morphology of plaques. OBJECTIVE To assess whether alterations in plaque across a range of density measurements provide a more detailed understanding of atherosclerotic disease progression. DESIGN, SETTING, AND PARTICIPANTS This cohort study enrolled 857 patients who underwent serial coronary computed tomography angiography 2 or more years apart and had quantitative measurements of coronary plaques throughout the entire coronary artery tree. The study was conducted from 2013 to 2016 at 13 sites in 7 countries. MAIN OUTCOMES AND MEASURES The main outcome was progression of plaque composition of individual coronary plaques. Six plaque composition types were defined on a voxel-level basis according to the plaque attenuation (expressed in Hounsfield units [HU]): low attenuation (-30 to 75 HU), fibro-fatty (76-130 HU), fibrous (131-350 HU), low-density calcium (351-700 HU), high-density calcium (701-1000 HU), and 1K (>1000 HU). The progression rates of these 6 compositional plaque types were evaluated according to the interaction between statin use and baseline plaque volume, adjusted for risk factors and time interval between scans. Plaque progression was also examined based on baseline calcium density. Analysis was performed among lesions matched at baseline and follow-up. Data analyses were conducted from August 2019 through March 2020. RESULTS In total, 2458 coronary lesions in 857 patients (mean [SD] age, 62.1 [8.7] years; 540 [63.0%] men; 548 [63.9%] received statin therapy) were included. Untreated coronary lesions increased in volume over time for all 6 compositional types. Statin therapy was associated with volume decreases in low-attenuation plaque (β, -0.02; 95% CI, -0.03 to -0.01; P = .001) and fibro-fatty plaque (β, -0.03; 95% CI, -0.04 to -0.02; P < .001) and greater progression of high-density calcium plaque (β, 0.02; 95% CI, 0.01-0.03; P < .001) and 1K plaque (β, 0.02; 95% CI, 0.01-0.03; P < .001). When analyses were restricted to lesions without low-attenuation plaque or fibro-fatty plaque at baseline, statin therapy was not associated with a change in overall calcified plaque volume (β, -0.03; 95% CI, -0.08 to 0.02; P = .24) but was associated with a transformation toward more dense calcium. Interaction analysis between baseline plaque volume and calcium density showed that more dense coronary calcium was associated with less plaque progression. CONCLUSIONS AND RELEVANCE The results suggest an association of statin use with greater rates of transformation of coronary atherosclerosis toward high-density calcium. A pattern of slower overall plaque progression was observed with increasing density. All findings support the concept of reduced atherosclerotic risk with increased densification of calcium.
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Machine learning of clinical variables and coronary artery calcium scoring for the prediction of obstructive coronary artery disease on coronary computed tomography angiography: analysis from the CONFIRM registry.
Al'Aref, SJ, Maliakal, G, Singh, G, van Rosendael, AR, Ma, X, Xu, Z, Alawamlh, OAH, Lee, B, Pandey, M, Achenbach, S, et al
European heart journal. 2020;(3):359-367
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AIMS: Symptom-based pretest probability scores that estimate the likelihood of obstructive coronary artery disease (CAD) in stable chest pain have moderate accuracy. We sought to develop a machine learning (ML) model, utilizing clinical factors and the coronary artery calcium score (CACS), to predict the presence of obstructive CAD on coronary computed tomography angiography (CCTA). METHODS AND RESULTS The study screened 35 281 participants enrolled in the CONFIRM registry, who underwent ≥64 detector row CCTA evaluation because of either suspected or previously established CAD. A boosted ensemble algorithm (XGBoost) was used, with data split into a training set (80%) on which 10-fold cross-validation was done and a test set (20%). Performance was assessed of the (1) ML model (using 25 clinical and demographic features), (2) ML + CACS, (3) CAD consortium clinical score, (4) CAD consortium clinical score + CACS, and (5) updated Diamond-Forrester (UDF) score. The study population comprised of 13 054 patients, of whom 2380 (18.2%) had obstructive CAD (≥50% stenosis). Machine learning with CACS produced the best performance [area under the curve (AUC) of 0.881] compared with ML alone (AUC of 0.773), CAD consortium clinical score (AUC of 0.734), and with CACS (AUC of 0.866) and UDF (AUC of 0.682), P < 0.05 for all comparisons. CACS, age, and gender were the highest ranking features. CONCLUSION A ML model incorporating clinical features in addition to CACS can accurately estimate the pretest likelihood of obstructive CAD on CCTA. In clinical practice, the utilization of such an approach could improve risk stratification and help guide downstream management.
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Changes in 3-month mineral and bone disorder patterns were associated with all-cause mortality in prevalent hemodialysis patients with secondary hyperparathyroidism.
Kato, C, Fujii, N, Miyakoshi, C, Asada, S, Onishi, Y, Fukuma, S, Nomura, T, Wada, M, Fukagawa, M, Fukuhara, S, et al
BMC nephrology. 2020;(1):432
Abstract
BACKGROUND There is limited evidence on the association between short-term changes in mineral and bone disorder parameters and survival in maintenance hemodialysis patients. METHODS We investigated the association between changing patterns of phosphorus, calcium and intact parathyroid hormone levels and all-cause mortality in hemodialysis patients with secondary hyperparathyroidism. Each parameter was divided into three categories (low [L], middle [M] and high [H]), and the changing patterns between two consecutive visits at 3-month intervals were categorized into nine groups (e.g., L-L and M-H). The middle category was defined as 4.0-7.0 mg/dL for phosphorous, 8.5-9.5 mg/dL for calcium and 200-500 pg/mL for intact parathyroid hormone. Adjusted incidence rates and rate ratios were analyzed by weighted Poisson regression models accounting for time-dependent exposures. RESULTS For phosphorus, shifts from low/high to middle category (L-M/H-M) were associated with a lower mortality compared with the L-L and H-H groups, whereas shifts from middle to low/high category (M-L/M-H) were associated with a higher mortality compared with the M-M group. For calcium, shifts from low/middle to high category (L-H/M-H) were associated with a higher mortality compared with the L-L and M-M groups, whereas shifts from high to middle category (H-M) were associated with a lower mortality compared with the H-H group. For intact parathyroid hormone, shifts from low to middle category (L-M) were associated with a lower mortality compared with the L-L group. CONCLUSIONS Changes in the 3-month patterns of phosphorus and calcium toward the middle category were associated with lower mortality. Our study also suggests the importance of avoiding hypercalcemia.
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Disentangling the Relationships Between the Renin-Angiotensin-Aldosterone System, Calcium Physiology, and Risk for Kidney Stones.
Bayomy, O, Zaheer, S, Williams, JS, Curhan, G, Vaidya, A
The Journal of clinical endocrinology and metabolism. 2020;(6):1937-46
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CONTEXT Complex relationships between aldosterone and calcium homeostasis have been proposed. OBJECTIVE To disentangle the influence of aldosterone and intravascular volume on calcium physiology. DESIGN Patient-oriented and epidemiology studies. SETTING Clinical research center and nationwide cohorts. PARTICIPANTS/INTERVENTIONS Patient-oriented study (n = 18): Participants were evaluated after completing a sodium-restricted (RES) diet to contract intravascular volume and after a liberalized-sodium (LIB) diet to expand intravascular volume. Cross-sectional studies (n = 3755): the association between 24h urinary sodium and calcium excretion and risk for kidney stones was assessed. RESULTS Patient-oriented study: compared to a RES-diet, a LIB-diet suppressed renin activity (LIB: 0.3 [0.1, 0.4] vs. RES: 3.1 [1.7, 5.3] ng/mL/h; P < 0.001) and plasma aldosterone (LIB: 2.0 [2.0, 2.7] vs. RES: 20.0 [16.1, 31.0] vs. ng/dL; P < 0.001), but increased calciuria (LIB: 238.4 ± 112.3 vs. RES: 112.9 ± 60.8 mg/24hr; P < 0.0001) and decreased serum calcium (LIB: 8.9 ± 0.3 vs. RES: 9.8 ± 0.4 mg/dL; P < 0.0001). Epidemiology study: mean urinary calcium excretion was higher with greater urinary sodium excretion. Compared to a urinary sodium excretion of < 120 mEq/day, a urinary sodium excretion of ≥220 mEq/day was associated with a higher risk for having kidney stones in women (risk ratio = 1.79 [95% confidence interval 1.05, 3.04]) and men (risk ratio = 2.06 [95% confidence interval 1.27, 3.32]). CONCLUSIONS High dietary sodium intake suppresses aldosterone, decreases serum calcium, and increases calciuria and the risk for developing kidney stones. Our findings help disentangle the influences of volume from aldosterone on calcium homeostasis and provide support for the recommendation to restrict dietary sodium for kidney stone prevention.
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Ionized calcium level at emergency department arrival is associated with return of spontaneous circulation in out-of-hospital cardiac arrest.
Kim, SJ, Kim, HS, Hwang, SO, Jung, WJ, Roh, YI, Cha, KC, Shin, SD, Song, KJ, ,
PloS one. 2020;(10):e0240420
Abstract
BACKGROUND Calcium level is associated with sudden cardiac death based on several cohort studies. However, there is limited evidence on the association between ionized calcium, active form of calcium, and resuscitation outcome. This study aimed to evaluate the potential role of ionized calcium in predicting resuscitation outcome in patients with out-of-hospital cardiac arrest. METHODS We analyzed the Korean Cardiac Arrest Research Consortium data (KoCARC) registry, a web-based multicenter registry that included 65 participating hospitals throughout the Republic of Korea. The patients with out-of-hospital cardiac arrest over 19 years old and acquired laboratory data including calcium, ionized calcium, potassium, phosphorus, creatinine, albumin at emergency department (ED) arrival were included. The primary outcome was successful rate of return of spontaneous circulation (ROSC) and the secondary outcomes were survival hospital discharge and favorable neurological outcome (cerebral performance category 1 or 2) at hospital discharge. RESULTS Eight-hundred and eighty-three patients were enrolled in the final analysis and 448 cases (54%) had ROSC. In multivariable logistic regression analysis, ionized calcium level was associated with ROSC (odds ratio, 1.77; 95% CI1.28-2.45; p = 0.001) even though calcium level was not associated with ROSC (odds ratio, 0.87; 95% CI 0.70-1.08; p = 0.199). However, ionized calcium level was not associated with survival discharge (odds ratio, 0.99; 95% CI 0.72-1.36; p = 0.948) or favorable neurologic outcome (odds ratio, 0.45; 95% CI 0.03-6.55, p = 0.560). CONCLUSION A high ionized calcium level measured during cardiopulmonary resuscitation was associated with an increased likelihood of ROSC.
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The Predictive Value of Coronary Artery Calcium Scoring for Major Adverse Cardiac Events According to Renal Function (from the Coronary Computed Tomography Angiography Evaluation for Clinical Outcomes: An International Multicenter [CONFIRM] Registry).
Lee, JH, Rizvi, A, Hartaigh, BÓ, Han, D, Park, MW, Roudsari, HM, Stuijfzand, WJ, Gransar, H, Lu, Y, Callister, TQ, et al
The American journal of cardiology. 2019;(9):1435-1442
Abstract
The prognostic performance of coronary artery calcium score (CACS) for predicting adverse outcomes in patients with decreased renal function remains unclear. We aimed to examine whether CACS improves risk stratification by demonstrating incremental value beyond a traditional risk score according to renal function status. 9,563 individuals without known coronary artery disease were enrolled. Estimated glomerular filtration rate (eGFR, ml/min/1.73 m2) was ascertained using the modified Modification of Diet in Renal Disease formula, and was categorized as: ≥90, 60 to 89, and <60. CACS was categorized as 0, 1 to 100, 101 to 400, and >400. Multivariable Cox regression was used to estimate hazard ratios (HR) with 95% confidence intervals (95% CI) for major adverse cardiac events (MACE), comprising all-cause mortality, myocardial infarction, and late revascularization (>90 days). Mean age was 55.8 ± 11.5 years (52.8% male). In total, 261 (2.7%) patients experienced MACE over a median follow-up of 24.5 months (interquartile range: 16.9 to 41.1). Incident MACE increased with higher CACS across each eGFR category, with the highest rate observed among patients with CACS >400 and eGFR <60 (95.1 per 1,000 person-years). A CACS >400 increased MACE risk with HR 4.46 (95% CI 1.68 to 11.85), 6.63 (95% CI 4.03 to 10.92), and 6.14 (95% CI 2.85 to 13.21) for eGFR ≥90, 60 to 89, and <60, respectively, as compared with CACS 0. Further, CACS improved discrimination and reclassification beyond Framingham 10-year risk score (FRS) (AUC: 0.70 vs 0.64; category free-NRI: 0.51, all p <0.001) for predicting MACE in patients with impaired renal function (eGFR < 90). In conclusion, CACS improved risk stratification and provided incremental value beyond FRS for predicting MACE, irrespective of eGFR status.
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An integrated analysis of safety and tolerability of etelcalcetide in patients receiving hemodialysis with secondary hyperparathyroidism.
Block, GA, Chertow, GM, Sullivan, JT, Deng, H, Mather, O, Tomlin, H, Serenko, M
PloS one. 2019;(3):e0213774
Abstract
BACKGROUND Calcimimetics have been shown to be effective and safe therapies for the treatment of secondary hyperparathyroidism (sHPT), a serious complication of disordered mineral metabolism associated with dialysis-dependent chronic kidney disease. Etelcalcetide, a recently approved intravenous calcimimetic, reduces serum parathyroid hormone (PTH), calcium, phosphorus, and fibroblast growth factor-23 concentrations. Here we report the first integrated safety profile of etelcalcetide using pooled data from five pivotal clinical trials. METHODS This analysis included data from patients receiving hemodialysis with moderate to severe sHPT enrolled in two randomized, placebo-controlled trials; a randomized active-controlled (with cinacalcet) trial; and two single-arm, open-label extension trials. Patients initially received etelcalcetide intravenously 5 mg three times weekly (TIW) after hemodialysis; with potential dose increases of 2.5 or 5 mg at 4-week intervals to a maximum dose of 15 mg TIW, depending on serum PTH and calcium levels. The nature, frequency, and severity of treatment-emergent adverse events (AEs) and changes in laboratory parameters were assessed. RESULTS Overall, we evaluated 1023 patients from the placebo-controlled trials, 683 from the active-controlled trial, and 1299 from open-label extensions. The frequency and nature of common treatment-emergent AEs reported for the etelcalcetide arm were consistent among the placebo-controlled and active-controlled trials. The most common AEs were those related to mineral metabolism (decreased blood calcium, hypophosphatemia, muscle spasms) or gastrointestinal abnormalities (diarrhea, nausea, vomiting). Hypocalcemia leading to discontinuation of either calcimimetic was experienced in ≤ 1% of patients. CONCLUSIONS This integrated safety assessment of etelcalcetide across placebo- and active-controlled trials showed an overall favorable risk/benefit profile, with safety similar to that of cinacalcet. Consistent with its mechanism of action, the most important risks associated with etelcalcetide were serum calcium reductions and hypocalcemia-related AEs; no new safety findings were identified in the pooled long-term extension trials.
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Effects of vitamin D and calcium on expression of MSH2 and transforming growth factors in normal-appearing colorectal mucosa of sporadic colorectal adenoma patients: A randomized clinical trial.
Kwan, AK, Um, CY, Rutherford, RE, Seabrook, ME, Barry, EL, Fedirko, V, Baron, JA, Bostick, RM
Molecular carcinogenesis. 2019;(4):511-523
Abstract
Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGFα (growth promoter) and TGFβ1 (growth inhibitor) is common during colorectal carcinogenesis. To estimate vitamin D and calcium effects on these biomarkers in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a pilot, randomized, double-blinded, placebo-controlled, modified 2 × 2 factorial chemoprevention clinical trial (N = 104) of supplemental vitamin D3 (1000 IU daily) and calcium (1200 mg daily), alone and in combination, versus placebo over 1 year. The expression of the three biomarkers and Ki-67/mib-1 in colorectal crypts in biopsies of normal-appearing rectal mucosa were detected using automated immunohistochemistry and quantified using image analysis. In the vitamin D3 and vitamin D3 plus calcium groups, relative to their reference groups, in the upper 40% (differentiation zone) of crypts, it was estimated that, respectively, the MSH2/mib-1 ratio increased by 47% (P = 0.14) and 62% (P = 0.08), TGFβ1 expression increased by 41% (P = 0.25) and 78% (P = 0.14), and the TGFα/TGFβ1 ratio decreased by 25% (P = 0.31) and 44% (P = 0.13). Although not statistically significant, these results support further research into (i) whether supplemental vitamin D3 , alone or in combination with calcium, may increase DNA mismatch repair relative to proliferation, increase TGFβ1 expression, and decrease autocrine/paracrine growth promotion relative to growth inhibition in the colorectal epithelium, all hypothesized to reduce risk for colorectal carcinogenesis; and (ii) the expression of MSH2 relative to mib-1, TGFβ1 alone, and TGFα relative to TGFβ1 in the normal-appearing rectal mucosa as potential modifiable, pre-neoplastic markers of risk for colorectal neoplasms.