Noninvasive Atherosclerotic Phenotyping: The Next Frontier into Understanding the Pathobiology of Coronary Artery Disease.

PURPOSE OF REVIEW: Despite recent advances, coronary artery disease remains one of the leading causes of mortality worldwide. Noninvasive imaging allows atherosclerotic phenotyping by measurement of plaque burden, morphology, activity and inflammation, which has the potential to refine patient risk stratification and guide personalized therapy. This review describes the current and emerging roles of advanced noninvasive cardiovascular imaging methods for the assessment of coronary artery disease. RECENT FINDINGS: Cardiac computed tomography enables comprehensive, noninvasive imaging of the coronary vasculature, and is used to assess luminal stenoses, coronary calcifications, and distinct adverse plaque characteristics, helping to identify patients prone to future events. Novel software tools, implementing artificial intelligence solutions, can automatically quantify and characterize atherosclerotic plaque from standard computed tomography datasets. These quantitative imaging biomarkers have been shown to improve patient risk stratification beyond clinical risk scores and current clinical interpretation of cardiac computed tomography. In addition, noninvasive molecular imaging in higher risk patients can be used to assess plaque activity and plaque thrombosis. Noninvasive imaging allows unique insight into the burden, morphology and activity of atherosclerotic coronary plaques. Such phenotyping of atherosclerosis can potentially improve individual patient risk prediction, and in the near future has the potential for clinical implementation.

Postoperative Myocardial Infarction Due to Coronary Embolization of Valve Tissue After Surgical Mitral Valve Replacement.

We present the case of a 61-year-old man with known Morbus Barlow disease, who presented with postoperative myocardial infarction and cardiac arrest within 1 hour after minimally invasive mitral valve surgery owing to coronary artery occlusion by native mitral valve tissue.

Intravenous versus oral hydration to reduce the risk of postcontrast acute kidney injury after intravenous contrast-enhanced CT in patients with severe chronic kidney disease (ENRICH): a study protocol for a single-centre, parallel-group, open-labelled non-inferiority randomised controlled trial in Denmark.

INTRODUCTION: Contrast-enhanced CT (CECT) is widely used for diagnostic purposes. The use of contrast medium carries a risk for postcontrast acute kidney injury (PC-AKI), especially in patients with AKI or chronic kidney disease (CKD). Current guidelines recommend prophylactic intravenous hydration to prevent PC-AKI in high-risk patients. Oral hydration is non-inferior to intravenous hydration in patients with moderate CKD, but it has not been evaluated in high-risk patients. METHODS AND ANALYSIS: The ENRICH trial will enrol 254 patients with estimated glomerular filtration rate ≤30 mL/min/1.73 m2 undergoing intravenous CECT, who are block randomised (2-4-2) with stratification for CKD stage, diabetes status, and indication for referral to prophylactic treatment with oral or intravenous hydration. PC-AKI is defined as an absolute increase in SCr of >0.3 mg/dL or >1.5 from baseline at 2-5 days. Renal function will also be evaluated <90 days, <7 days and 1-3 days before intravenous CECT, and 25-40 days after intravenous CECT. Secondary outcomes include dialysis, renal adverse events, hospitalisation due to hydration-related or contrast-related sequelae, and all-cause mortality ≤30 days postcontrast. Pre- and postcontrast plasma and urinary biomarkers will be evaluated for diagnostic and prognostic accuracy of the primary and secondary outcomes. ETHICS AND DISSEMINATION: Oral hydration is patient-friendly and less costly compared with intravenous hydration. If oral hydration is non-inferior to intravenous hydration in high-risk patients, it could be implemented as new hydration strategy, which will facilitate the clinical diagnosing of elective patients with severe CKD without unnecessary resource utilisation. The protocol is approved by the Regional Scientific Ethical Committee for Southern Denmark (S-20210126), and the Data Protection Agency (21/66779). The study is conducted in accordance with the Declaration of Helsinki. Positive as well as negative findings will be reported in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05283512.

Effects of vitamins K2 and D3 supplementation in patients with severe coronary artery calcification: a study protocol for a randomised controlled trial.

INTRODUCTION: Coronary artery calcification (CAC) and especially progression in CAC is a strong predictor of acute myocardial infarction and cardiovascular mortality. Supplementation with vitamin K2 and D3 has been suggested to have a protective role in the progression of CAC. In this study, we will examine the effect of vitamins K2 and D3 in men and women with severe CAC. We hypothesise that supplementation with vitamins K2 and D3 will slow down the calcification process. METHOD AND ANALYSIS: In this multicentre and double-blinded placebo-controlled study, 400 men and women with CAC score≥400 are randomised (1:1) to treatment with vitamin K2 (720 µg/day) and vitamin D3 (25 µg/day) or placebo treatment (no active treatment) for 2 years. Among exclusion criteria are treatment with vitamin K antagonist, coagulation disorders and prior coronary artery disease. To evaluate progression in coronary plaque, a cardiac CT-scan is performed at baseline and repeated after 12 and 24 months of follow-up. Primary outcome is progression in CAC score from baseline to follow-up at 2 years. Among secondary outcomes are coronary plaque composition and cardiac events. Intention-to-treat principle is used for all analyses. ETHICS AND DISSEMINATION: There are so far no reported adverse effects associated with the use of vitamin K2. The protocol was approved by the Regional Scientific Ethical Committee for Southern Denmark and the Data Protection Agency. It will be conducted in accordance with the Declaration of Helsinki. Positive as well as negative findings will be reported. TRIAL REGISTRATION NUMBER: NCT05500443.

Vitamin K2 and D in Patients With Aortic Valve Calcification: A Randomized Double-Blinded Clinical Trial.

BACKGROUND: Menaquinone-7 (MK-7), also known as vitamin K2, is a cofactor for the carboxylation of proteins involved in the inhibition of arterial calcification and has been suggested to reduce the progression rate of aortic valve calcification (AVC) in patients with aortic stenosis. METHODS: In a randomized, double-blind, multicenter trial, men from the community with an AVC score >300 arbitrary units (AU) on cardiac noncontrast computer tomography were randomized to daily treatment with tablet 720 µg MK-7 plus 25 µg vitamin D or matching placebo for 24 months. The primary outcome was the change in AVC score. Selected secondary outcomes included change in aortic valve area and peak aortic jet velocity on echocardiography, heart valve surgery, change in aortic and coronary artery calcification, and change in dp-ucMGP (dephosphorylated-undercarboxylated matrix Gla-protein). Safety outcomes included all-cause death and cardiovascular events. RESULTS: From February 1, 2018, to March 21, 2019, 365 men were randomized. Mean age was 71.0 (±4.4) years. The mean (95% CI) increase in AVC score was 275 AU (95% CI, 225-326 AU) and 292 AU (95% CI, 246-338 AU) in the intervention and placebo groups, respectively. The mean difference on AVC progression was 17 AU (95% CI, -86 to 53 AU; P=0.64). The mean change in aortic valve area was 0.02 cm2 (95% CI, -0.09 to 0.12 cm2; P=0.78) and in peak aortic jet velocity was 0.04 m/s (95% CI, -0.11 to 0.02 m/s; P=0.21). The progression in aortic and coronary artery calcification score was not significantly different between patients treated with MK-7 plus vitamin D and patients receiving placebo. There was no difference in the rate of heart valve surgery (1 versus 2 patients; P=0.99), all-cause death (1 versus 4 patients; P=0.37), or cardiovascular events (10 versus 10 patients; P=0.99). Compared with patients in the placebo arm, a significant reduction in dp-ucMGP was observed with MK-7 plus vitamin D (-212 pmol/L versus 45 pmol/L; P<0.001). CONCLUSIONS: In elderly men with an AVC score >300 AU, 2 years MK-7 plus vitamin D supplementation did not influence AVC progression. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03243890.

Mitral Annulus Calcification and Cardiac Conduction Disturbances: A DANCAVAS Sub-study.

BACKGROUND: Due to its location very close to the bundle of His, mitral annulus calcification (MAC) might be associated with the development of atrioventricular (AV) conduction disturbances. This study assessed the association between MAC and AV conduction disturbances identified by cardiac implantable electronic device (CIED) use and electrocardiographic parameters. The association between MAC and traditional cardiovascular risk factors was also assessed. METHODS: This cross-sectional study analyzed 14,771 participants, predominantly men aged 60-75 years, from the population-based Danish Cardiovascular Screening trial. Traditional cardiovascular risk factors were obtained. Using cardiac non-contrast computed tomography imaging, MAC scores were measured using the Agatston method and divided into absent versus present and score categories. CIED implantation data were obtained from the Danish Pacemaker and Implantable Cardioverter Defibrillator Register. A 12-lead electrocardiogram was available for 2,107 participants. Associations between MAC scores and AV conduction disturbances were assessed using multivariate regression analyses. RESULTS: MAC was present in 22.4% of the study subjects. Participants with pacemakers for an AV conduction disturbance had significantly higher MAC scores (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.01-1.23) than participants without a CIED, whereas participants with a CIED for other reasons did not. Prolonged QRS-interval was significantly associated with the presence of MAC (OR, 1.45; 95% CI, 1.04-2.04), whereas prolonged PQ-interval was not. Female sex and most traditional cardiovascular risk factors were significantly associated with high MAC scores. CONCLUSIONS: MAC was associated with AV conduction disturbances, which could improve our understanding of the development of AV conduction disturbances.

Extent of arterial calcification by conventional vitamin K antagonist treatment.

BACKGROUND AND AIMS: Vitamin K antagonists (VKA) remain the most frequently prescribed oral anticoagulants worldwide despite the introduction of non-vitamin K antagonist oral anticoagulants (NOAC). VKA interfere with the regeneration of Vitamin K1 and K2, essential to the activation of coagulation factors and activation of matrix-Gla protein, a strong inhibitor of arterial calcifications. This study aimed to clarify whether VKA treatment was associated with the extent of coronary artery calcification (CAC) in a population with no prior cardiovascular disease (CVD). METHODS: We collected data on cardiovascular risk factors and CAC scores from cardiac CT scans performed as part of clinical examinations (n = 9,672) or research studies (n = 14,166) in the period 2007-2017. Data on use of anticoagulation were obtained from the Danish National Health Service Prescription Database. The association between duration of anticoagulation and categorized CAC score (0, 1-99, 100-399, ≥400) was investigated by ordered logistic regression adjusting for covariates. RESULTS: The final study population consisted of 17,254 participants with no prior CVD, of whom 1,748 and 1,144 had been treated with VKA or NOAC, respectively. A longer duration of VKA treatment was associated with higher CAC categories. For each year of VKA treatment, the odds of being in a higher CAC category increased (odds ratio (OR) = 1.032, 95%CI 1.009-1.057). In contrast, NOAC treatment duration was not associated with CAC category (OR = 1.002, 95%CI 0.935-1.074). There was no significant interaction between VKA treatment duration and age on CAC category. CONCLUSIONS: Adjusted for cardiovascular risk factors, VKA treatment-contrary to NOAC-was associated to higher CAC category.

Association of aortic valve calcification and vitamin K antagonist treatment.

AIMS: Vitamin K antagonists (VKAs) are suspected of causing aortic valve calcification (AVC). The objective of this study was to clarify whether patients undergoing VKA treatment have increased AVC scores compared to patients treated with new oral anticoagulants (NOACs) and patients who never have been treated with VKA/NOAC. METHODS AND RESULTS: We included participants from the population-based DANCAVAS trial (n = 15 048). Information on confounders was collected, and the AVC scores were measured on non-contrast computed tomography scans. The participants' medication data, including VKA and NOAC data, were collected from the Danish National Health Service Prescription Database. The final population consisted of 14 604 participants (67.4 years, 95% men) of whom 873 had been treated with VKA and 602 with NOAC. The association between AVC score and duration of anticoagulant use was investigated in an adjusted zero-inflated negative binomial regression model. For every year treated with VKA, the AVC score increased, on average, by 6% [ratio of expected counts (RECs) = 1.06; 95% confidence interval (CI) 1.02-1.10] compared to non-use. The results were consistent in sensitivity analyses excluding patients with known cardiovascular disease and statin users (REC = 1.07; 95% CI 1.02-1.11 and REC = 1.10; 95% CI 1.03-1.17, respectively). NOAC treatment was not significantly associated with AVC score in any of the corresponding models (REC = 1.03, 1.02, and 0.96). CONCLUSION: Compared to no treatment with anticoagulants, VKA use was associated with increased AVC score, while a similar association could not be established for NOAC.