Post-Myocardial Infarction Remodeling and Hyperkinetic Remote Myocardium in Sheep Measured by Cardiac MRI Feature Tracking.

BACKGROUND: Cardiac MRI feature tracking (FT) allows objective assessment of segmental left ventricular (LV) function following a myocardial infarction (MI), but its utilization in sheep, where interventions can be tested, is lacking. PURPOSE: To apply and validate FT in a sheep model of MI and describe post-MI LV remodeling. STUDY TYPE: Animal model, longitudinal. ANIMAL MODEL: Eighteen lambs (6 months, male, n = 14; female, n = 4; 25.2 ± 4.5 kg). FIELD STRENGTH/SEQUENCE: Two-dimensional balanced steady-state free precession (bSSFP) and 3D inversion recovery fast low angle shot (IR-FLASH) sequences at 3 T. ASSESSMENT: Seven lambs underwent test-retest imaging to assess FT interstudy reproducibility. MI was induced in the remaining 11 by coronary ligation with MRI being undertaken before and 15 days post-MI. Injury size was measured by late gadolinium enhancement (LGE) and LV volumes, LV mass, ejection fraction (LVEF), and wall thickness (LVWT) were measured, with FT measures of global and segmental radial, circumferential, and longitudinal strain. STATISTICAL TESTS: Sampling variability, inter-study, intra and interobserver reproducibility were assessed using Pearson's correlation, Bland-Altman analyses, and intra-class correlation coefficients (ICC). Diagnostic performance of segmental strain to predict LGE was assessed using receiver operating characteristic curve analysis. Significant differences were considered P < 0.05. RESULTS: Inter-study reproducibility of FT was overall good to excellent, with global strain being more reproducible than segmental strain (ICC = 0.89-0.98 vs. 0.77-0.96). MI (4.0 ± 3.7% LV mass) led to LV remodeling, as evident by significantly increased LV volumes and LV mass, and significantly decreased LVWT in injured regions, while LVEF was preserved (54.9 ± 6.9% vs. 55.6 ± 5.7%; P = 0.778). Segmental circumferential strain (CS) correlated most strongly with LGE. Basal and mid- CS increased significantly, while apical CS significantly decreased post-MI. DATA CONCLUSION: FT is reproducible and compensation by hyperkinetic remote myocardium may manifest as overall preserved global LV function. EVIDENCE LEVEL: N/A TECHNICAL EFFICACY: Stage 2.

A rare case report of type 1 congenital disorders of glycosylation with acute decompensated heart failure and the incidental discovery of congenital disorders of glycosylation associated dilated cardiomyopathy and acute myocarditis.

Background: Congenital disorders of glycosylation (CDG) are rare genetically inherited defects leading to enzyme deficiency or malfunction in the glycosylation pathway. Normal glycosylation is essential to the development of normal cardiac anatomy and function. Congenital disorders of glycosylation-related cardiomyopathy are often the first manifestation detected in early life and may lead to sudden cardiac death. Approximately one-fifth of CDG types are related to cardiac diseases that include cardiomyopathy, rhythm disturbances, pericardial effusions, and structural heart disease. Case summary: We report a rare case of a 26-year-old lady with CDG-1 who presented with acute-onset dyspnoea. She had respiratory tract symptoms for the past 2 weeks. With the relevant clinical and biochemical findings, including supportive findings on echocardiogram and cardiac magnetic resonance imaging, we have managed to arrive at a diagnosis of severe pneumonia leading to acute decompensated heart failure, as well as the discovery of an underlying CDG-associated dilated cardiomyopathy (DCM) and acute myocarditis. Anti-failure medications and i.v. methylprednisolone were commenced, and she showed gradual clinical improvement with an increase of her left ventricular function. She was discharged home well with anti-failure therapy, prednisolone, and a follow-up echocardiogram with further review in the heart failure clinic. Discussion: In conclusion, this case report highlights the need for accurate diagnosis and prompt management of CDG-associated DCM, leading to a successful recovery and discharge from hospital care. With this, we hope to add to the increasing number of reported cases of CDG-related cardiac disease in the medical literature to emphasize the importance of screening and follow-up for any underlying cardiac diseases in patients with CDG.

Stress Perfusion Cardiac Magnetic Resonance vs SPECT Imaging for Detection of Coronary Artery Disease.

BACKGROUND: GadaCAD2 was 1 of 2 international, multicenter, prospective, Phase 3 clinical trials that led to U.S. Food and Drug Administration approval of gadobutrol to assess myocardial perfusion and late gadolinium enhancement (LGE) in adults with known or suspected coronary artery disease (CAD). OBJECTIVES: A prespecified secondary objective was to determine if stress perfusion cardiovascular magnetic resonance (CMR) was noninferior to single-photon emission computed tomography (SPECT) for detecting significant CAD and for excluding significant CAD. METHODS: Participants with known or suspected CAD underwent a research rest and stress perfusion CMR that was compared with a gated SPECT performed using standard clinical protocols. For CMR, adenosine or regadenoson served as vasodilators. The total dose of gadobutrol was 0.1 mmol/kg body weight. The standard of reference was a 70% stenosis defined by quantitative coronary angiography (QCA). A negative coronary computed tomography angiography could exclude CAD. Analysis was per patient. CMR, SPECT, and QCA were evaluated by independent central core lab readers blinded to clinical information. RESULTS: Participants were predominantly male (61.4% male; mean age 58.9 ± 10.2 years) and were recruited from the United States (75.0%), Australia (14.7%), Singapore (5.7%), and Canada (4.6%). The prevalence of significant CAD was 24.5% (n = 72 of 294). Stress perfusion CMR was statistically superior to gated SPECT for specificity (P = 0.002), area under the receiver operating characteristic curve (P < 0.001), accuracy (P = 0.003), positive predictive value (P < 0.001), and negative predictive value (P = 0.041). The sensitivity of CMR for a 70% QCA stenosis was noninferior and nonsuperior to gated SPECT. CONCLUSIONS: Vasodilator stress perfusion CMR, as performed with gadobutrol 0.1 mmol/kg body weight, had superior diagnostic accuracy for diagnosis and exclusion of significant CAD vs gated SPECT.

Burden of mood symptoms and disorders in implantable cardioverter defibrillator patients: a systematic review and meta-analysis of 39 954 patients.

AIMS: Implantable cardioverter defibrillators (ICDs) prevent sudden cardiac death. Anxiety, depression, and post-traumatic stress disorder (PTSD) are underappreciated symptoms. We aimed to systematically synthesize prevalence estimates of mood disorders and symptom severities, pre- and post-ICD insertions. Comparisons were made with control groups, as well as within ICD patients by indication (primary vs. secondary), sex, shock status, and over time. METHODS: Databases (Medline, PsycINFO, PubMed, and Embase) were searched without limits from inception to 31 August 2022; 4661 articles were identified, 109 (39 954 patients) of which met criteria. RESULTS: Random-effects meta-analyses revealed clinically relevant anxiety in 22.58% (95%CI 18.26-26.91%) of ICD patients across all timepoints following insertion and depression in 15.42% (95%CI 11.90-18.94%). Post-traumatic stress disorder was seen in 12.43% (95%CI 6.90-17.96%). Rates did not vary relative to indication group. Clinically relevant anxiety and depression were more likely in ICD patients who experienced shocks [anxiety odds ratio (OR) = 3.92 (95%CI 1.67-9.19); depression OR = 1.87 (95%CI 1.34-2.59)]. Higher symptoms of anxiety were seen in females than males post-insertion [Hedges' g = 0.39 (95%CI 0.15-0.62)]. Depression symptoms decreased in the first 5 months post-insertion [Hedges' g = 0.13 (95%CI 0.03-0.23)] and anxiety symptoms after 6 months [Hedges' g = 0.07 (95%CI 0-0.14)]. CONCLUSION: Depression and anxiety are highly prevalent in ICD patients, especially in those who experience shocks. Of particular concern is the prevalence of PTSD following ICD implantation. Psychological assessment, monitoring, and therapy should be offered to ICD patients and their partners as part of routine care.

The Burden of Uncontrolled Cardiovascular Risk Factors in Men With Prostate Cancer: A RADICAL-PC Analysis.

Background: Cardiovascular disease (CVD) incidence is higher in men with prostate cancer (PC) than without. Objectives: We describe the rate and correlates of poor cardiovascular risk factor control among men with PC. Methods: We prospectively characterized 2,811 consecutive men (mean age 68 ± 8 years) with PC from 24 sites in Canada, Israel, Brazil, and Australia. We defined poor overall risk factor control as ≥3 of the following: suboptimal low-density lipoprotein cholesterol (>2 mmol/L if Framingham Risk Score [FRS] ≥15 and ≥3.5 mmol/L if FRS <15), current smoker, physical inactivity (<600 MET min/wk), suboptimal blood pressure (BP) (≥140/90 mm Hg if no other risk factors, systolic BP ≥120 mm Hg if known CVD or FRS ≥15, and ≥130/80 mm Hg if diabetic), and waist:hip ratio >0.9. Results: Among participants (9% with metastatic PC and 23% with pre-existing CVD), 99% had ≥1 uncontrolled cardiovascular risk factor, and 51% had poor overall risk factor control. Not taking a statin (odds ratio [OR]: 2.55; 95% CI: 2.00-3.26), physical frailty (OR: 2.37; 95% CI: 1.51-3.71), need for BP drugs (OR: 2.36; 95% CI: 1.84-3.03), and age (OR per 10-year increase: 1.34; 95% CI: 1.14-1.59) were associated with poor overall risk factor control after adjustment for education, PC characteristics, androgen deprivation therapy, depression, and Eastern Cooperative Oncology Group functional status. Conclusions: Poor control of modifiable cardiovascular risk factors is common in men with PC, highlighting the large gap in care and the need for improved interventions to optimize cardiovascular risk management in this population.

Utility of cardiovascular magnetic resonance in patients with stable troponin elevation.

AIMS: Cardiovascular magnetic resonance (CMR) imaging has a potential role in the evaluation of symptomatic patients with stable troponin elevation; however, its utility remains unexplored. We sought to determine the incremental diagnostic value of CMR in this unique cohort and assess the long-term clinical outcomes. METHODS AND RESULTS: Two hundred twenty-five consecutive patients presenting with cardiac chest pain/dyspnoea, stable troponin elevation, and undergoing CMR assessment were identified retrospectively from registry database. The study cohort was prospectively followed for major adverse cardiac events (MACEs) (defined as composite of all-cause mortality and cardiovascular readmissions). The primary outcome measure was the diagnostic utility of CMR, i.e. percentage of patients for whom CMR identified the cause of stable troponin elevation. Secondary outcome measures included the incremental value of CMR and occurrence of MACE. CMR was able to identify the cause for stable troponin elevation in 160 (71%) patients. A normal CMR was identified in 17% and an inconclusive CMR in 12% of the patients. CMR changed the referral diagnosis in 59 (26%) patients. Utilizing a baseline prediction model (pre-CMR referral diagnosis), the net reclassification index was 0.11 and integrated discriminatory improvement index measured 0.33 following CMR. Over a median follow-up of 4.3 years (interquartile range 2.8-6.3), 72 (32%) patients experienced MACE. CONCLUSION: CMR identified a cause for stable troponin elevation in 7 of 10 cases, and a new diagnosis was evident in 1 of 4 cases. CMR improved the net reclassification of patients with stable troponin elevation.

Prevalence and Prognostic Implications of Moderate or Severe Mitral Regurgitation in Patients with Bicuspid Aortic Valve.

BACKGROUND: Significant (moderate or greater) mitral regurgitation (MR) could augment the hemodynamic effects of aortic valvular disease in patients with bicuspid aortic valve (BAV), imposing a greater hemodynamic burden on the left ventricle and atrium, possibly culminating in a faster onset of left ventricular dilation and/or symptoms. The aim of this study was to determine the prevalence and prognostic implications of significant MR in patients with BAV. METHODS: In this large, multicenter, international registry, a total of 2,932 patients (mean age, 48 ± 18 years; 71% men) with BAV were identified. All patients were evaluated for the presence of significant primary or secondary MR by transthoracic echocardiography and were followed up for the end points of all-cause mortality and event-free survival. RESULTS: Overall, 147 patients (5.0%) had significant primary (1.5%) or secondary (3.5%) MR. Significant MR was associated with all-cause mortality (hazard ratio [HR], 2.80; 95% CI, 1.91-4.11; P < .001) and reduced event-free survival (HR, 1.97; 95% CI, 1.58-2.46; P < .001) on univariable analysis. MR was not associated with all-cause mortality (adjusted HR, 1.33; 95% CI, 0.85-2.07; P = .21) or event-free survival (adjusted HR, 1.10; 95% CI, 0.85-1.42; P = .49) after multivariable adjustment. However, sensitivity analyses demonstrated that significant MR not due to aortic valve disease retained an independent association with mortality (adjusted HR, 1.81; 95% CI, 1.04-3.15; P = .037). Subgroup analyses demonstrated an independent association between significant MR and all-cause mortality for individuals with significant aortic regurgitation (HR, 2.037; 95% CI, 1.025-4.049; P = .042), although this association was not observed for subgroups with significant aortic stenosis or without significant aortic valve dysfunction. CONCLUSIONS: Significant MR is uncommon in patients with BAV. Following adjustment for important confounding variables, significant MR was not associated with adverse prognosis in this large study of patients with BAV, except for the patient subgroup with moderate to severe aortic regurgitation. In addition, significant MR not due to aortic valve disease demonstrated an independent association with all-cause mortality.

Role of interatrial conduction in atrial fibrillation: Mechanistic insights from renewal theory-based fibrillatory dynamic analysis.

Background: Interatrial conduction has been postulated to play an important role in atrial fibrillation (AF). The pathways involved in interatrial conduction during AF remain incompletely defined. Objective: We recently showed physiological assessment of fibrillatory dynamics could be performed using renewal theory, which determines rates of phase singularity formation (λf) and destruction (λd). Using the renewal approach, we aimed to understand the role of the interatrial septum and other electrically coupled regions during AF. Method: RENEWAL-AF is a prospective multicenter observational study recruiting AF ablation patients (ACTRN 12619001172190). We studied unipolar electrograms obtained from 16 biatrial locations prior to ablation using a 16-electrode Advisor HD Grid catheter. Renewal rate constants λf and λd were calculated, and the relationships between these rate constants in regions of interatrial connectivity were examined. Results: Forty-one AF patients (28.5% female) were recruited. A positive linear correlation was observed between λf and λd (1) across the interatrial septum (λf r2 = 0.5, P < .001, λd r2 = 0.45, P < .001), (2) in regions connected by the Bachmann bundle (right atrial appendage-left atrial appendage λf r2 = 0.29, P = .001; λd r2 = 0.2, P = .008), and (3) across the inferior interatrial routes (cavotricuspid isthmus-left atrial septum λf r2 = 0.67, P < .001; λd r2 = 0.55, P < .001). Persistent AF status and left atrial volume were found to be important effect modifiers of the degree of interatrial renewal rate statistical correlation. Conclusion: Our findings support the role of interseptal statistically determined electrical disrelation in sustaining AF. Additionally, renewal theory identified preferential conduction through specific interatrial pathways during fibrillation. These findings may be of importance in identifying clinically significant targets for ablation in AF patients.

Cardiac magnetic resonance diagnosis of Fabry disease leads to incidental diagnosis of Klinefelter syndrome: a case report.

Background: Fabry disease is an X-linked lysosomal storage disorder resulting in deficient activity of alpha-galactosidase. Males are general more severely affected however heterozygous females can variably express the disease depending on the degree of random X chromosome inactivation (Lyonization). We present a case where cardiac magnetic resonance diagnosis of late onset Fabry Disease leads to an incidental diagnosis of Klinefelter syndrome. Case summary: A 55-year-old male was referred for cardiology assessment after developing atrial fibrillation. Echocardiography demonstrated moderate, concentric LVH (left ventricular hypertrophy). Cardiac magnetic resonance imaging confirmed the presence of concentric increase in LV wall thickness and increased LV (left ventricular) mass. T1 mapping values (Shortened Modified Look-Locker Inversion recovery sequences) were elevated in the basal-mid inferolateral segments and low in the remaining segments. Late gadolinium acquisition showed a pattern suggestive of Fabry disease. Genetic testing of the GLA gene revealed a null variant classified as pathogenic. The variant was found to be heterozygous. This raised the possibility of Klinefelter's syndrome and the diagnosis was confirmed by chromosomal microarray and karyotype. The patient was then referred to Fabry clinic for consideration of enzyme replacement therapy and to the endocrine clinic for testosterone replacement. Discussion: The atypical 'cardiac variant' Fabry disease should be included in differential diagnosis of left ventricular hypertrophy. In a 'late onset' presentation of Fabry Disease, the concomitant presence of Klinefelter syndrome cannot be excluded due to GLA variant present in the heterozygous state.

Predictors of Left Main Coronary Artery Disease in the ISCHEMIA Trial.

BACKGROUND: Detection of ≥50% diameter stenosis left main coronary artery disease (LMD) has prognostic and therapeutic implications. Noninvasive stress imaging or an exercise tolerance test (ETT) are the most common methods to detect obstructive coronary artery disease, though stress test markers of LMD remain ill-defined. OBJECTIVES: The authors sought to identify markers of LMD as detected on coronary computed tomography angiography (CTA), using clinical and stress testing parameters. METHODS: This was a post hoc analysis of ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches), including randomized and nonrandomized participants who had locally determined moderate or severe ischemia on nonimaging ETT, stress nuclear myocardial perfusion imaging, or stress echocardiography followed by CTA to exclude LMD. Stress tests were read by core laboratories. Prior coronary artery bypass grafting was an exclusion. In a stepped multivariate model, the authors identified predictors of LMD, first without and then with stress testing parameters. RESULTS: Among 5,146 participants (mean age 63 years, 74% male), 414 (8%) had LMD. Predictors of LMD were older age (P < 0.001), male sex (P < 0.01), absence of prior myocardial infarction (P < 0.009), transient ischemic dilation of the left ventricle on stress echocardiography (P = 0.05), magnitude of ST-segment depression on ETT (P = 0.004), and peak metabolic equivalents achieved on ETT (P = 0.001). The models were weakly predictive of LMD (C-index 0.643 and 0.684). CONCLUSIONS: In patients with moderate or severe ischemia, clinical and stress testing parameters were weakly predictive of LMD on CTA. For most patients with moderate or severe ischemia, anatomical imaging is needed to rule out LMD. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

Evidence-based cardiovascular magnetic resonance cost-effectiveness calculator for the detection of significant coronary artery disease.

BACKGROUND: Although prior reports have evaluated the clinical and cost impacts of cardiovascular magnetic resonance (CMR) for low-to-intermediate-risk patients with suspected significant coronary artery disease (CAD), the cost-effectiveness of CMR compared to relevant comparators remains poorly understood. We aimed to summarize the cost-effectiveness literature on CMR for CAD and create a cost-effectiveness calculator, useable worldwide, to approximate the cost-per-quality-adjusted-life-year (QALY) of CMR and relevant comparators with context-specific patient-level and system-level inputs. METHODS: We searched the Tufts Cost-Effectiveness Analysis Registry and PubMed for cost-per-QALY or cost-per-life-year-saved studies of CMR to detect significant CAD. We also developed a linear regression meta-model (CMR Cost-Effectiveness Calculator) based on a larger CMR cost-effectiveness simulation model that can approximate CMR lifetime discount cost, QALY, and cost effectiveness compared to relevant comparators [such as single-photon emission computed tomography (SPECT), coronary computed tomography angiography (CCTA)] or invasive coronary angiography. RESULTS: CMR was cost-effective for evaluation of significant CAD (either health-improving and cost saving or having a cost-per-QALY or cost-per-life-year result lower than the cost-effectiveness threshold) versus its relevant comparator in 10 out of 15 studies, with 3 studies reporting uncertain cost effectiveness, and 2 studies showing CCTA was optimal. Our cost-effectiveness calculator showed that CCTA was not cost-effective in the US compared to CMR when the most recent publications on imaging performance were included in the model. CONCLUSIONS: Based on current world-wide evidence in the literature, CMR usually represents a cost-effective option compared to relevant comparators to assess for significant CAD.

Long-term clinical outcomes in patients with a working diagnosis of myocardial infarction with non-obstructed coronary arteries (MINOCA) assessed by cardiovascular magnetic resonance imaging.

BACKGROUND: Myocardial infarction with non-obstructed coronary arteries (MINOCA) is a distinct entity among patients presenting with troponin-positive acute chest pain. We have previously reported on the incremental diagnostic capability of cardiovascular magnetic resonance (CMR) in this cohort. There is paucity of evidence on the long-term (> 5 years) clinical outcomes of these patients as graded by their acute CMR diagnosis. METHODS AND RESULTS: A total of 229 patients with a working diagnosis of MINOCA who underwent CMR assessment during the acute admission (2010-2017) were prospectively studied. The primary endpoint was major adverse cardiac events (MACE) defined as a composite of all-cause mortality and cardiovascular readmissions, identified from hospital and primary care records. CMR performed at a median of 6 days (IQR 2, 8) from presentation provided a diagnosis in 85% of the patients (38% myocarditis, 28% acute myocardial infarction and 19% Takotsubo cardiomyopathy). Over a median follow-up of 7.1 years (IQR 3.7, 8.2), 56 (24%) patients experienced a MACE. We found a strong association between CMR diagnosis and MACE (log rank 30.47, p < 0.001). In multivariate analysis, age (hazard ratio = 1.07; 95% confidence interval = 1.05, 1.10; p < 0.001) and CMR diagnosis of acute myocardial infarction (hazard ratio = 8.87; 95% confidence interval = 2.58, 30.4; p = 0.001) were independent predictors of MACE. CONCLUSIONS: In a large cohort of patients with a working diagnosis of MINOCA, one in four suffer a MACE during long-term clinical follow-up. CMR diagnosis of acute myocardial infarction and age were significant predictors of MACE even in the absence of significant coronary artery obstruction.

Prognostic implications of left atrial dilation in aortic regurgitation due to bicuspid aortic valve.

OBJECTIVE: To investigate the prognostic value of left atrial volume index (LAVI) in patients with moderate to severe aortic regurgitation (AR) and bicuspid aortic valve (BAV). METHODS: 554 individuals (45 (IQR 33-57) years, 80% male) with BAV and moderate or severe AR were selected from an international, multicentre registry. The association between LAVI and the combined endpoint of all-cause mortality or aortic valve surgery was investigated with Cox proportional hazard regression analyses. RESULTS: Dilated LAVI was observed in 181 (32.7%) patients. The mean indexed aortic annulus, sinus of Valsalva, sinotubular junction and ascending aorta diameters were 13.0±2.0 mm/m2, 19.4±3.7 mm/m2, 16.5±3.8 mm/m2 and 20.4±4.5 mm/m2, respectively. After a median follow-up of 23 (4-82) months, 272 patients underwent aortic valve surgery (89%) or died (11%). When compared with patients with normal LAVI (<35 mL/m2), those with a dilated LAVI (≥35 mL/m2) had significantly higher rates of aortic valve surgery or mortality (43% and 60% vs 23% and 36%, at 1 and 5 years of follow-up, respectively, p<0.001). Dilated LAVI was independently associated with reduced event-free survival (HR=1.450, 95% CI 1.085 to 1.938, p=0.012) after adjustment for LV ejection fraction, aortic root diameter, LV end-diastolic diameter and LV end-systolic diameter. CONCLUSIONS: In this large, multicentre registry of patients with BAV and moderate to severe AR, left atrial dilation was independently associated with reduced event-free survival. The role of this parameter for the risk stratification of individuals with significant AR merits further investigation.

A Randomized, double-blind, dose ranging clinical trial of intravenous FDY-5301 in acute STEMI patients undergoing primary PCI.

BACKGROUND: Ischemia-reperfusion injury remains a major clinical problem in patients with ST-elevation myocardial infarction (STEMI), leading to myocardial damage despite early reperfusion by primary percutaneous coronary intervention (PPCI). There are no effective therapies to limit ischemia-reperfusion injury, which is caused by multiple pathways activated by rapid tissue reoxygenation and the generation of reactive oxygen species (ROS). FDY-5301 contains sodium iodide, a ubiquitous inorganic halide and elemental reducing agent that can act as a catalytic anti-peroxidant. We tested the feasibility, safety and potential utility of FDY-5301 as a treatment to limit ischemia-reperfusion injury, in patients with first-time STEMI undergoing emergency PPCI. METHODS: STEMI patients (n = 120, median 62 years) presenting within 12 h of chest pain onset were randomized at 20 PPCI centers, in a double blind Phase 2 clinical trial, to receive FDY-5301 (0.5, 1.0 or 2.0 mg/kg) or placebo prior to reperfusion, to evaluate the feasibility endpoints. Participants underwent continuous ECG monitoring for 14 days after PPCI to address pre-specified cardiac arrhythmia safety end points and cardiac magnetic resonance imaging (MRI) at 72 h and at 3 months to assess exploratory efficacy end points. RESULTS: Intravenous FDY-5301 was delivered before re-opening of the infarct-related artery in 97% participants and increased plasma iodide levels ~1000-fold within 2 min. There was no significant increase in the primary safety end point of incidence of cardiac arrhythmias of concern. MRI at 3 months revealed median final infarct sizes in placebo vs. 2.0 mg/kg FDY-5301-treated patients of 14.9% vs. 8.5%, and LV ejection fractions of 53.9% vs. 63.2%, respectively, although the study was not powered to detect statistical significance. In patients receiving FDY-5301, there was a significant reduction in the levels of MPO, MMP2 and NTproBNP after PPCI, but no reduction with placebo. CONCLUSIONS: Intravenous FDY-5301, delivered immediately prior to PPCI in acute STEMI, is feasible, safe, and shows potential efficacy. A larger trial is justified to test the effects of FDY-5301 on acute ischemia-reperfusion injury and clinical outcomes. CLINICAL TRIAL REGISTRATION: CT.govNCT03470441; EudraCT 2017-000047-41.

Non-linear Mendelian randomization analyses support a role for vitamin D deficiency in cardiovascular disease risk.

AIMS: Low vitamin D status is associated with a higher risk for cardiovascular diseases (CVDs). Although most existing linear Mendelian randomization (MR) studies reported a null effect of vitamin D on CVD risk, a non-linear effect cannot be excluded. Our aim was to apply the non-linear MR design to investigate the association of serum 25-hydroxyvitamin D [25(OH)D] concentration with CVD risk. METHODS AND RESULTS: The non-linear MR analysis was conducted in the UK Biobank with 44 519 CVD cases and 251 269 controls. Blood pressure (BP) and cardiac-imaging-derived phenotypes were included as secondary outcomes. Serum 25(OH)D concentration was instrumented using 35 confirmed genome-wide significant variants.We also estimated the potential reduction in CVD incidence attributable to correction of low vitamin D status. There was a L-shaped association between genetically predicted serum 25(OH)D and CVD risk (Pnon-linear = 0.007), where CVD risk initially decreased steeply with increasing concentrations and levelled off at around 50 nmol/L. A similar association was seen for systolic (Pnon-linear = 0.03) and diastolic (Pnon-linear = 0.07) BP. No evidence of association was seen for cardiac-imaging phenotypes (P = 0.05 for all). Correction of serum 25(OH)D level below 50 nmol/L was predicted to result in a 4.4% reduction in CVD incidence (95% confidence interval: 1.8- 7.3%). CONCLUSION: Vitamin D deficiency can increase the risk of CVD. Burden of CVD could be reduced by population-wide correction of low vitamin D status.

The Future of Cardiac Magnetic Resonance Clinical Trials.

Over the past 2 decades, cardiac magnetic resonance (CMR) has become an essential component of cardiovascular clinical care and contributed to imaging-guided diagnosis and management of coronary artery disease, cardiomyopathy, congenital heart disease, cardio-oncology, valvular, and vascular disease, amongst others. The widespread availability, safety, and capability of CMR to provide corresponding anatomical, physiological, and functional data in 1 imaging session can improve the design and conduct of clinical trials through both a reduction of sample size and provision of important mechanistic data that may augment clinical trial findings. Moreover, prospective imaging-guided strategies using CMR can enhance safety, efficacy, and cost-effectiveness of cardiovascular pathways in clinical practice around the world. As the future of large-scale clinical trial design evolves to integrate personalized medicine, cost-effectiveness, and mechanistic insights of novel therapies, the integration of CMR will continue to play a critical role. In this document, the attributes, limitations, and challenges of CMR's integration into the future design and conduct of clinical trials will also be covered, and recommendations for trialists will be explored. Several prominent examples of clinical trials that test the efficacy of CMR-imaging guided pathways will also be discussed.