A pilot open-label study of aldose reductase inhibition with AT-001 (caficrestat) in patients hospitalized for COVID-19 infection: Results from a registry-based matched-control analysis.

BACKGROUND AND AIMS: Cardiometabolic disease may confer increased risk of adverse outcomes in COVID-19 patients by activation of the aldose reductase pathway. We hypothesized that aldose reductase inhibition with AT-001 might reduce viral inflammation and risk of adverse outcomes in diabetic patients with COVID-19. METHODS: We conducted an open-label prospective phase 2 clinical trial to assess safety, tolerability and efficacy of AT-001 in patients hospitalized with COVID-19 infection, history of diabetes mellitus and chronic heart disease. Eligible participants were prospectively enrolled and treated with AT-001 1500 mg BID for up to 14 days. Safety, tolerability, survival and length of hospital stay (LOS) were collected from the electronic medical record and compared with data from two matched control groups (MC1 and MC2) selected from a deidentified registry of COVID-19 patients at the same institution. RESULTS: AT-001 was safe and well tolerated in the 10 participants who received the study drug. In-hospital mortality observed in the AT-001 group was 20% vs. 31% in MC1 and 27% in MC2. Mean LOS observed in the AT-001 group was 5 days vs. 10 days in MC1 and 25 days in MC2. CONCLUSIONS: In hospitalized patients with COVID-19 and co-morbid diabetes mellitus and heart disease, treatment with AT-001 was safe and well tolerated. Exposure to AT-001 was associated with a trend of reduced mortality and shortened LOS. While the observed trend did not reach statistical significance, the present study provides the rationale for investigating potential benefit of AT-001 in COVID 19 affected patients in future studies.

Right Ventricular Ejection Fraction for the Prediction of Major Adverse Cardiovascular and Heart Failure-Related Events: A Cardiac MRI Based Study of 7131 Patients With Known or Suspected Cardiovascular Disease.

BACKGROUND: There is increasing evidence that right ventricular ejection fraction (RVEF) may provide incremental value to left ventricular (LV) ejection fraction for the prediction of major adverse cardiovascular events. To date, generalizable utility for RVEF quantification in patients with cardiovascular disease has not been established. Using a large prospective clinical outcomes registry, we investigated the prognostic value of RVEF for the prediction of major adverse cardiovascular events- and heart failure-related outcomes. METHODS: Seven thousand one hundred thirty-one consecutive patients with known or suspected cardiovascular disease undergoing cardiovascular magnetic resonance imaging were prospectively enrolled. Multichamber volumetric quantification was performed by standardized operational procedures. Patients were followed for the primary composite outcome of all-cause death, survived cardiac arrest, admission for heart failure, need for transplantation or LV assist device, acute coronary syndrome, need for revascularization, stroke, or transient ischemic attack. A secondary, heart failure focused outcome of heart failure admission, need for transplantation/LV assist device or death was also studied. RESULTS: Mean age was 54±15 years. The mean LV ejection fraction was 55±14% (range 6%-90%) with a mean RVEF of 54±10% (range 9%-87%). At a median follow-up of 908 days, 870 (12%) patients experienced the primary composite outcome and 524 (7%) the secondary outcome. Each 10% drop in RVEF was associated with a 1.3-fold increased risk of the primary outcome (P<0.001) and 1.5-fold increased risk of the secondary outcome (P<0.001). RVEF was an independent predictor following comprehensive covariate adjustment, inclusive of LV ejection fraction. Patients with an RVEF<40% experienced a 3.1-fold risk of the primary outcome (P<0.001) with a 1-year cumulative event rate of 22% versus 7% above this cutoff. CONCLUSIONS: RVEF is a powerful and independent predictor of major adverse cardiac events with broad generalizability across patients with known or suspected cardiovascular disease. These findings support migration towards biventricular phenotyping for the classification of risk in clinical practice. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04367220.

COVID-19 and the Heart and Vasculature: Novel Approaches to Reduce Virus-Induced Inflammation in Patients With Cardiovascular Disease.

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented challenge and opportunity for translational investigators to rapidly develop safe and effective therapeutic interventions. Greater risk of severe disease in COVID-19 patients with comorbid diabetes mellitus, obesity, and heart disease may be attributable to synergistic activation of vascular inflammation pathways associated with both COVID-19 and cardiometabolic disease. This mechanistic link provides a scientific framework for translational studies of drugs developed for treatment of cardiometabolic disease as novel therapeutic interventions to mitigate inflammation and improve outcomes in patients with COVID-19.

Prognostic Value of Late Gadolinium Enhancement for the Prediction of Cardiovascular Outcomes in Dilated Cardiomyopathy: An International, Multi-Institutional Study of the MINICOR Group.

BACKGROUND: Dilated cardiomyopathy is associated with increased risk of major cardiovascular events. Late gadolinium enhancement (LGE) cardiac magnetic resonance imaging is a unique tissue-based marker that, in single-center studies, suggests strong prognostic value. We retrospectively studied associations between LGE presence and adverse cardiovascular events in patients with dilated cardiomyopathy in a multicenter setting as part of an emerging global consortium (MINICOR [Multi-Modal International Cardiovascular Outcomes Registry]). METHODS: Consecutive patients with dilated cardiomyopathy referred for cardiac magnetic resonance (2000-2017) at 12 institutions in 4 countries were studied. Using multivariable Cox proportional hazard and semiparametric Fine and Gray models, we evaluated the association between LGE and the composite primary end point of all-cause mortality, heart transplantation, or left ventricular assist device implant and a secondary arrhythmic end point of sudden cardiac death or appropriate implantable cardioverter-defibrillator shock. RESULTS: We studied 1672 patients, mean age 56±14 years (29% female), left ventricular ejection fraction 33±11%, and 25% having New York Heart Association class III to IV; 650 patients (39%) had LGE. During 2.3 years (interquartile range, 1.0-4.3) follow-up, 160 patients experienced the primary end point, and 88 experienced the arrhythmic end point. In multivariable analyses, LGE was associated with 1.5-fold (hazard ratio, 1.45 [95% CI, 1.03-2.04]) risk of the primary end point and 1.8-fold (hazard ratio, 1.82 [95% CI, 1.20-3.06]) risk of the arrhythmic end point. Primary end point risk was increased in patients with multiple LGE patterns, although arrhythmic risk was higher among patients receiving primary prevention implantable cardioverter-defibrillator and widening QRS. CONCLUSIONS: In this large multinational study of patients with dilated cardiomyopathy, the presence of LGE showed strong prognostic value for identification of high-risk patients. Randomized controlled trials evaluating LGE-based care management strategies are warranted.

Food as Medicine for Secondary Prevention of Cardiovascular Events Following an Acute Coronary Syndrome.

Cardiovascular disease is the leading cause of death in men and women in the USA. Once a patient experiences an acute coronary syndrome (ACS), they are at increased risk for hospital readmission within 30 days and 6 months after discharge and more importantly, they have worse survival. Hospital readmissions lead to poor clinical outcomes for the patient and also significantly increase healthcare costs due to repeat diagnostic evaluation, imaging, and coronary interventions. The goal after hospital discharge is to modify cardiovascular (CV) risk factors including hypertension, hyperlipidemia, and diabetes to prevent repeat coronary events; however, drug therapy is only one aspect. Several diets have been shown to decrease weight and reduce these risk factors over short durations; however, most people typically cannot sustain their diet and regain the weight. The Intelligent Quisine (IQ) diet is a prepared meal plan that was designed to meet the American Heart Association and American Diabetes Association nutritional guidelines and simplify the daily consumption of a nutritionally complete, calorie conscious meal. The IQ diet has been shown to significantly reduce blood pressure, cholesterol levels, glucose levels, and weight over a 10-week period. Additional studies have shown that patients are able to remain compliant on the diet for a year and maintain the reduction of their CV risk factors. If patients are consistent with a healthy calorie conscious and nutritionally complete diet modifying CV risk factors long term, then food could be as powerful in reducing CV events as evidence-based drug therapy. There is a need to begin conceptualizing food as medicine. To this end, it is time for a randomized control trial implementing the IQ diet versus current standard dietary recommendations in a large number of patients and measuring hard CV endpoints. Many readmissions can be avoided with proper patient education and support emphasizing lifestyle modifications such as eating healthy and smoking cessation on a foundation of optimal medical therapy.

Is intra-procedure three-dimensional transesophageal echocardiogram an alternative to preprocedure multidetector computed tomography for the measurement of the aortic annulus in patients undergoing transcatheter aortic valve replacement?

BACKGROUND: The role of three-dimensional transesophageal echocardiography (3DTEE) vs multidetector computed tomography (MDCT) in aortic annular sizing has been poorly defined in patients undergoing transcatheter aortic valve replacements (TAVR). We set to determine the correlation between 3DTEE and MDCT in measuring the aortic annulus prior to TAVR. METHODS: In an observational, retrospective study, we compared aortic annular areas measured by MDCT and 3DTEE in TAVR patients. The aortic annular area was measured by planimetry of images obtained by MDCT pre-TAVR and by intra-TAVR TEE using 3D rendering of the aortic annulus followed by planimetry. Our primary outcome was degree of correlation between mean aortic annulus area by 3DTEE and MDCT. RESULTS: Of the 111 consecutive patients undergoing TAVR who had measurements from both modalities available for comparison between February 2012 and April 2015, 87 met inclusion criteria. The mean aortic annular area by MDCT was 4.44±0.88 cm2 and by 3DTEE was 4.33±0.78 cm2 . There was a strong positive linear correlation between aortic annular area measurements obtained from these two modalities with mild relative underestimation by 3DTEE (ρ=.833). This relationship can be estimated using the predictive formula: [Formula: see text] CONCLUSIONS: Three-dimensional transesophageal echocardiography measurements have a high degree of correlation with MDCT measurements and thus can assist in proper valve prosthesis selection for TAVR. Our study thus supports use of 3DTEE as a reasonable alternative imaging modality in patients undergoing TAVR.

Design of the Magnetic Resonance Imaging Evaluation of Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis (MAGMA) Trial.

Mineralocorticoid receptor (MR) activation plays an essential role in promoting inflammation, fibrosis, and target organ damage. Currently, no studies are investigating MR antagonism in patients with type 2 diabetes mellitus (T2DM) with chronic kidney disease, at high risk for cardiovascular complications, who are otherwise not candidates for MR antagonism by virtue of heart failure. Further, there is limited information on candidate therapies that may demonstrate differential benefit from this therapy. We hypothesized that MR antagonism may provide additional protection from atherosclerosis progression in higher-risk patients who otherwise may not be candidates for such a therapeutic approach. In this double-blind, randomized, placebo-controlled trial, subjects with T2DM with chronic kidney disease (≥ stage 3) will be randomized in a 1:1 manner to placebo or spironolactone (12.5 mg with eventual escalation to 25 mg daily over a 4-week period). The co-primary efficacy endpoint will be percentage change in total atheroma volume in thoracic aorta and left ventricular mass at 52 weeks in patients treated with spironolactone vs placebo. Secondary outcomes include 24-hour mean systolic blood pressure, central aortic blood pressure, and insulin resistance (HOMA-IR) at 6 weeks. A novel measure in the study will be changes in candidate miRNAs that regulate expression of NR3C2 (MR gene) as well as measuring monocyte/macrophage polarization in response to therapy with spironolactone. We envision that our strategy of simultaneously probing the effects of a drug combined with analysis of mechanisms of action and predictive response will likely provide key information with which to design event-based trials.

Prognostic Value of Late Gadolinium Enhancement in Nonischemic Cardiomyopathy.

The purpose of this study was to determine the prognostic value of late gadolinium enhancement seen on cardiac magnetic resonance (CMR) imaging in patients with nonischemic cardiomyopathy (NICMP). Patients with NICMP are at increased risk for cardiovascular events and death. The presence of late gadolinium enhancement (LGE) in CMR may be associated with a poor prognosis, but its significance is still under investigation. We retrospectively studied 105 consecutive patients with NICMP and left ventricular ejection fraction (LVEF) ≤40% referred for CMR. The cohort was analyzed for the presence of LGE and left and right ventricular functional parameters. Patients were followed for the composite end point of hospitalization for congestive heart failure, appropriate implantable cardioverter-defibrillator therapy, or all-cause mortality. LGE was observed in 68% (n = 71) of the cohort. Both groups were similar in age, LVEF and LV end-diastolic volume. The LGE+ patients were more often men and had larger right ventricular volumes. At a mean follow-up of 806 ± 582 days, there were 26 patients (23 in the LGE+ group) who reached the primary end point. Event-free survival was significantly worse for the LGE+ patients. After adjusting for traditional risk factors (age, gender, and LVEF), patients with LGE had an increased risk of experiencing the primary end point (hazard ratio 4.47, 95% CIs 1.27 to 15.74, p = 0.02). The presence of LGE in patients with NICMP strongly predicts the occurrence of adverse events. In conclusion, this may be important in risk stratification and management.

A phase 2 randomized, double-blind, placebo-controlled study of the effect of VIA-2291, a 5-lipoxygenase inhibitor, on vascular inflammation in patients after an acute coronary syndrome.

OBJECTIVE: Arachidonate 5-lipoxygenase (5-LO) is a key enzyme in the synthesis of leukotrienes. VIA-2291 is a potent 5-LO inhibitor, which has been shown to reduce hsCRP and noncalcified coronary plaque volume following an acute coronary syndrome (ACS). We aim to evaluate the effect of VIA-2291 on vascular inflammation compared to placebo using FDG-PET. METHODS: A Phase II, randomized, double-blind, parallel-group study was conducted in 52 patients with recent ACS assigned 1:1 to either 100 mg VIA-2291 or placebo for 24 weeks. The primary outcome was the effect of VIA-2291 relative to placebo on arterial inflammation detected by (18)fluorodeoxyglucose positron emission tomography (FDG-PET) within the index vessel after 24 weeks of daily treatment, compared to baseline. RESULTS: VIA-2291 was relatively well tolerated and was associated with a significant inhibition of the potent chemo-attractant LTB4, with a mean inhibition of activity of 92.8% (p<0.0001) at 6 weeks in the VIA-2291 group, without further significant change in inhibition at 24 weeks. However, for VIA-2291 was not associated with significant difference in inflammation (target-to-background ratio) compared to placebo at 24 weeks or 6 weeks of treatment. Further, VIA-2291 was not associated with a significant reduction in hsCRP from baseline after either 6 or 24 weeks of treatment. CONCLUSIONS: VIA-2291 is well-tolerated and effectively reduces leukotriene production. However, inhibition of 5-LO with VIA-2291 is not associated with significant reductions in vascular inflammation (by FDG-PET) or in blood inflammatory markers. Accordingly, this study does not provide evidence to support a significant anti-inflammatory effect of VIA-2291 in patients with recent ACS.

Automated analysis of coronary artery disease by computed tomography.

Computer-assisted detection systems are widely used in many areas of radiology. Coronary computed tomography angiography is a growing area of clinical cardiology and computer-assisted detection systems play an integral part in analysis. Truly automated systems are still in clinical-trial stages, but manually assisted programs are in clinical use today for calcium scoring as well as plaque burden, composition, and stenosis analysis. They are being used as a tool for confirmation more than for diagnosis. Accurate plaque-composition analysis would be a critical tool for better understanding the mechanisms and effectiveness of novel therapies for coronary atherosclerosis. A need for a complete quick, safe, noninvasive plaque analysis is the goal of automated coronary stenosis detection systems; however, their potential clinical benefit remains unknown.

Usefulness of cardiac computed tomographic delayed contrast enhancement of the left atrial appendage before pulmonary vein ablation.

Left atrial appendage (LAA) contrast filling defects are commonly found in patients undergoing multidetector cardiac computed tomography (CCT) before catheter ablation of atrial fibrillation. Delayed CCT allows quantification of the LAA delayed/initial attenuation ratio and improves accuracy for LAA thrombus detection, which may obviate routine transesophageal echocardiography (TEE) before ablation. CCT with contrast-enhanced scans (initial CCT) and with noncontrast-enhanced scans (delayed CCT) was performed in 176 patients. LAA was evaluated for filling defects. LAA apex, left atrial (LA) body, and ascending aorta (AA) attenuations (Hounsfield units) were measured on initial and delayed cardiac computed tomograms to calculate LAA, LA, LAA/LA, and LAA/AA attenuation ratios. LAA, initial LAA/LA, and initial LAA/AA attenuation ratios differed significantly in patients with versus without filling defects on cardiac computed tomogram, those with atrial fibrillation versus normal sinus rhythm, and those with abnormal left ventricular ejection fraction versus larger LA volumes (p <0.05). In 70 patients (40%) who underwent TEE, 13 LAA filling defects were seen on initial cardiac computed tomogram. Two defects persisted on delayed cardiac computed tomogram and thrombus was confirmed on transesophageal echocardiogram. Sensitivity, specificity, and positive and negative predictive values of initial CCT for LAA thrombi detection were 100%, 84%, 15%, and 100%, respectively. With delayed CCT these values increased to 100%. Intraobserver and interobserver reproducibilities for cardiac computed tomographic measurements were good (intraclass correlation 0.72 to 0.97, kappa coefficients 0.93 to 1.00). In conclusion, delayed CCT provided an increase in diagnostic accuracy of CCT for detection of LAA thrombus in patients with atrial fibrillation before ablation, which may decrease the need for routine TEE before the procedure.

Evaluation of cardiac valves using multidetector CT.

Cardiac CT is an accurate and reasonable alternative modality for valvular imaging. It is used primarily for the evaluation of coronary artery disease; however, important information regarding valvular anatomy and function can be derived from CT. Calcification is a common CT finding in various valvular abnormalities and carries important diagnostic and prognostic value. In addition, valvular morphology, stenosis, and regurgitation also are detected on contrast enhanced scans, with good correlation with trans-thoracic echocardiography and other techniques.

New noninvasive imaging technologies in coronary artery disease.

Coronary artery disease affects a large population. Recent emphasis on primary and secondary prevention has made an impact on the detection of atherosclerosis, yet the incidence of acute coronary syndromes continues to increase. This has steered the cardiology community toward improving and developing new imaging techniques that are capable of detecting disease at a very early preclinical state. Coronary CT angiography is capable of characterizing plaques and detecting eccentric lesions that would not appear on stress testing or cardiac catheterization. Cardiac MRI provides high-resolution imaging of plaques in addition to tissue characterization without the ionizing radiation associated with other imaging techniques. Positron emission tomography is a rapidly growing imaging tool that detects inflammation associated with coronary atherosclerosis. In the near future, these new noninvasive modalities will play an intricate part in primary prevention and in diagnosis and treatment follow-up.

Antithrombotic effects of factor Xa inhibition with DU-176b: Phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber.

Direct and specific inhibition of factor Xa is an emerging therapeutic strategy for atherothrombotic disease. Parenteral factor Xa inhibitors promise efficacy comparable to standard therapies, which could be extended to ambulatory patients with oral agents. We evaluated the antithrombotic effect of the oral, direct factor Xa inhibitor DU-176b in a phase-I study. Healthy subjects (n = 12) received a single, 60 mg dose of DU-176b. Antithrombotic effects were assessed by comparing ex-vivo thrombus formation at 1.5, 5, and 12 hours post-dose versus baseline, along with factor Xa activity, thrombin generation and clotting parameters. Under venous flow after 1.5 and 5 hours, the thrombus was 28% and 21% smaller versus baseline, respectively (p < 0.05). Under arterial condition, the reduction was 26% and 17% (p < 0.05). Thrombin generation decreased by 28% at 1.5 hours and 10% at 5 hours. Changes in PT and INR correlated well with plasma drug concentrations (R2 = 0.79 and 0.78). Direct and specific inhibition of factor Xa by DU-176b significantly reduced ex-vivo thrombus formation at both venous and arterial rheologies, up to 5 hours post-dose. The effects mirrored changes in clotting parameters, suggesting their potential usefulness for monitoring in a clinical setting.

Clinical and experimental experience with factor Xa inhibitors.

Cardiovascular disease is the major cause of mortality in the industrial world today. We are constantly moving towards new and better ways of fighting this epidemic. Advances have been made in various fields such as patient education, imaging techniques, interventional cardiology, and novel therapeutic agents. In particular, antithrombotics are being studied with great interest and hope. Amid this class of agents, factor Xa inhibitors have already begun to show promising results in trials involving patients with acute coronary syndromes. Whereas DX-9065a is in late stage clinical trials, fondaparinux sodium is available for clinical use. Promising results have been obtained with fondaparinux sodium in patients with coronary artery disease in the PENTUA (Pentasaccharide in Unstable Angina) and PENTALYSE (Pentasaccharide as an Adjunct to Fibrinolysis in ST-Elevation Acute Myocardial Infarction) trials. Besides having a direct effect on the coagulation cascade, they have shown properties that indirectly influence the remodeling of plaques in the coronary circulation. Available evidence on factor Xa inhibitors does not ensure a remedy to acute coronary syndromes but it gives hope of improving current treatments and reducing the morbidity and mortality of cardiovascular disease. The efficacy and tolerability of fondaparinux sodium in the prevention and treatment of deep vein thrombosis (with or without pulmonary embolism) has been established in several large trials such as PENTATHLON (Pentasaccharide in Total Hip Replacement Surgery), PENTAMAKS (Pentasaccharide in Major Knee Surgery), EPHESUS (European Pentasaccharide Hip Elective Surgery), PENTHIFRA (Pentasaccharide in Hip-Fracture Surgery), and PENTHIFRA-Plus. Whereas fondaparinux sodium offers benefits over low molecular weight heparins and unfractionated heparin, the incidence of bleeding complications was greater with fondaparinux sodium than with unfractionated heparin. Treatment with factor VIIa can reverse the anticoagulant effect of fondaparinux sodium and this may be particularly important in patients who need to undergo emergency surgical procedures. Fondaparinux sodium has been recently approved for use, in conjunction with warfarin, in patients with symptomatic deep vein thrombosis or acute pulmonary embolism based on the results of two large trials conducted by the Matisse investigators. In conclusion, these observations strongly suggest the clinical potential of this class of agents in preventing arterial and venous thrombosis.