Association between plaque localization in proximal coronary segments and MACE outcomes in patients with mild CAC: Results from the EISNER study.

Objective: Coronary artery calcium score (CAC) is a validated tool to predict and reclassify cardiovascular risk. Additional metrics such as regional distribution and extent of CAC over Agatston CAC score may allow further risk stratification. In this study, we evaluate the prognostic significance of proximal CAC involvement in asymptomatic population from the prospective EISNER (Early-Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) registry, focusing on patients with mild CAC (score 1-99). Methods: This study included a total of 2,047 adult asymptomatic subject who underwent baseline CAC scan and 14-year follow-up for MACE, defined as myocardial infarction, late revascularization, or cardiac death. Proximal involvement was defined as presence of CAC in the LM, proximal LAD, LCX or RCA. CAC was categorized as 0, 1-99, and ≥100. Results: 1,090 (53.2%) subjects had no CAC, 576 (28.1%) had CAC 1-99, and 381 (18.7%) had CAC ≥100. Proximal involvement was seen in 67.2% of subjects with CAC 1-99 and 97.3% of subjects with CAC ≥100. In the CAC 1-99 category, the presence of proximal CAC was associated with increased MACE risk after adjustment for CAC score, CAC extent and conventional risk factors compared to those without proximal CAC (HR: 2.84 95% CI: 1.29-6.25, p=0.009). Conclusion: In asymptomatic subjects with CAC scores of 1-99, the presence and extent of proximal CAC plaques provides strong independent prognostic information in predicting MACE.

Deep Learning for Explainable Estimation of Mortality Risk From Myocardial Positron Emission Tomography Images.

BACKGROUND: We aim to develop an explainable deep learning (DL) network for the prediction of all-cause mortality directly from positron emission tomography myocardial perfusion imaging flow and perfusion polar map data and evaluate it using prospective testing. METHODS: A total of 4735 consecutive patients referred for stress and rest 82Rb positron emission tomography between 2010 and 2018 were followed up for all-cause mortality for 4.15 (2.24-6.3) years. DL network utilized polar maps of stress and rest perfusion, myocardial blood flow, myocardial flow reserve, and spill-over fraction combined with cardiac volumes, singular indices, and sex. Patients scanned from 2010 to 2016 were used for training and validation. The network was tested in a set of 1135 patients scanned from 2017 to 2018 to simulate prospective clinical implementation. RESULTS: In prospective testing, the area under the receiver operating characteristic curve for all-cause mortality prediction by DL (0.82 [95% CI, 0.77-0.86]) was higher than ischemia (0.60 [95% CI, 0.54-0.66]; P <0.001), myocardial flow reserve (0.70 [95% CI, 0.64-0.76], P <0.001) or a comprehensive logistic regression model (0.75 [95% CI, 0.69-0.80], P <0.05). The highest quartile of patients by DL had an annual all-cause mortality rate of 11.87% and had a 16.8 ([95% CI, 6.12%-46.3%]; P <0.001)-fold increase in the risk of death compared with the lowest quartile patients. DL showed a 21.6% overall reclassification improvement as compared with established measures of ischemia. CONCLUSIONS: The DL model trained directly on polar maps allows improved patient risk stratification in comparison with established methods for positron emission tomography flow or perfusion assessments.

Bempedoic acid and its role in contemporary management of hyperlipidemia in atherosclerosis.

Atherosclerotic heart disease is the leading cause of mortality and morbidity in the USA. Low density lipoprotein (LDL) has been the target for many hypolipidemic agents to modify atherosclerotic risk. Bempedoic acid is a novel hypolipidemic drug that inhibits the enzymatic activity of ATP citrate lyase in the cholesterol synthesis pathway. CLEAR Harmony, CLEAR Wisdom, CLEAR Tranquillity and CLEAR Serenity have shown safety and efficacy associated with long term administration of this drug. Studies have shown effectiveness in reducing LDL-C in both statin intolerant patients and in patients on maximally tolerated doses of statin. The fixed drug combination of bempedoic acid and ezetimibe in a recent phase III showed significant reduction in LDL compared with placebo, which might be a promising future for LDL reduction among statin intolerant patients. Bempedoic acid also reduced inflammatory markers like hs-CRP. Given these results, bempedoic acid alone and in combination with ezetimibe received the USA FDA approval for adults with heterozygous familial hypercholesterolaemia or established atherosclerotic cardiovascular disease. We present a comprehensive review exploring the underlying mechanism, pre-clinical studies, and clinical trials of bempedoic acid and discuss the potential future role of the drug in treating hyperlipidaemia.

Discovery of Tricuspid Fibroelastoma on Echocardiography.

Papillary fibroelastoma (PFE) is a benign cardiac tumor usually incidentally found on cardiac imaging. They are typically located on the left-sided heart valves and are concerning primarily due to their risk for embolization into the periphery. Right-sided PFE, however, is very rare and their management is not well known. We present a 66-year-old male with a past medical history of HIV on antiretroviral therapy presenting with new exertional dyspnea. Upon workup, he was found to have a mass on the tricuspid valve seen on echocardiography which was ultimately resected and found to be a tricuspid fibroelastoma. The clinical management of right-sided PFE is poorly documented. Treatment of PFE in an asymptomatic is dependent on characteristics such as location, mobility, and risk of embolization. Echocardiography has made the incidental diagnosis of PFE a common issue in asymptomatic patients such as ours.

Endomyocardial Fibrosis Found Incidentally on Cardiac Imaging.

Endomyocardial fibrosis (EMF) is a rare disease in the developed world characterized by the fibrosis of the endocardium in one or both of the ventricles causing restrictive-type cardiomyopathy. We present a case of a 47-year-old Chinese female with a past medical history of breast cancer treated in 2014 currently on tamoxifen therapy presented to the cardiology office for multiple presyncopal and syncopal events at rest. She was found to have apical hypertrophic cardiomyopathy (HCM) on echocardiogram. Subsequently, cardiac magnetic resonance imaging (cMRI) showed severe apical hypertrophy without left ventricular aneurysm, and evidence of small apical thrombus with subendocardial enhancement. There was no resolution of the left ventricular thrombus after a year-long course of therapeutic anticoagulation, a finding more consistent with EMF. Though the diagnosis of EMF initially depends on echocardiographic findings, cMRI is an essential imaging modality that allows clinicians to easily differentiate between potential diagnoses with the information that it provides. Early diagnosis, differentiation, and treatment for HCM are important for a good prognosis.

An update on pharmacotherapies in diabetic dyslipidemia.

Hyperlipidemia plays a crucial role in the underlying pathogenesis of multiple cardiovascular diseases (CVD), including coronary artery disease, peripheral arterial disease, carotid stenosis, and heart failure. The risk of developing such diseases in the diabetic population is relatively high. Diabetes mellitus (DM) is an independent risk factor for premature atherosclerosis. The hallmark of DM dyslipidemia is a demonstrably high level of atherogenic triglyceride rich lipids including very low-density lipoprotein, chylomicrons, and small dense low-density lipoprotein (LDL). Moderate to high intensity statins, targeting LDL cholesterol reduction, remain the cornerstone in the management of this unique disorder. Many 'non-statin' drugs have recently been studied in the DM patients who were either on a 'maximally tolerated statin' or 'statin intolerant'. Ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are particularly important and were incorporated in the recent guidelines by the European Society of Cardiology, American College of Cardiology, American Heart Association, and American Diabetes Association. Icosapent Ethyl has garnered huge interest this year following publication of the REDUCE-IT trial. There are several newer hypolipidemic drugs, including Bempedoic acid, Inclisiran and RVX-208, that are in different phases of clinical trials. In this article, we review the underlying pathophysiology of DM dyslipidemia, existing guidelines related to its management, and the potential of newer hypolipidemic and anti-inflammatory drugs being incorporated in the management of DM.

Fish Oil and Cardiometabolic Diseases: Recent Updates and Controversies.

Fatty acids derived from fish oil are long-chain omega-3 (n-3) polyunsaturated fatty acids. The important polyunsaturated fatty acids of fish oil are eicosapentaenoic acid, and docosahexaenoic acid. For decades, there has been a debate about the use of omega-3 fatty acids and their benefits on cardiovascular health. The more recent trials including the JELIS, VITAL, STRENGTH, and ASCEND trials, addressed the paucity of data of omega-3 fatty acids on primary and secondary prevention of cardiovascular events and the risk-benefit balance of these supplements. Prior to these studies, many large randomized controlled trials have shown conflicting results on the effect of polyunsaturated fatty acids in patients with prior coronary artery disease, stroke, or major vascular events. These inconsistent results warrant a better understanding of the effects of omega-3 fatty acids on the subtypes of cardiovascular diseases, and their use in primary and secondary prevention. More recently, icosapent ethyl showed a significant reduction in cardiovascular mortality and ischemic events in patients with elevated triglyceride (TG) and established cardiovascular disease or diabetes. The REDUCE-IT trial paved the way to further reduce cardiovascular risk in patients with high TG despite being on a maximally tolerated statin. The aim of this review is to discuss these recent updates on the use of various forms of fish oil, including prescription form and supplement in cardiometabolic diseases, and their surrounding controversies.

Durability Data for Bioprosthetic Surgical Aortic Valve: A Systematic Review.

Importance: Although several studies have reported data on surgical aortic valve durability, variability in study methodologies and definitions as well as inadequate follow-up make the interpretation of data from these studies difficult to interpret. Objective: To review available data on structural valve deterioration (SVD) of surgical bioprosthetic aortic valves by examining the published literature as well as data reported to the US Food and Drug Administration (FDA). Evidence Review: A systematic review using Preferred Reporting Items for Systematic Review and Meta-Analysis reporting guidelines to obtain all available data from preexisting literature on the actuarial freedom from SVD and outcomes of SVD. Data were collected from database inception to November 2016. Additionally, data reported to the FDA were obtained. Findings: In total, 167 studies and 12 FDA reports including 101 650 patients and 17 different valve types were analyzed. There were 11 different definitions of SVD used in the studies. Core laboratory data were available for 11 studies. Mean follow-up ranged from less than 1 year to 14 years. Kaplan-Meier estimates were reported for up to 30 years of follow-up, with 0% to 37% of patients remaining at risk at maximum follow-up. Food and Drug Administration-reported data are similarly variable in duration (mean follow-up range, 1.2 to 7 years) and completeness of follow-up, with final follow-up of 0.1% to 95%. Conclusions and Relevance: There is considerable variability in reporting SVD of surgical aortic valves, with different definitions and inadequate long-term systematically collected core laboratory data. Rigorously collected long-term data with standardized definitions for surgical valves are needed to provide a benchmark for the durability of rapidly evolving transcatheter valves.

Peripheral vascular interventional advances in 2017.

Aim of this review is to inform major clinical trials in peripheral vascular interventions in the year of 2017.

Utility of ankle-brachial index in screening for peripheral arterial disease in rural India: A cross-sectional study and review of literature.

BACKGROUND: Peripheral arterial disease (PAD) is an underdiagnosed illness often affecting the elderly population. Ankle brachial index (ABI) is a good diagnostic tool for PAD in outpatient practice, but remains underused. MATERIALS AND METHODS: Patients were recruited from an outpatient medical camp in rural India, and assessed for symptoms and pre-existing risk factors. Measured ABI≤0.9 was considered abnormal and considered PAD. RESULTS: Out of 100 patients recruited, PAD was diagnosed in 57 patients. Associated risk factors were like age >55years (67%), hypertension (66%), smoking (69%) and diabetes mellitus (35%) were common. CONCLUSION: PAD is a very common and underdiagnosed illness in rural India. A simple tool like ABI can help diagnosis in underserved areas.

Clinical and procedural outcomes with the SAPIEN 3 versus the SAPIEN XT prosthetic valves in transcatheter aortic valve replacement: A systematic review and meta-analysis.

OBJECTIVES: The SAPIEN 3 valve (S3V) was designed to overcome the shortcomings of its predecessor, the SAPIEN XT (SXT) valve. We conducted a meta-analysis to compare their clinical outcomes and procedural characteristics. METHODS: PUBMED, EMBASE, and Cochrane CENTRAL were searched by two independent reviewers. The clinical outcomes of interest were paravalvular leakage (PVL), major vascular complications (MVC), bleeding, acute kidney injury (AKI), device success, need for post dilation all-cause mortality and procedural details. RESULTS: Fifteen observational cohort studies were included in the analysis involving a total of 4,496 patients. Of these, 1,700 were S3V recipients and 2,796 were SXT recipients. The S3V group showed fewer complications compared to the SXT group with respect to PVL (5.58% vs. 19.35%, OR: 0.27, P: 0.000), MVC (4.07% vs. 9.13%, OR: 0.44, P: 0.002), bleeding (6.40% vs. 12.03%, OR: 0.50, P: 0.003), 30-day mortality (3.29% vs. 5.68%, OR: 0.51, P: 0.000), and stroke (1.48% vs. 2.86%, OR: 0.49, P: 0.014). Device success was higher in the S3V (98.18% vs. 93.76%, OR: 3.14, P: 0.000). Cardiovascular mortality, myocardial infarction, AKI and post-dilatation were not significantly different. Permanent pacemaker implantation (PPI) was higher in S3V recipients (13.29% vs. 9.23%, OR: 1.58, P: 0.000). Procedure time was shorter for the S3V (71.94 vs. 86.85, P: 0.016) and used less contrast volume (129.36 vs. 161.18, P: 0.049). CONCLUSIONS: Patients receiving the S3V had lower risk of PVL, MVC, bleeding, mortality, and stroke. PPI was somewhat higher in the S3V group. S3V implantation was faster and used less contrast.

Diagnosis and management challenges of in-stent restenosis in coronary arteries.

Over the course of the 3 decades, percutaneous coronary intervention (PCI) with stent implantation transformed the practice of cardiology. PCI with stenting is currently the most widely performed procedure for the treatment of symptomatic coronary disease. In large trials, drug-eluting stents (DES) have led to a significant reduction in in-stent restenosis (ISR) rates, one of the major limitations of bare-metal stents. Due to these favorable findings, DES was rapidly and widely adopted enabling more complex coronary interventions. Nevertheless, ISR remains a serious concern as late stent complications. ISR mainly results from aggressive neointimal proliferation and neoatherosclerosis. DES-ISR treatment continues to be challenging complications for interventional cardiologists.

Serelaxin in acute heart failure: Most recent update on clinical and preclinical evidence.

Heart failure continues to be a widely prevalent disease across the world, affecting millions of Americans annually. Acute heart failure (AHF) has a substantial effect on rising healthcare costs and is one of the major causes of morbidity and mortality. The search for new drugs for symptom relief and to improve long-term outcomes in heart failure has led to development of serelaxin, a recombinant human relaxin-2 hormone. Relaxin was discovered in pregnancy, but eventually found to have a number of other physiological actions, not only in pregnancy, but also in nonpregnant women and men. The actions of serelaxin are primarily via nitric oxide, leading to the observed vasodilatory effects, and increase in renal plasma flow. It has also been found to increase expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-2 and MMP-9. The antifibrotic and antiinflammatory effects of the drug also play a role in heart failure. In Phase II studies, serelaxin has shown reduction in pulmonary arterial pressure, pulmonary capillary wedge pressure, and NT-proBNP. The recently published results of the RELAX-AHF, a phase III clinical trial on serelaxin, has opened new avenues into our understanding of its effects in heart failure. The trial showed improvement in short-term dyspnea scores and 180-day mortality, but, interestingly, failed to show any improvement of the secondary endpoints of death or readmission at 60 days. Ongoing Phase III trials like RELAX-AHF-2 and RELAX-AHF-ASIA would explain these data better and improve understanding of the use of serelaxin in clinical practice. This article summarizes the most updated published preclinical and clinical study data on serelaxin, including pharmacokinetic, pharmacodynamic, safety studies in hepatic, renal impaired patients, Phase II and Phase III trials.

Failure Mechanisms and Neoatherosclerosis Patterns in Very Late Drug-Eluting and Bare-Metal Stent Thrombosis.

BACKGROUND: There are few clinical studies on the pathophysiological mechanisms of very late stent thrombosis (VLST). We report optical coherence tomography findings in patients with VLST and compare the findings between bare-metal stents (BMS) and drug-eluting stents (DES). METHODS AND RESULTS: We conducted a registry of stent thrombosis at 4 North American centers with optical coherence tomography imaging programs SAFE registry (The Study of Late Stent Failure Evaluated by OCT). Images were acquired in 61 patients (42 DES and 19 BMS) presenting with definite VLST. The median duration from implantation to VLST presentation was 51.4 months in the DES and 69.9 months in the BMS group (P=0.011). Uncovered and malapposed struts were observed in 70.5% (43/61) and 62.3% (38/61) of patients, respectively, whereas neoatherosclerosis was revealed in 49.2% (30/61). Stent underexpansion was observed in 42.4% of patients. Malapposed struts and stent underexpansion were more frequently demonstrated in DES than in BMS patients, whereas neoatherosclerosis was frequently observed in BMS (40.5% in DES and 68.4% in BMS; P=0.056). The percentage of frames with neoatherosclerosis was lower in DES than in BMS (15.56% [12.24-28.57] versus, 56.41% [40.74-70.00], respectively; P<0.001). Maximum consecutive lipid neointima length was shorter in DES than in BMS (2.4 [1.2-3.6] and 5.3 [3.0-7.0] mm; P=0.011). CONCLUSIONS: Optical coherence tomography imaging demonstrated that VLST in DES and BMS had a wide variety of abnormal findings, such as neoatherosclerosis, uncovered strut, and malapposed strut. Neoatherosclerosis and lipid neointima were more frequently observed and had more longitudinal extension in BMS compared with DES.

Combined Neprilysin and RAS Inhibition in Cardiovascular Diseases: A Review of Clinical Studies.

The aim of this comprehensive review article is to emphasize on the possible exploration of a new therapeutic approach in the management of heart failure (HF) and other cardiovascular diseases: the renin-angiotensin-aldosterone system-neprilysin combination inhibitors, also called angiotensin receptor neprilysin inhibitor, valsartan/sacubitril (LCZ696). Sacubitril is an inhibitor of neutral endopeptidase (NEP) which degrades vasoactive peptides such as atrial natriuretic peptide and brain natriuretic peptide. Valsartan is an angiotensin receptor blocker which is usually used in hypertension. Although HF has been a global health burden, for decades there has been lack of novel therapeutic options as many trials failed due to potential side effects. With the published results of the landmark trial Prospective comparison of ARNI with ACEI to Determine the Impact on Global Mortality and morbidity in HF (PARADIGM-HF), a new direction in the treatment of HF is anticipated. This trial showed that LCZ696 was able to reduce the primary composite end point of cardiovascular death or HF hospitalization, and similar reduction was observed for cardiovascular death. This review article also highlights the results of 4 published trials of LCZ696 in both HTN and HF. After the results of PARADIGM-HF trial, the major challenge will be outcome in regular clinical practice, as subjects in the trial were mostly stable New York Heart Association class II patients with no comorbidities. In addition, many trials are simultaneously in progress regarding the use of LCZ696 in patients with diabetes, renal failure, and hepatic impairment. To conclude, sacubitril/valsartan significantly improved morbidity and mortality in patients with chronic HF, but it will need meticulous attention when used in real outpatient practice.

Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data.

The Vitamin K antagonist warfarin was the only oral anticoagulant available for decades for the treatment of thrombosis and prevention of thromboembolism until Direct Oral Anticoagulants (DOACs); a group of new oral anticoagulants got approved in the last few years. Direct thrombin inhibitor: dabigatran and factor Xa inhibitors: apixaban, rivaroxaban, and edoxaban directly inhibit the coagulation cascade. DOACs have many advantages over warfarin. However, the biggest drawback of DOACs has been the lack of specific antidotes to reverse the anticoagulant effect in emergency situations. Activated charcoal, hemodialysis, and activated Prothrombin Complex Concentrate (PCC) were amongst the nonspecific agents used in a DOAC associated bleeding but with limited success. Idarucizumab, the first novel antidote against direct thrombin inhibitor dabigatran was approved by US FDA in October 2015. It comprehensively reversed dabigatran-induced anticoagulation in a phase I study. A phase III trial on Idarucizumab also complete reversal of anticoagulant effect of dabigatran. Andexanet alfa (PRT064445), a specific reversal agent against factor Xa inhibitors, showed a complete reversal of anticoagulant activity of apixaban and rivaroxaban within minutes after administration without adverse effects in two recently completed parallel phase III trials ANNEXA-A and ANNEXA-R respectively. It is currently being studied in ANNEXA-4, a phase IV study. Aripazine (PER-977), the third reversal agent, has shown promising activity against dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH. This review article summarizes pharmacological characteristics of these novel antidotes, coagulation's tests affected, available clinical and preclinical data, and the need for phase III and IV studies.