Journal: Prog Cardiovasc Dis

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Abstract

Implications for REDUCE IT in clinical practice.

Bittner V

Statin therapy is effective in primary and secondary prevention, but substantial residual risk remains on statin treatment, especially among high risk and very high risk patients. Add-on therapy with ezetimibe and proprotein convertase subtilisin /kexin type 9 (PCSK9) inhibitors provides additional risk reduction through further reduction in low density lipoprotein cholesterol. Elevated triglycerides/triglyceride rich lipoproteins contribute to atherogenesis and to the residual risk on statin therapy. Addition of icosapent ethyl to statins has recently been shown to markedly lower risk of cardiovascular disease (CVD) events in patients with established atherosclerotic CVD (ASCVD) and high risk patients with type II diabetes mellitus. These data are discussed in the context of current guidelines and synthesized in a decision pathway to guide combination lipid-lowering therapy in patients at high ASCVD risk.

Copyright © 2019 Anesthesia History Association. Published by Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 08 Nov 2019; epub ahead of print
Bittner V
Prog Cardiovasc Dis: 08 Nov 2019; epub ahead of print | PMID: 31715195
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Abstract

Coronary artery calcium scoring for individualized cardiovascular risk estimation in important patient subpopulations after the 2019 AHA/ACC primary prevention guidelines.

Dzaye O, Dudum R, Reiter-Brennan C, Kianoush S, ... Cainzos-Achirica M, Blaha MJ

The 2018 and 2019 American Heart Association and American College of Cardiology (AHA/ACC) guidelines for primary prevention of atherosclerotic cardiovascular disease (ASCVD) recommend consideration of so-called \"risk-enhancing factors\" in borderline to intermediate risk individuals. These include high-risk race/ethnicity (e.g. South Asian origin), chronic kidney disease, a family history of premature ASCVD, the metabolic syndrome, chronic inflammatory disorders (e.g. rheumatoid arthritis [RA], psoriasis, or chronic human immunodeficiency virus [HIV]), and conditions specific to women, among others. Studies suggest, however, that risk may be highly heterogeneous within these subgroups. The AHA/ACC guidelines also recommend consideration of coronary artery calcium (CAC) scoring for further risk assessment in borderline to intermediate risk individuals in whom management is uncertain. Although the combination of risk enhancing factors and CAC burden (together with Pooled Cohort estimates) may lead to more accurate ASCVD risk assessment, few publications have closely examined the interplay between risk enhancing factors and CAC scoring for personalized risk estimation. Our aim is to review the relevant literature in this area. Although further research is clearly needed, CAC assessment seems a highly valuable option to inform individualized ASCVD risk management in these important, often highly heterogeneous patient subgroups.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 08 Nov 2019; epub ahead of print
Dzaye O, Dudum R, Reiter-Brennan C, Kianoush S, ... Cainzos-Achirica M, Blaha MJ
Prog Cardiovasc Dis: 08 Nov 2019; epub ahead of print | PMID: 31715194
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Abstract

Impact of fitness and changes in fitness on lipids and survival.

Lavie CJ, Kachur S, Sui X

In the past five decades, cardiorespiratory fitness (CRF) has become fairly established as an important risk factor or marker for cardiovascular disease (CVD), as well as CVD - and all-cause mortality. Substantial evidence supports a strong inverse association between baseline levels of CRF and the risk of developing CVD risk factors, including dyslipidemia. Additionally, accumulating evidence also supports that maintaining or improving a certain level of CRF over time leads to a lower rate of developing CVD risk factors, such as dyslipidemia, and also improves survival. Recent evidence also supports the role of resistance exercise and muscular strength to reduce the development of metabolic syndrome and hypercholesterolemia and potentially reduce development of diabetes as well, in addition to improving survival. Therefore, great efforts are needed to increase both CRF and muscle strength with aerobic exercise and resistance exercise in the primary and secondary prevention of CVD.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 07 Nov 2019; epub ahead of print
Lavie CJ, Kachur S, Sui X
Prog Cardiovasc Dis: 07 Nov 2019; epub ahead of print | PMID: 31711788
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Abstract

Coconut oil intake and its effects on the cardiometabolic profile - A structured literature review.

Santos HO, Howell S, Earnest CP, Teixeira FJ

In recent years, health professionals and laypersons have disseminated misinformation regarding the consumption of coconut oil. Those encouraging the supplementation of coconut oil argue that it provides health benefits and protective cardiovascular effects. Our article examines the effects of coconut oil intake on the cardiometabolic profile by exploring various lipid indices, as well as potential non-lipid effects, such as weight loss. The majority of randomized controlled trials show that coconut oil intake or its supplementation increases low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDLC), and total cholesterol when compared with other vegetable oils. Lauric acid, a medium-chain fatty acid and the main constituent of coconut oil, increases LDL-C and HDL-C concentrations, since it plays a main role as a substrate for apolipoprotein (apo)A1 and apoB synthesis, which are the key molecules in HDL-C and LDL-C particles, respectively. Despite some findings demonstrating an increase in HDLC, definitive long-term clinical trials are imperative to ascertain whether this effect is clinically relevant given that the consumption of saturated fatty acids (SFA), independent of coconut oil, may also increase HDL-C concentrations. Despite the promotion in the mainstream media, coconut oil intake has failed as a weight loss strategy and should not be considered as a supplementation strategy to increase satiety and/or thermogenesis. If one desires to include coconut oil in the diet, then we suggest that it should be limited and encompassed within the current recommendations of SFA intake, which are up to 10% of total caloric intake.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 06 Nov 2019; epub ahead of print
Santos HO, Howell S, Earnest CP, Teixeira FJ
Prog Cardiovasc Dis: 06 Nov 2019; epub ahead of print | PMID: 31707063
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Abstract

Transcatheter innovations in tricuspid regurgitation: Navigate.

Elgharably H, Harb SC, Kapadia S, Svensson LG, Navia JL

Patients with isolated functional or recurrent tricuspid regurgitation are often considered high risk and denied surgery. There has been growing experience for transcatheter tricuspid valve implantation through valve-in-valve or valve-in-ring, and recently, but to a lesser extent, in native annulus. The NaviGate is a novel self-expanding valved-stent designed with unique features to treat tricuspid regurgitation, particularly, in the settings of severely dilated tricuspid annulus. Herein, we present the innovation facets and clinical application of the NaviGate system.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 06 Nov 2019; epub ahead of print
Elgharably H, Harb SC, Kapadia S, Svensson LG, Navia JL
Prog Cardiovasc Dis: 06 Nov 2019; epub ahead of print | PMID: 31707062
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Abstract

Tricuspid regurgitation is a public health crisis.

Enriquez-Sarano M, Messika-Zeitoun D, Topilsky Y, Tribouilloy C, Benfari G, Michelena H

Tricuspid regurgitation (TR) has long been a forgotten valve disease of benign reputation. However, TR deserves higher attention and represents a growing public health crisis. Indeed, recent epidemiological data suggest that 1.6 million US residents are affected by moderate or severe TR. Furthermore, large recent cohorts demonstrate that higher degrees of TR are associated with considerable excess mortality, independent of all background clinical and hemodynamic contexts. Finally, analysis of recent cohorts also shows that >90% of patients with moderate or severe TR are never offered surgical treatment and remain untreated. Therefore, TR is frequent, severely impacts outcomes, and is rarely treated, justifying the development of new strategies and methods for its treatment.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 06 Nov 2019; epub ahead of print
Enriquez-Sarano M, Messika-Zeitoun D, Topilsky Y, Tribouilloy C, Benfari G, Michelena H
Prog Cardiovasc Dis: 06 Nov 2019; epub ahead of print | PMID: 31707061
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Abstract

Implications of cost-effectiveness analyses of lipid-lowering therapies: From the policy-maker\'s desk to the patient\'s bedside.

Kazi DS, Virani SS

In our increasingly cost-conscious health system, patients, clinicians, hospitals, and payers all agree about the urgent need to rein in runaway healthcare costs. High pharmaceutical costs make drugs unaffordable to many patients who may benefit from them, including some insured patients who face prohibitive out-of-pocket costs. Health systems and payers can use the systematic framework of cost-effectiveness analysis and estimated budgetary impact to prioritize the adoption of new therapies and technologies. In this review article, we discuss basic principles of cost-effectiveness research for practicing clinicians, the concept of cost-effectiveness versus affordability, other considerations relevant to resource allocation, and limitations of cost-effectiveness research. We use the example of lipid lowering therapies to discuss application of cost-effectiveness research in informing health care policy, its use for health care systems and in the development of clinical practice guidelines, and its implications for clinicians and patients. As clinicians and patients become more cognizant of the cost-implications of new therapies, professional societies can help improve the quality of decision-making by incorporating unbiased value statements into their expert guidelines.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 27 Oct 2019; epub ahead of print
Kazi DS, Virani SS
Prog Cardiovasc Dis: 27 Oct 2019; epub ahead of print | PMID: 31672610
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Abstract

Understanding why REDUCE-IT was positive - Mechanistic overview of eicosapentaenoic acid.

Harris WS

The REDUCE-IT study found that patients at elevated risk for cardiovascular disease (CVD) who were already taking statins obtained a marked benefit by taking 4 g/d of eicosapentaenoic acid ethyl esters (icosapent ethyl, IPE; Vascepa) over about 5 years. Although approved for triglyceride (TG) lowering, IPE had only a modest TG-lowering effect in REDUCE-IT, largely because median TG levels were relatively low already. Hence the question of what mechanisms IPE might be working through is of great interest. At present, it appears that the best mechanistic candidates would be anti-platelet effects and/or anti-inflammatory effects. Whatever the cause, the powerful effects of IPE on CVD risk have renewed interest in the clinical utility of omega-3 fatty acids.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 26 Oct 2019; epub ahead of print
Harris WS
Prog Cardiovasc Dis: 26 Oct 2019; epub ahead of print | PMID: 31666183
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Abstract

New insights into managing symptoms during statin therapy.

Robinson JG

Symptoms during statin therapy are common and often attributed to statin intolerance. Recent data suggest few patients are truly intolerant to statins. Muscle symptoms are similar in statin and control groups in blinded treatment periods of clinical trials. The \"nocebo\" effect may occur during open-label statin treatment, when previously asymptomatic study participants report symptoms attributed to statin therapy, or during placebo-controlled trials. Most patients reporting statin intolerance can tolerate blinded moderate intensity statin therapy. In clinical practice the large majority of patients are willing to retry a statin, and of those who do, >80-90% successfully remain on statin therapy long-term. Emerging evidence from brain imaging studies and contemporary approaches to pain management suggests that building trust and managing patient expectations can minimize the \"nocebo\" effect in statin-treated patients.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 25 Oct 2019; epub ahead of print
Robinson JG
Prog Cardiovasc Dis: 25 Oct 2019; epub ahead of print | PMID: 31669768
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Abstract

Transcatheter innovations in tricuspid regurgitation: Cardioband.

Mangieri A, Latib A

Functional tricuspid regurgitation (FTR) has been neglected for a long time, however its prevalence and clinical relevance is not negligible. In presence of FTR, a certain quote of annular dilatation is present thus contributing to the mechanism of regurgitation. Historically, surgical annuloplasty has been the main treatment to correct FTR; however surgical repair is limited by a high risk of mortality and morbidity. For this reason, percutaneous tricuspid annuloplasty is an attractive tool for the treatment of FTR in patients at high surgical risk. A number of both direct and indirect percutaneous annuloplasty systems are currently under pre-clinical and clinical development. This review will discuss the Cardioband system, a novel direct annuloplasty device with promising result in terms of clinical safety and efficacy.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 24 Oct 2019; epub ahead of print
Mangieri A, Latib A
Prog Cardiovasc Dis: 24 Oct 2019; epub ahead of print | PMID: 31669500
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Abstract

Lipid management beyond the guidelines.

Robinson JG

The 2018 AHA/ACC cholesterol guideline builds on the 2013 ACC/AHA cholesterol guideline statin recommendations to provide more detailed recommendations for the use of nonstatin therapy risk stratification for primary prevention statin use. New information has become available after the development of the 2018 AHA/ACC cholesterol guideline that can further inform clinical practice. Proprotein convertase subtilisin kexin type-9 (PCSK9) monoclonal antibodies are now a reasonable or even good value following over 60% reductions in their acquisition price, and the identification of high risk patient groups most likely to benefit from further low-density lipoprotein cholesterol (LDL-C) lowering. Meta-analyses and clinical trial data now show that patients with LDL-C ≥ 100 mg/dl are more likely to experience progressively greater reductions in the risk of cardiovascular and total mortality and coronary heart disease events for progressively higher LDL-C levels. Icosapent ethyl, a highly concentrated form of modified EPA has been shown to reduce cardiovascular events in high risk patients with moderate hypertriglyceridemia on statin therapy. Comparisons with other statin guidelines revealed that statin initiation for those with ≥7.5% 10-year atherosclerotic cardiovascular disease (ASCVD) risk is the most effective strategy for reducing the most ASCVD events for the proportion of the population treated. Data from younger populations finally became available for coronary artery calcium (CAC) scoring (mean age of 51 years) which confirmed the value of CAC > 0 for identifying individuals at increased ASCVD risk most likely to benefit from statin initiation. This analysis also found that statins could keep CAC = 0 in those with risk factors. Epidemiologic pooling studies now clearly show that LDL-C and non-high-density lipoprotein cholesterol levels in young adulthood confer excess risk for ASCVD later in life. Accumulating data support earlier risk factor intervention trials as the next research priority.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 24 Oct 2019; epub ahead of print
Robinson JG
Prog Cardiovasc Dis: 24 Oct 2019; epub ahead of print | PMID: 31669499
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Abstract

Reducing cardiovascular risk in patients with familial hypercholesterolemia: Risk prediction and lipid management.

Miname MH, Santos RD

Familial hypercholesterolemia (FH) is a frequent genetic disorder characterized by elevated low-density lipoprotein (LDL)-cholesterol (LDL-C) levels and early onset of atherosclerotic cardiovascular disease. FH is caused by mutations in genes that regulate LDL catabolism, mainly the LDL receptor (LDLR), apolipoprotein B (APOB) and gain of function of proprotein convertase subtilisin kexin type 9 (PCSK9). However, the phenotype may be encountered in individuals not carrying the latter monogenic defects, in approximately 20% of these effects of polygenes predominate, and in many individuals no molecular defects are encountered at all. These so-called FH phenocopy individuals have an elevated atherosclerotic cardiovascular disease risk in comparison with normolipidemic individuals but this risk is lower than in those with monogenic disease. Individuals with FH are exposed to elevated LDL-C levels since birth and this explains the high cardiovascular, mainly coronary heart disease, burden of these subjects. However, recent studies show that this risk is heterogenous and depends not only on high LDL-C levels but also on presence of previous cardiovascular disease, a monogenic cause, male sex, smoking, hypertension, diabetes, low HDL-cholesterol, obesity and elevated lipoprotein(a). This heterogeneity in risk can be captured by risk equations like one from the SAFEHEART cohort and by detection of subclinical coronary atherosclerosis. High dose high potency statins are the main stain for LDL-C lowering in FH, however, in most situations these medications are not powered enough to reduce cholesterol to adequate levels. Ezetimibe and PCSK9 inhibitors should also be used in order to better treat LDL-C in FH patients.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 24 Oct 2019; epub ahead of print
Miname MH, Santos RD
Prog Cardiovasc Dis: 24 Oct 2019; epub ahead of print | PMID: 31669498
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Abstract

Assessment and procedural guidance with echocardiography for transcatheter tricuspid regurgitation devices.

Hahn RT

Echocardiographic imaging is an integral part of characterizing patients with tricuspid regurgitation (TR) and helps in determining the timing of intervention and procedural guidance for transcatheter interventions. The rapid advances in both two-dimensional and three-dimensional imaging however have facilitated the development and deployment of novel transcatheter devices to address the unmet need for patients with symptomatic severe TR.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 24 Oct 2019; epub ahead of print
Hahn RT
Prog Cardiovasc Dis: 24 Oct 2019; epub ahead of print | PMID: 31669497
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Abstract

Transcatheter repair of tricuspid regurgitation with MitraClip.

Sorajja P, Cavalcante J, Goessl M, Bae R

Transcatheter therapy with the MitraClip system (Abbott Structural, Menlo Park, CA) is the most commonly used transcatheter therapy for patients with tricuspid regurgitation, with over 1000 cases performed worldwide. The procedure is an off-label approach that requires meticulous attention to anatomical features obtained via comprehensive echocardiography and, in some cases, using cardiac computed tomography. Herein, we describe patient selection, procedural performance, and clinical outcomes of this therapy.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 22 Oct 2019; epub ahead of print
Sorajja P, Cavalcante J, Goessl M, Bae R
Prog Cardiovasc Dis: 22 Oct 2019; epub ahead of print | PMID: 31655080
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Abstract

Patients\' selection for transcatheter tricuspid valve interventions: Who will benefit?

Harb SC, Kapadia SR

Tricuspid regurgitation (TR) is a common valvular pathology and is associated with significant morbidity and mortality. However, there is no currently defined optimal management strategy: medical therapy is limited to diuretics, and tricuspid valve surgery is rarely performed and associated with high risks. This has led to the emergence of numerous transcatheter therapies that are showing promising early results but are faced with multiple challenges. The tricuspid valve anatomy is complex and variable, imaging of tricuspid valve by echocardiography can be difficult, and current grading of TR severity and right ventricular size and function is mostly subjective. Also, the optimal timing of the intervention and appropriate selection of patients who will benefit remain topics of debate with limited supporting data. In this review, we present the current challenges and considerations in patients\' selection and propose a trial design and selection criteria aimed to address these limitations.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 10 Sep 2019; epub ahead of print
Harb SC, Kapadia SR
Prog Cardiovasc Dis: 10 Sep 2019; epub ahead of print | PMID: 31520604
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Abstract

Cross-country skiing and running\'s association with cardiovascular events and all-cause mortality: A review of the evidence.

Laukkanen JA, Kunutsor SK, Ozemek C, Mäkikallio T, ... Wisloff U, Lavie CJ

A large body of evidence demonstrates positive, graded effects of PA on cardiovascular disease (CVD) morbidity and mortality with increasing intensity compared with lower PA intensity. Running is often designated as a high-intensity PA with substantial evidence supporting its health benefits. Cross-country skiing is among the most demanding aerobic endurance exercises and requires engaging the upper- and lower-body. Cross-country skiing is often regarded as high-intensity PA, which has been associated with significant health benefits. However, a robust body of evidence identifying the dose-response relation between cross-country skiing volume and health outcomes is sparse. Therefore, this review aims to summarize the available evidence linking cross-country skiing with CVD morbidity and all-cause mortality; postulated pathways that may elucidate the relation between these associations; outline areas of ongoing uncertainty; and the implications for primary and secondary CVD prevention. To put the findings into perspective, we also summarized the evidence linking running with CVD morbidity and all-cause mortality. Though a head-to-head comparison is not available, the evidence indicates that performing PA as cross-country skiing associates with lower mortality risk when compared with that observed in those undertaking their PA as running. Potential adverse effects of extreme high weekly doses of cross-country skiing over decades may be cardiac arrhythmias, such as atrial fibrillation. Evidence suggests that cross-country skiing may reduce the risk of CVD events and all-cause mortality via anti-inflammatory pathways, improvements in endothelial function and reduced levels of CVD risk factors, such as lipids, glucose, and blood pressure; and enhancement of cardiorespiratory fitness.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 06 Sep 2019; epub ahead of print
Laukkanen JA, Kunutsor SK, Ozemek C, Mäkikallio T, ... Wisloff U, Lavie CJ
Prog Cardiovasc Dis: 06 Sep 2019; epub ahead of print | PMID: 31505192
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Abstract

Obesity, risk of diabetes and role of physical activity, exercise training and cardiorespiratory fitness.

Carbone S, Del Buono MG, Ozemek C, Lavie CJ

The epidemic of obesity contributes to the burden of type 2 diabetes mellitus (T2DM) in the United States and worldwide. Importantly, obesity is not only preventable but can be treated, particularly with lifestyle modifications to forestall T2DM in those with excess adiposity. The mechanisms linking obesity to T2DM are numerous and involve adipose tissue remodeling as a result of unhealthy behaviors, including unhealthy diet, reduced physical activity (PA) and exercise training (ET), and increased sedentary behaviors. Taken together, these factors markedly reduce cardiorespiratory fitness (CRF), one of the strongest predictors for cardiovascular outcomes and all-cause mortality in the general population, but also in those with T2DM. In this review we describe the mechanisms leading to adipose tissue remodeling resulting in obesity, as well as the mechanisms linking excess adiposity to insulin resistance and, in turn, T2DM. We then present the therapeutic strategies that can be implemented in obesity to prevent T2DM, with a brief discussion on weight loss, and greater emphasis on PA and ET. We finally present the evidence to support the beneficial effects of such strategies in patients with established T2DM and discuss the importance of achieving improvements in CRF in this population to potentially improve clinical outcomes.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:327-333
Carbone S, Del Buono MG, Ozemek C, Lavie CJ
Prog Cardiovasc Dis: 30 Dec 1999; 62:327-333 | PMID: 31442513
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Abstract

An update on pharmacotherapies in diabetic dyslipidemia.

Gupta M, Tummala R, Ghosh RK, Blumenthal C, ... Ventura H, Deedwania P

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.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:334-341
Gupta M, Tummala R, Ghosh RK, Blumenthal C, ... Ventura H, Deedwania P
Prog Cardiovasc Dis: 30 Dec 1999; 62:334-341 | PMID: 31442512
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Abstract

Cardiovascular outcome trials of the newer anti-diabetic medications.

Acharya T, Deedwania P

Concerns of elevated cardiovascular disease (CVD) risk with some anti-diabetic medications warranted phase 4 clinical trials to demonstrate CVD safety of newly marketed anti-diabetic drugs. Although initially designed to evaluate safety, some of these CVD outcome trials (CVOTs) have in fact shown CVD benefits. New medication classes, like glucagon-like peptide 1 (GLP-1) analogues and sodium-glucose co-transporter 2 (SGLT2) inhibitors, have shown reductions in the risk of major adverse cardiovascular events (MACE) including, myocardial infarction, stroke, CV death, and heart failure (HF). Perhaps more importantly, SGLT2 inhibitors demonstrated reduction in the risk of HF hospitalizations, being the first class of anti-diabetic drugs to do so. Conversely, dipeptidyl peptidase 4 (DPP-4) inhibitors did not significantly affect atherosclerotic CVD end-points and some actually increased the risk of HF hospitalizations. Further, the adverse/beneficial CVD effects of these medications may not be class specific. This review focuses on the main results of these CVOTs while highlighting the heterogeneity of CVD end-points within each class and discusses important mechanistic insights and adverse effect profiles.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:342-348
Acharya T, Deedwania P
Prog Cardiovasc Dis: 30 Dec 1999; 62:342-348 | PMID: 31442511
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Abstract

The elephant in the room: Why cardiologists should stop ignoring type 2 diabetes.

O\'Keefe JH, Nassif ME, Magwire ML, O\'Keefe EL, Lavie CJ

Type 2 Diabetes (T2D) is a growing public health threat that is evolving into a global pandemic with debilitating, expensive and often lethal complications. Even when hemoglobin A1c (HbA1C) levels are well controlled, and concomitant cardiovascular (CV) risk factors are effectively treated, two out of every three patients with T2D are destined to die from CV complications. Several large randomized controlled trials (RCT) indicate that two classes of glucose-lowering medications, oral sodium-glucose cotransporter type 2 inhibitors (SGLT2-i) and injectable glucagon-like peptide-1 receptor agonists (GLP-1RA), confer significant CV benefits, including reductions in: hospitalizations for heart failure (HF), progression of diabetic kidney disease, atherosclerotic CV events, and (with some agents) CV death. These CV benefits appear to be independent of the glucose-lowering effects of these agents. These compelling findings are triggering a fundamental paradigm shift in T2D management whereby the focus is no longer on HbA1c alone, but instead on implementing a comprehensive CV risk reduction strategy prioritizing the use of these evidence-based therapies (along with other evidence-based treatment strategies) with the objective of reducing the risk of morbid complications, and improving the quantity and quality of life of patients with T2D. Cardiologists are uniquely positioned to become more involved in the management of T2D and established CV disease, which at this time should include initiation (either by prescribing or by making recommendations) of agents proven to reduce CV risk. Specifically, SGLT2-is and/or GLP-1RA have now been shown to have a favorable risk-benefit balance, and are being increasingly emphasized by the practice guidelines as preferable treatment options in vulnerable patients with T2D. The cardiology community should collaborate with other care providers to ensure that when and where appropriate these new T2D therapies are used along with other evidence-based therapies to improve patient outcomes.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 30 Dec 1999; 62:364-369
O'Keefe JH, Nassif ME, Magwire ML, O'Keefe EL, Lavie CJ
Prog Cardiovasc Dis: 30 Dec 1999; 62:364-369 | PMID: 31408637
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Abstract

Mechanistic insights regarding the role of SGLT2 inhibitors and GLP1 agonist drugs on cardiovascular disease in diabetes.

Garg V, Verma S, Connelly K

The treatment landscape for patients with established or at high risk for cardiovascular disease and type 2 diabetes mellitus has entirely changed over the past decade, with the introduction of several anti-hyperglycemic agents. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists are two anti-hyperglycemic classes which have been of special interest after multiple large cardiovascular disease (CVD) outcomes studies have demonstrated superiority of these agents compared to placebo for major adverse CVD events and in some cases, hospitalization for heart failure. Despite the dramatic results of these trials, only recently have we began to understand the mechanisms underlying these CVD benefits. Here we review the underlying mechanisms which have the greatest plausibility for both of these agents including the impact of ventricular loading conditions, direct effects on cardiac structure and function, myocardial energetics and sodium/hydrogen exchange for SGLT2 inhibitors, and the anti-atherosclerotic, anti-inflammatory, and modulation of endothelial function for GLP-1 agonists.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:349-357
Garg V, Verma S, Connelly K
Prog Cardiovasc Dis: 30 Dec 1999; 62:349-357 | PMID: 31381891
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Abstract

The role of coronary artery bypass surgery versus percutaneous intervention in patients with diabetes and coronary artery disease.

Godoy LC, Ko DT, Rao V, Farkouh ME

Patients with diabetes mellitus (DM) often exhibit a complex coronary anatomy, making coronary revascularization challenging. Coronary artery bypass grafting surgery (CABG) is currently considered the preferred revascularization method in patients with DM and multivessel disease. Percutaneous coronary intervention (PCI) has advanced with new stent generations having been developed in the recent years, but they have not yet been adequately compared against CABG in the population with DM. Comorbidities, such as renal disease and heart failure, lead to worse prognosis following a revascularization procedure and require especial consideration when choosing between CABG versus PCI. The presence of significant left main disease may also impose additional challenges to coronary revascularization, particularly when accompanied by the involvement of multivessel disease. Most of the evidence regarding revascularization in patients with DM is compiled from studies enrolling patients with stable ischemic heart disease, and trials with patients in the acute coronary syndrome setting are lacking.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 30 Dec 1999; 62:358-363
Godoy LC, Ko DT, Rao V, Farkouh ME
Prog Cardiovasc Dis: 30 Dec 1999; 62:358-363 | PMID: 31377224
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Abstract

Diabetes, heart failure, and renal dysfunction: The vicious circles.

Braunwald E

The prevalence of Type 2 diabetes mellitus (T2DM) has reached pandemic proportions. T2DM frequently causes macrovascular and/or microvascular pathologic changes and thereby increases the risks for the development of myocardial infarction, heart failure, stroke, renal failure, and reduced survival. This article describes the important interactions between T2DM, heart failure, and renal dysfunction, forming vicious circles. The interruption of these circles represents important therapeutic goals.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:298-302
Braunwald E
Prog Cardiovasc Dis: 30 Dec 1999; 62:298-302 | PMID: 31377223
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Impact:
Abstract

Atherosclerotic cardiovascular disease and heart failure: Determinants of risk and outcomes in patients with diabetes.

Nelson AJ, Peterson ED, Pagidipati NJ

Cardiovascular disease (CVD) is the most common cause of morbidity and mortality for patients with diabetes mellitus (DM). Although the burden of atherosclerotic CVD (ASCVD) is well documented, heart failure (HF) has been an under-appreciated CVD complication of DM. However, as more patients with DM live longer and survive acute ASCVD events, the distribution of CVD complications has evolved. This review summarizes the epidemiology of DM, the relative risk and prognosis of both ASCVD and HF following a diagnosis of DM, and the likelihood of cause-specific CVD mortality in patients with DM.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:306-314
Nelson AJ, Peterson ED, Pagidipati NJ
Prog Cardiovasc Dis: 30 Dec 1999; 62:306-314 | PMID: 31301314
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Impact:
Abstract

Is sauna bathing protective of sudden cardiac death? A review of the evidence.

Laukkanen JA, Kunutsor SK

Sudden cardiac death (SCD) is a global public health burden accounting for 15-20% of all deaths. Though established atherosclerotic risk factors explain a large proportion of the risk of SCD, these factors are often absent in a large proportion of SCD victims and the pathogenesis of SCD is still not fully established. It therefore appears that additional factors may be involved. Sauna bathing is a traditional Finnish activity that is mainly used for the purposes of relaxation and pleasure. Beyond its use for these purposes, sauna bathing has been linked with several health benefits. Emerging evidence suggests that sauna bathing is associated with reduced risk of adverse cardiovascular (CV) disease (CVD) and non-CVD outcomes as well as mortality. A number of reports have linked sauna bathing with reduced or increased risk of SCD, but the evidence is uncertain. This review summarizes available studies linking sauna bathing with SCD, the postulated mechanistic pathways underlying these associations, outlines areas of outstanding uncertainty, and the implications for prevention. We employed a comprehensive search for observational studies, randomized controlled trials (RCTs), and non-RCTs from MEDLINE and Embase since their inception until March 2019. Observational data suggest that regular sauna bathing is associated with a substantial risk reduction in SCD. Furthermore, the data suggest that a combination of regular physical activity and sauna baths confers substantial risk reduction for SCD compared with either modality alone. Few reports have linked sauna baths with SCDs, but these single case incidents have been attributed to the effects of dehydration, hypotension, and cardiac arrhythmias due to a combination of sauna exposure and alcohol consumption. Sauna bathing is generally safe for most healthy people and even among patients with stable CVD, if used sensibly and with caution. Plausible pathways underlying the protective effect of sauna bathing on SCD may be linked to the impact on CV function via reduced arterial stiffness, decreases in inflammation and oxidative stress, stabilization of the autonomic nervous system, beneficial changes in circulating lipid profiles and other CVD risk markers, and lowering of systemic blood pressure. Sauna is a potential novel tool to promote SCD prevention in addition to other known means, being an enjoyable way to take care of general health and well-being.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:288-293
Laukkanen JA, Kunutsor SK
Prog Cardiovasc Dis: 30 Dec 1999; 62:288-293 | PMID: 31102597
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Abstract

Sudden cardiac death in Long QT syndrome (LQTS), Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT).

Singh M, Morin DP, Link MS

Sudden cardiac death (SCD) accounts for 230,000 to 350,000 deaths per year in the United States. While many who suffer SCD possess underlying structural heart disease, inherited arrhythmia syndromes are also important contributors to SCD. In patients without structural heart disease, inherited arrhythmia syndromes are identified in >50% of the remaining patients. In this review, we will focus on the presentation and management of three major inherited syndromes that lead to SCD in patients without structural heart disease: long QT syndrome (LQTS), Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). All these syndromes can present in patients who are asymptomatic or, at the other extreme, with syncope and even SCD. LQTS syndrome and Brugada are the most common inherited arrhythmogenic syndromes, while CPVT is much rarer. Determining which patients need pharmacologic treatment and those who would benefit from more aggressive treatment such as sympathectomies and implantable defibrillators is not always clear.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 30 Dec 1999; 62:227-234
Singh M, Morin DP, Link MS
Prog Cardiovasc Dis: 30 Dec 1999; 62:227-234 | PMID: 31078562
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Abstract

Targeted temperature management for cardiac arrest.

Mody P, Kulkarni N, Khera R, Link MS

Therapeutic hypothermia, or targeted temperature management (TTM), is a strategy of reducing the core body temperature of survivors of sudden cardiac arrest (SCA) to minimize neurological damage caused by severe hypoxia. Initial clinical trials examining this technique demonstrated significant improvement in neurological function among survivors of out-of-hospital SCA with an initial shockable rhythm. Since then, TTM has become an integral part of the care provided to comatose survivors of SCA. However, multiple questions persist regarding the target cooling temperature, duration of cooling, and utility of TTM in patient populations such as survivors of out-of-hospital SCA with non-shockable rhythms or in-hospital SCA. This review article summarizes the current evidence regarding optimal application of TTM and compares the recommendations for TTM in current guidelines.

Published by Elsevier Inc.

Prog Cardiovasc Dis: 30 Dec 1999; 62:272-278
Mody P, Kulkarni N, Khera R, Link MS
Prog Cardiovasc Dis: 30 Dec 1999; 62:272-278 | PMID: 31078561
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Abstract

The wearable cardioverter-defibrillator vest: Indications and ongoing questions.

Sandhu U, Rajyaguru C, Cheung CC, Morin DP, Lee BK

Multiple clinical trials have demonstrated the efficacy of implantable cardioverter-defibrillators (ICDs) for the prevention of sudden cardiac death (SCD) among specific high-risk populations. However, it remains unclear how to optimally treat those patients who are at elevated risk of cardiac arrest but are not among the presently identified groups proven to benefit from an ICD, are unable to tolerate surgical device implantation, or refuse invasive therapies. The wearable cardioverter-defibrillator (WCD) is an alternative antiarrhythmic device that provides continuous cardiac monitoring and defibrillation capabilities through a noninvasive, electrode-based system. The WCD has been shown to be highly effective at restoration of sinus rhythm in patients with a ventricular tachyarrhythmia, and one randomized trial using the WCD in patients with recent myocardial infarction at elevated risk for arrhythmic death reported a decrease in overall mortality despite no SCD mortality benefit. The current clinical indications for WCD use are varied and continue to evolve as experience with this technology increases.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:256-264
Sandhu U, Rajyaguru C, Cheung CC, Morin DP, Lee BK
Prog Cardiovasc Dis: 30 Dec 1999; 62:256-264 | PMID: 31077726
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Impact:
Abstract

Sudden cardiac death in nonischemic cardiomyopathy.

Kadakia RS, Link MS, Dominic P, Morin DP

Sudden cardiac death (SCD) is a major cause of mortality in patients with nonischemic cardiomyopathy (NICM). Identifying patients who are at highest risk for SCD is an ongoing challenge. At present, guidelines recommend the use of an implantable cardioverter-defibrillator (ICD) in patients with NICM with a reduced left ventricular ejection fraction (LVEF) and heart failure (HF) symptoms. Some recent data, however, suggest that ICDs may not increase longevity in this population. Conversely, community-based studies have demonstrated that many at-risk individuals who may benefit from ICD therapy remain unprotected. Current recommendations for ICD implantation are continually debated, justifying comprehensive individualized risk assessment. Various promising techniques for further risk stratification are under evaluation, including cardiac magnetic resonance imaging, electrocardiographic assessment of electrical instability, and genetic testing. However, none of these strategies has been fully adapted into guidelines. Hence, clinical risk stratification practice today depends on LVEF and HF symptoms, which have poor sensitivity and specificity for predicting SCD risk.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:235-241
Kadakia RS, Link MS, Dominic P, Morin DP
Prog Cardiovasc Dis: 30 Dec 1999; 62:235-241 | PMID: 31075279
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Abstract

The role of cardiorespiratory fitness on the risk of sudden cardiac death at the population level: A systematic review and meta-analysis of the available evidence.

Jiménez-Pavón D, Lavie CJ, Blair SN

Cardiorespiratory fitness (CRF) has been widely studied as a powerful and independent predictor of all-cause and disease-specific mortality. Sudden cardiac death (SCD) is recognized as a significant cause of mortality among the general population, including the general population without previous symptoms of any coronary heart disease (CHD). Consequently, SCD is an important public health problem, which constitutes a clinical challenge. Thus, prevention of SCD by detecting early risk factors could be a useful tool, contributing to the American Heart Association\'s goal of decreasing the incidence of SCD at the population level. The identification of these risk factors for CVD would facilitate the large-scale screening of those participants at higher risk of SCD. This systematic review collects information about the role of CRF on the risk of SCD at the available evidence, and analyzes the long-term influence of CRF as a risk factor and independent predictor of SCD.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:279-287
Jiménez-Pavón D, Lavie CJ, Blair SN
Prog Cardiovasc Dis: 30 Dec 1999; 62:279-287 | PMID: 31075278
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Abstract

Non-arrhythmic causes of sudden death: A comprehensive review.

Bob-Manuel T, Jenkins JS, Morin DP

Sudden cardiac death (SCD) is a major public health issue in the United States and worldwide. It is estimated to affect between 1 and 1.5 million patients worldwide annually, with the global burden expected to rise due to the concomitant rise in coronary artery disease in the developing world. Although arrhythmic causes of SCD such as ventricular tachycardia and ventricular fibrillation are common and well-studied, non-arrhythmic causes are also important, with diverse etiologies from ischemia-related structural heart disease to non-ischemic heart diseases, non-atherosclerotic coronary pathologies, and inflammatory states. Recent research has also found that risk factors and/or demographics predispose certain individuals to a higher risk of non-arrhythmia-related SCD. This review discusses the epidemiology, mechanisms, etiologies, and management of non-arrhythmic SCD.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:265-271
Bob-Manuel T, Jenkins JS, Morin DP
Prog Cardiovasc Dis: 30 Dec 1999; 62:265-271 | PMID: 31075277
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Abstract

Imaging for sudden cardiac death risk stratification: Current perspective and future directions.

van der Bijl P, Delgado V, Bax JJ

Sudden cardiac death (SCD) accounts for one fifth of global deaths, and occurs when a trigger (e.g. myocardial ischemia, premature ventricular contraction) interacts with an arrhythmic substrate (e.g. myocardial scar, dilated cardiomyopathy). Multimodality imaging (echocardiographic, cardiac magnetic resonance and nuclear techniques) can potentially visualize many predisposing substrates and triggers. Implantable cardioverter-defibrillator (ICD) is the most effective approach to primary prevention of SCD, and current guidelines regarding ICD implantation are based on a left ventricular ejection fraction (LVEF) ≤35%. This practice is limited by a low sensitivity and specificity, and has limited value when applied to different etiologies. In this review, the role of multimodality imaging in SCD risk-stratification and the limitations of an LVEF-based approach, are discussed. Additional randomized, prospective data are eagerly awaited to inform on the role of imaging in SCD risk-stratification, and ongoing/ planned trials are subsequently discussed.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:205-211
van der Bijl P, Delgado V, Bax JJ
Prog Cardiovasc Dis: 30 Dec 1999; 62:205-211 | PMID: 31054859
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Abstract

Sudden death related cardiomyopathies - Hypertrophic cardiomyopathy.

Goff ZD, Calkins H

Hypertrophic cardiomyopathy (HCM) is a form of inherited cardiomyopathy. Most individuals with HCM experience minimal symptoms throughout their lifetime. However, those with HCM are at risk of ventricular arrhythmias and sudden cardiac death (SCD), the most feared complication of HCM. Implantable cardioverter defibrillator (ICD) implantation has played a large role in transforming this disease from one with an ominous prognosis to one with mortality rates that are on par with the general public. Since the early 2000s, balance between SCD prevention and unnecessary ICD placement has been sought, this is reflected in the evolution of SCD risk stratification models for patients with HCM. This review discusses key concepts pertaining to HCM, with emphasis on prevention of SCD, and summarizes and compares the recommendations for ICD implantation in current guidelines.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:212-216
Goff ZD, Calkins H
Prog Cardiovasc Dis: 30 Dec 1999; 62:212-216 | PMID: 31004609
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Abstract

Sudden death related cardiomyopathies - Arrhythmogenic right ventricular cardiomyopathy, arrhythmogenic cardiomyopathy, and exercise-induced cardiomyopathy.

Goff ZD, Calkins H

Sudden cardiac death (SCD) is a devastating possible outcome of all cardiomyopathies. The risk of SCD is increased in patients with structural heart disease and continues to increase as ventricular dysfunction worsens. There is, however, a subset of cardiomyopathy, so-called \"arrhythmogenic cardiomyopathy\" (ACM), that carries an inherent propensity for arrhythmia in all stages of the disease, even preceding ventricular dysfunction. The aim of this review is to identify cardiomyopathies, other than ischemic and dilated cardiomyopathies, that are associated with ventricular arrhythmias (VAs) and SCD. We discuss prevalence, diagnosis, natural history and management of arrhythmogenic right ventricular dysplasia/cardiomyopathy, ACM, and exercise-induced cardiomyopathy, with emphasis on the morbidity and mortality of VAs associated with these cardiomyopathies and how they can be mitigated through lifestyle modification, medical management, and implantation of cardioverter defibrillators.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:217-226
Goff ZD, Calkins H
Prog Cardiovasc Dis: 30 Dec 1999; 62:217-226 | PMID: 31004608
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Abstract

Can cardiac resynchronization therapy be used as a tool to reduce sudden cardiac arrest risk?

Galand V, Singh JP, Heist EK

Patients with cardiomyopathy and reduced left ventricular (LV) ejection fraction are at risk of heart failure (HF) symptoms and sudden cardiac arrest (SCA). In selected HF patients, cardiac resynchronization therapy (CRT) provides LV reverse remodeling and improves the cellular and molecular function. However controversial results have been published regarding the effect of CRT on the residual ventricular arrhythmia risk. Indeed, the decrease in SCA risk is inconsistent and some factors strongly influence the residual post implantation arrhythmic risk. Conversely, proarrhythmic effect of CRT has been previously described. In this review we aim to describe the relationship between CRT implantation and the SCA risk decrease and discuss the patients who only require cardiac resynchronization therapy-pacemaker and those who need a concomitant implantable cardioverter defibrillator.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 30 Dec 1999; 62:242-248
Galand V, Singh JP, Heist EK
Prog Cardiovasc Dis: 30 Dec 1999; 62:242-248 | PMID: 31004607
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Abstract

Evolution of extravascular implantable defibrillator technologies.

Pfenniger A, Knight BP

The implantable cardioverter-defibrillator (ICD) has been successfully treating patients with lethal ventricular arrhythmias for decades. The main acute and chronic complications of this therapy modality are related to the use of a transvenous lead. An entirely extravascular ICD concept was developed over the last 20 years, with emergence of the subcutaneous ICD (S-ICD). This device was approved for clinical use seven years ago, and accumulating real-life experience confirms its safety and efficacy. The main limitations related to this system include the lack of pacing capabilities for bradycardia, tachycardia or resynchronization therapy, a large size, and relatively high energy requirements for effective defibrillation. This review article summarizes current knowledge and potential future developments of the extravascular ICD technologies.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:249-255
Pfenniger A, Knight BP
Prog Cardiovasc Dis: 30 Dec 1999; 62:249-255 | PMID: 31004606
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Abstract

Diabetic cardiomyopathy - A comprehensive updated review.

Murtaza G, Virk HUH, Khalid M, Lavie CJ, ... Shanmugasundaram M, Paul TK

Diabetes causes cardiomyopathy and increases the risk of heart failure independent of hypertension and coronary heart disease. This condition called \"Diabetic Cardiomyopathy\" (DCM) is becoming a well- known clinical entity. Recently, there has been substantial research exploring its molecular mechanisms, structural and functional changes, and possible development of therapeutic approaches for the prevention and treatment of DCM. This review summarizes the recent advancements to better understand fundamental molecular abnormalities that promote this cardiomyopathy and novel therapies for future research. Additionally, different diagnostic modalities, up to date screening tests to guide clinicians with early diagnosis and available current treatment options has been outlined.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:315-326
Murtaza G, Virk HUH, Khalid M, Lavie CJ, ... Shanmugasundaram M, Paul TK
Prog Cardiovasc Dis: 30 Dec 1999; 62:315-326 | PMID: 30922976
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Abstract

Exercise Reveals Proline Dehydrogenase as a Potential Target in Heart Failure.

Moreira JBN, Wohlwend M, Fenk S, Åmellem I, ... Bjørkøy G, Wisløff U

The benefits of physical activity in cardiovascular diseases have long been appreciated. However, the molecular mechanisms that trigger and sustain the cardiac benefits of exercise are poorly understood, and it is anticipated that unveiling these mechanisms will identify novel therapeutic targets. In search of these mechanisms we took advantage of unbiased RNA-sequencing (RNA-seq) technology to discover cardiac gene targets whose expression is disrupted in heart failure (HF) and rescued by exercise in a rat model. Upon exhaustive validation in a separate rat cohort (qPCR) and human datasets, we shortlisted 16 targets for a cell-based screening, aiming to evaluate whether targeted disruption of these genes with silencing RNA would affect the abundance of a CVD biomarker (BNP, B-type natriuretic peptide) in human cardiomyocytes. Overall, these experiments showed that Proline Dehydrogenase (PRODH) expression is reduced in human failing hearts, rescued by exercise in a rat model of HF, and its targeted knockdown increases BNP expression in human cardiomyocytes. On the other hand, overexpression of PRODH increases the abundance of metabolism-related gene transcripts, and PRODH appears to be crucial to sustain normal mitochondrial function and maintenance of ATP levels in human cardiomyocytes in a hypoxic environment, as well as for redox homeostasis in both normoxic and hypoxic conditions. Altogether our findings show that PRODH is a novel molecular target of exercise in failing hearts and highlight its role in cardiomyocyte physiology, thereby proposing PRODH as a potential experimental target for gene therapy in HF.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:193-202
Moreira JBN, Wohlwend M, Fenk S, Åmellem I, ... Bjørkøy G, Wisløff U
Prog Cardiovasc Dis: 30 Dec 1999; 62:193-202 | PMID: 30867130
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Abstract

A role for FNDC5/Irisin in the beneficial effects of exercise on the brain and in neurodegenerative diseases.

Young MF, Valaris S, Wrann CD

The beneficial effects of exercise on the brain are well known. However, the underlying molecular mechanisms are much less well understood. Interestingly, myokines, hormones secreted by muscle in response to exercise, gained attention as such beneficial mediators. In this review, we will focus on FNDC5 and its secreted form, the newly discovered myokine \"irisin\". We will discuss their role in the beneficial effects of exercise and its potential application in neurodegenerative disorders.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:172-178
Young MF, Valaris S, Wrann CD
Prog Cardiovasc Dis: 30 Dec 1999; 62:172-178 | PMID: 30844383
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Abstract

Global physical activity levels - Need for intervention.

Ozemek C, Lavie CJ, Rognmo Ø

Substantial evidence shows that physical inactivity (PI) and sedentary behavior (SB) increases the risk of many chronic diseases and shortens life expectancy. We describe evidence that certain domains of physical activity (PA) in the United States (US) population have declined substantially over 5 decades. The prevalence of PI is very high worldwide, which has contributed to 6%-10% of the burden of many chronic diseases and premature mortality. Reduction or elimination of PI would likely produce substantial increases in life expectancy of the world\'s population. Great efforts are needed to reduce PI and SB and increase levels of PA in the US and worldwide.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:102-107
Ozemek C, Lavie CJ, Rognmo Ø
Prog Cardiovasc Dis: 30 Dec 1999; 62:102-107 | PMID: 30802461
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Abstract

Are the neuroprotective effects of exercise training systemically mediated?

Tari AR, Norevik CS, Scrimgeour NR, Kobro-Flatmoen A, ... Moreira JBN, Wisløff U

To date there is no cure available for dementia, and the field calls for novel therapeutic targets. A rapidly growing body of literature suggests that regular endurance training and high cardiorespiratory fitness attenuate cognitive impairment and reduce dementia risk. Such benefits have recently been linked to systemic neurotrophic factors induced by exercise. These circulating biomolecules may cross the blood-brain barrier and potentially protect against neurodegenerative disorders such as Alzheimer\'s disease. Identifying exercise-induced systemic neurotrophic factors with beneficial effects on the brain may lead to novel molecular targets for maintaining cognitive function and preventing neurodegeneration. Here we review the recent literature on potential systemic mediators of neuroprotection induced by exercise. We focus on the body of translational research in the field, integrating knowledge from the molecular level, animal models, clinical and epidemiological studies. Taken together, the current literature provides initial evidence that exercise-induced, blood-borne biomolecules, such as BDNF and FNDC5/irisin, may be powerful agents mediating the benefits of exercise on cognitive function and may form the basis for new therapeutic strategies to better prevent and treat dementia.

Copyright © 2019 The Author. Published by Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:94-101
Tari AR, Norevik CS, Scrimgeour NR, Kobro-Flatmoen A, ... Moreira JBN, Wisløff U
Prog Cardiovasc Dis: 30 Dec 1999; 62:94-101 | PMID: 30802460
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Impact:
Abstract

Personal Activity Intelligence (PAI): A new standard in activity tracking for obtaining a healthy cardiorespiratory fitness level and low cardiovascular risk.

Nauman J, Nes BM, Zisko N, Revdal A, ... Kaminsky LA, Wisløff U

Despite all the evidence of health benefits related to physical activity (PA) and cardiorespiratory fitness (CRF), low levels of PA have reached pandemic proportions, and inactivity is the fourth leading cause of death worldwide. Lack of time, and inability to self-manage are often cited as main barriers to getting adequate PA. Recently, a new personalized metric for PA tracking named Personal Activity Intelligence (PAI) was developed with the aim to make it easier to quantify how much PA per week is needed to reduce the risk of premature mortality from non-communicable diseases. PAI can be integrated in self-assessment heart rate devices and defines a weekly beneficial heart rate pattern during PA by considering the individual\'s sex, age, and resting and maximal heart rates. Among individuals ranging from the general population to subgroups of patients with cardiovascular disease (CVD), a PAI score ≥100 per week at baseline, an increase in PAI score, and a sustained high PAI score over time were found to delay premature death from CVD and all causes, regardless of whether or not the current PA recommendations were met. Importantly, a PAI score ≥100 at baseline, maintaining ≥100 PAIs and an increasing PAI score over time was associated with multiple years of life gained. Moreover, obtaining a weekly PAI ≥100 attenuated the deleterious association between CVD risk factor clustering and prolonged sitting time. PAI and objectively measured CRF (as indicated by VO) were positively associated in a graded fashion, and individuals with a PAI score between 100 and 150 had expected age and sex specific average VO values. A PAI score ≥100 was associated with higher VO in both men (4.1 mL·kg·min; 95% CI, 3.5 to 4.6) and women (2.9 mL·kg·min; 95% CI, 2.4 to 3.3), compared to the reference group of <100 PAI. The combined analysis of PAI, PA and VO demonstrated that a PAI score ≥100 was associated with high VO values regardless of meeting or not meeting the current PA recommendations. Collectively, these findings suggest that PAI has the potential to be a useful tool to motivate people to become and stay physically active by quantifying the amount of PA needed to produce significant health benefits.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:179-185
Nauman J, Nes BM, Zisko N, Revdal A, ... Kaminsky LA, Wisløff U
Prog Cardiovasc Dis: 30 Dec 1999; 62:179-185 | PMID: 30797801
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Abstract

Curing breast cancer and killing the heart: A novel model to explain elevated cardiovascular disease and mortality risk among women with early stage breast cancer.

Kirkham AA, Beaudry RI, Paterson DI, Mackey JR, Haykowsky MJ

Due to advances in prevention, early detection and treatment, early breast cancer mortality has decreased by nearly 40% during the last four decades. Yet, the risk of cardiovascular disease (CVD) mortality is significantly elevated following a breast cancer diagnosis, and it is a leading cause of death in this population. This review will discuss the most recent evidence for risks, pathology, mechanisms, and prevention of CVD morbidity and mortality in women with breast cancer. This evidence will be synthesized into a new model \'the compounding risk and protection model.\' This model proposes that the balance between risk factors (i.e., older age, pre-existing traditional CVD risk factors and shared biologic pathways for CVD and cancer such as inflammation, as well as treatment-related and lifestyle toxicity) and potential protection factors (i.e., lifelong non-smoking, regular physical activity, a healthy diet rich in fruits and vegetables, and management of body weight and stress, heart failure therapy) determine the individual risk of CVD morbidity and mortality after diagnosis of early breast cancer.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:116-126
Kirkham AA, Beaudry RI, Paterson DI, Mackey JR, Haykowsky MJ
Prog Cardiovasc Dis: 30 Dec 1999; 62:116-126 | PMID: 30797800
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Abstract

Physical activity, exercise and cardiac troponins: Clinical implications.

Aakre KM, Omland T

Cardiac troponins constitute essential components of the cardiac contractile apparatus and are released into the bloodstream following cardiomyocyte injury. Because of their cardiac specificity, cardiac troponin I or T are the recommended biomarkers for diagnosing acute myocardial infarction. However, cardiac troponin concentrations also frequently increase acutely after strenuous prolonged exercise, making the interpretation of cardiac troponin test results in patients presenting with acute chest pain challenging. This acute troponin response following exercise is commonly considered to be physiological and without adverse long-term consequences, but the possibility of exercise-induced, minor myocardial injury that may become clinically relevant if repeated over decades, has not been ruled out. Attempts to biochemically differentiate between physiological cardiac troponin release versus release after acute ischemic myocardial injury has so far proved largely unsuccessful, but future measurement of specific troponin fragments could be promising. Cardiac troponins also provide strong prognostic information across the spectrum of cardiovascular (CV) disease (CVD). In the chronic setting, low-level elevation of cardiac troponins has been associated with adverse outcome, and concentrations even within the normal range provide independent information concerning risk of developing heart failure (HF) and CVD death. Exercise exerts many beneficial effects on the CV system, and longitudinal observational data from epidemiological studies suggest that higher physical activity (PA) is associated with lower concentrations of cardiac troponins. Conversely, a sedentary life-style has been associated with higher cardiac troponin concentrations and a parallel increase in the risk of HF. Serial measurement of cardiac troponins using high sensitivity assays for monitoring the effect of life-style intervention, including PA appears promising.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:108-115
Aakre KM, Omland T
Prog Cardiovasc Dis: 30 Dec 1999; 62:108-115 | PMID: 30797799
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Impact:
Abstract

Active 10 - A new approach to increase physical activity in inactive people in England.

Brannan MGT, Foster CE, Timpson CM, Clarke N, ... Amlani A, Murphy MH

Public health physical activity (PA) guidelines are failing to increase levels of population PA, requiring a new approach. A national integrated marketing campaign was developed based on published literature and ethnographic research to get inactive lower socioeconomic 40-60 year olds to walk briskly for bouts of 10 or more minutes per day and move towards recommended levels of PA. National and local communications campaigns and partnerships promoted key messages and directed people to a free mobile phone app that provided the user with time, intensity and periodicity of walking, and included goal setting and encouragement to support behaviour change. Campaigns in the summers of 2017 and 2018 achieved around 500,000 downloads of the mobile phone app, with evaluation suggesting increases in brand and app awareness, and those taking action. Active 10 is a promising example of a physical activity promotion campaign based on evidence-based messages tailored for a target audience to change social norms rather than guidelines, an approach recognised as an effective population intervention for increasing walking.

Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:135-139
Brannan MGT, Foster CE, Timpson CM, Clarke N, ... Amlani A, Murphy MH
Prog Cardiovasc Dis: 30 Dec 1999; 62:135-139 | PMID: 30796943
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Abstract

Non-alcoholic fatty liver disease: Prevalence and all-cause mortality according to sedentary behaviour and cardiorespiratory fitness. The HUNT Study.

Croci I, Coombes JS, Bucher Sandbakk S, Keating SE, ... Macdonald GA, Wisloff U
Purpose
Sedentary behaviour (SB) and low physical activity (PA) are independently associated with non-alcoholic fatty liver disease (NAFLD). Compared to PA, high cardiorespiratory fitness (CRF) has been associated with a higher protection against all-cause mortality and a number of specific diseases. However, this relationship has not been investigated in NAFLD. This study examined the roles of SB and CRF on: i) the likelihood of having NAFLD in the general population, and ii) the risk of mortality over 9 years within individuals having NAFLD.
Methods
A cross-sectional analysis of 15,781 adults (52% female; age range 19-95 years) was conducted. Self-reported SB was divided into tertiles. CRF was estimated using validated non-exercise models, and the presence of NAFLD from the Fatty Liver Index. Adjusted Odds Ratios and 95% Confidence Intervals for NAFLD were estimated using logistic regression analyses. Hazard Ratios for all-cause mortality were estimated using Cox proportional hazard regression in individuals with NAFLD.
Results
For each additional 1 h/d of SB, the likelihood of having NAFLD was significantly increased by 4% (CI, 3-6%). In combined analyses, compared with the reference group [high CRF and low (≤4 h/d) SB], individuals with low CRF had a markedly higher likelihood of having NAFLD (OR, 16.9; CI 12.9-22.3), even if they had SB ≤ 4 h/d. High CRF attenuated the negative role of SB up to 7 h/d on NAFLD. Over 9.4 ± 1.3 years of follow-up, individuals with NAFLD and low CRF had the risk of mortality increased by 52% (CI, 10-106%) compared to those with high CRF, regardless of SB or meeting PA guidelines.
Conclusions
Low CRF increases the risk of premature death in individuals with NAFLD, and is strongly associated with higher likelihood of having NAFLD, outweighing the influence of SB.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 30 Dec 1999; 62:127-134
Croci I, Coombes JS, Bucher Sandbakk S, Keating SE, ... Macdonald GA, Wisloff U
Prog Cardiovasc Dis: 30 Dec 1999; 62:127-134 | PMID: 30796942
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Impact:
Abstract

Guidelines for the delivery and monitoring of high intensity interval training in clinical populations.

Taylor JL, Holland DJ, Spathis JG, Beetham KS, ... Keating SE, Coombes JS

High intensity interval training (HIIT) is now recognized in international clinical-based exercise guidelines as an appropriate and beneficial adjunct to moderate intensity continuous training. HIIT involves alternating periods of high intensity aerobic exercise with light recovery exercise or no exercise, allowing for greater physiological stimulus and adaptation than moderate intensity continuous training (MICT) for cardiorespiratory fitness and other cardiometabolic processes. However, there is no universal criteria or framework for the prescription and monitoring of HIIT in clinical populations, and safety concerns remain a common barrier for implementing HIIT as standard care. Historically, exercise intensity has been prescribed using heart rate (HR) targets derived from either a predicted maximal HR (HR) or from an attempt to objectively measure HR. However, using this approach alone has a number of limitations. Here we provide guidelines to improve the delivery of HIIT in cardiometabolic populations using 1) a framework for HIIT prescription using a combination of objective and subjective measures of exercise intensity, and 2) clinical considerations for assessment and monitoring to maximize patient safety. The framework involves an individualized step-by-step process to calculate, validate, and calibrate HR target zones for HIIT training to allow for appropriate workload prescription and progression. We strongly recommend this framework be used in future clinical trials investigating HIIT.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:140-146
Taylor JL, Holland DJ, Spathis JG, Beetham KS, ... Keating SE, Coombes JS
Prog Cardiovasc Dis: 30 Dec 1999; 62:140-146 | PMID: 30685470
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Impact:
Abstract

Implementing behaviour change theory and techniques to increase physical activity and prevent functional decline among adults aged 61-70: The PreventIT project.

Boulton E, Hawley-Hague H, French DP, Mellone S, ... Vereijken B, Todd C

The health and wellbeing benefits of engaging in physical activity (PA), and of improving strength and balance, are well documented. The World Health Organization\'s recommendations of 150 min per week of moderate intensity physical activity have been adopted across the world in policy and practice recommendations. However, the number of older adults engaging in this level of PA remains low. The European Project, PreventIT, has adapted the Lifestyle-integrated Functional Exercise (LiFE) programme, which reduced falls in people 75 years and over, for a younger cohort (aLiFE). aLiFE incorporates challenging strength and balance/agility tasks, as well as specific recommendations for increasing physical activity and reducing sedentary behaviour in young-older adults, aged 60-70 years. Personalised advice is given on how to integrate strength, balance and physical activities into daily life. aLiFE has been further developed to be delivered using smartphones and smartwatches (eLiFE), providing the opportunity to send timely motivational messages and real-time feedback to the user. Both aLiFE and eLiFE are behaviour change interventions, supporting older adults to form long-term physical activity habits. PreventIT has taken the original LiFE concept and further developed the behaviour change elements, explicitly mapping them to Social Cognitive Theory, Habit Formation Theory and 30 Behaviour Change Techniques (BCTs). Goal setting, planning, prompts and real-time feedback are used to deliver a person-centred experience. Over 1300 motivational messages have been written, mapped to psychological theory, BCTs and evidence regarding the importance of strength, balance and PA. A motivational assessment tool has been developed to enable us to investigate stated motivational drivers with actual performed behaviour within the feasibility Randomised Controlled Trial. The PreventIT mHealth intervention focusses on behaviour change from initiation to long-term maintenance, addressing the different phases of adopting a healthier lifestyle. As such, it makes a strong contribution to the developing field of evidence-based mobile health (mHealth).

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:147-156
Boulton E, Hawley-Hague H, French DP, Mellone S, ... Vereijken B, Todd C
Prog Cardiovasc Dis: 30 Dec 1999; 62:147-156 | PMID: 30685469
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Impact:
Abstract

Precision medicine and healthy living: The importance of the built environment.

Hills AP, Farpour-Lambert NJ, Byrne NM

The built environment encompasses the major physical spaces, including buildings, streets, homes, schools, parks, playgrounds and other infrastructure in which we live, work and play. In an ideal world, the built environment should support and facilitate a healthy engagement in physical activity across the lifespan. However, in the context of an environment characterized by increased mechanization and urbanization, physical inactivity and higher levels of overweight and obesity, too many settings are not conducive to physical activity and/or are not safe and walkable. In the knowledge that there are multiple challenges to redress the low levels of physical activity seen in many parts of the world, this paper provides some examples of opportunities for healthy living (HL) in a built environment characteristic of an increasingly urbanized world. Particular foci include opportunities for HL fostered in child-friendly cities, in which walkability is high, and active transport is encouraged and supported.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:34-38
Hills AP, Farpour-Lambert NJ, Byrne NM
Prog Cardiovasc Dis: 30 Dec 1999; 62:34-38 | PMID: 30639136
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Impact:
Abstract

Cardiorespiratory fitness and cardiovascular disease - The past, present, and future.

Kaminsky LA, Arena R, Ellingsen Ø, Harber MP, ... Ozemek C, Ross R

The importance of cardiorespiratory fitness (CRF) is now well established and it is increasingly being recognized as an essential variable which should be assessed in health screenings. The key findings that have established the clinical significance of CRF are reviewed in this report, along with an overview of the current relevance of exercise as a form of medicine that can provide a number of positive health outcomes, including increasing CRF. Current assessment options for assessing CRF are also reviewed, including the direct measurement via cardiopulmonary exercise testing which now can be interpreted with age and sex-specific reference values. Future directions for the use of CRF and related measures are presented.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:86-93
Kaminsky LA, Arena R, Ellingsen Ø, Harber MP, ... Ozemek C, Ross R
Prog Cardiovasc Dis: 30 Dec 1999; 62:86-93 | PMID: 30639135
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Impact:
Abstract

Precision Measurements to Assess Baseline Status and Efficacy of Healthy Living Medicine.

Hwang CL, Bishop J, Ching J, Elokda A, ... Laddu D, Phillips SA

Precision medicine recently has gained popularity, calling for more individualized approaches to prevent and/or reduce chronic-disease risk and to reduce non-communicable diseases such as cardiovascular disease (CVD). Encompassed under Precision medicine initiatives is the concept of healthy living medicine (HLM), which emphasizes the promotion of lifestyle and behavioral practices including physical activity and healthy dietary pattern. Precision measurements have the potential to improve the understanding of how risk factors influence disease trajectory, and further inform on how to precisely tailor clinical strategies to manage risk factors to prevent disease manifestation, and refine therapies according the patient\'s demographic, environment, and disease etiology. The purpose of this review is to summarize the application of established and emerging measurements that may be used in HLM to manage and optimize care in CVD prevention.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:55-59
Hwang CL, Bishop J, Ching J, Elokda A, ... Laddu D, Phillips SA
Prog Cardiovasc Dis: 30 Dec 1999; 62:55-59 | PMID: 30610884
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Impact:
Abstract

Furthering Precision Medicine Genomics With Healthy Living Medicine.

Standley RA, Vega RB

The Precision Medicine Initiative seeks to develop new approaches for disease treatment and prevention that considers the individual variation in genes, environment, and lifestyle for each person. To date, the focus has been on genetic drivers of disease risk and development but has now begun to incorporate lifestyle induced changes in phenotype to enhance treatments. Healthy Living Medicine is an emerging paradigm that focuses on moving more and sitting less, consuming a healthy diet, maintaining body weight and not smoking. A wealth of clinical trials has demonstrated the protective effects of high cardiorespiratory fitness, physical activity (PA), and exercise on all-cause mortality, and prevention of developing cardiovascular disease (CVD), obesity and type 2 diabetes (T2D). This review will summarize the impact of PA and exercise on modifying risk of disease from genetics in the general population and those with CVD, obesity and T2D.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:60-67
Standley RA, Vega RB
Prog Cardiovasc Dis: 30 Dec 1999; 62:60-67 | PMID: 30610883
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Impact:
Abstract

Outcomes of Healthy Eating Ad Campaigns: A Systematic Review.

Abril EP, Dempsey PR

Social marketing campaigns seeking to promote healthy eating hold promise in precision messaging and behavior change related to a key component of healthy living medicine. A systematic review that examines the behaviors promoted against their success is lacking. Of interest is the consideration of stop or go behaviors, such as not eating fast food or increasing the consumption of fruits and vegetables, respectively. We systematically searched five databases for peer-reviewed quantitative articles examining healthy eating campaigns that included at least one ad. We found evidence that campaigns with both stop and go outcomes (such as swapping) and outcomes that were not clarifying whether they were stop or go (such as calling a coach) tended to be more successful than campaigns with simple stop or go outcomes. Further, campaigns that were longer than six months seemed consistently successful. However, with 14 included studies, it is clear that further research is needed.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:39-43
Abril EP, Dempsey PR
Prog Cardiovasc Dis: 30 Dec 1999; 62:39-43 | PMID: 30610882
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Impact:
Abstract

Precision Medicine in Weight Loss and Healthy Living.

Severin R, Sabbahi A, Mahmoud AM, Arena R, Phillips SA

Obesity affects 600 million people globally and over one third of the American population. Along with associated comorbidities, including cardiovascular disease, stroke, diabetes, and cancer; the direct and indirect costs of managing obesity are 21% of the total medical costs. These factors shed light on why developing effective and pragmatic strategies to reduce body weight in obese individuals is a major public health concern. An estimated 60-70% of obese Americans attempt to lose weight each year, with only a small minority able to achieve and maintain long term weight loss. To address this issue a precision medicine approach for weight loss has been considered, which places an emphasis on sustainability and real-world application to individualized therapy. In this article we review weight loss interventions in the context of precision medicine and discuss the role of genetic and epigenetic factors, pharmacological interventions, lifestyle interventions, and bariatric surgery on weight loss.

Copyright © 2018. Published by Elsevier Inc.

Prog Cardiovasc Dis: 30 Dec 1999; 62:15-20
Severin R, Sabbahi A, Mahmoud AM, Arena R, Phillips SA
Prog Cardiovasc Dis: 30 Dec 1999; 62:15-20 | PMID: 30610881
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Impact:
Abstract

Precision Medicine, Healthy Living and the Complex Patient: Managing the Patient With Multimorbidity.

Holland AE, Lee AL

Multimorbidity is the most common chronic health condition in adults and is associated with poor health outcomes. Optimal care for people with multimorbidity requires a person-centred approach that considers goals and preferences, improves quality of life and coordinates care across services. Because care is focused on patient outcomes, rather than disease outcomes, this provides an ideal setting for delivery of the Healthy Living Polypill (HLPP). Precision in delivery of the HLPP for people with multimorbidity involves active participation of patients in goal setting, strategies to address functional limitations and frailty, and support to develop the self-management skills necessary to adopt and sustain healthy behaviours. The multidisciplinary team is a key feature of integrated care for people with multimorbidity and all members should have the necessary skills to deliver the HLPP. Integration and continuity across health and social care sectors enhances outcomes and increases opportunities for personalised delivery of the HLPP.

Copyright © 2019 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:29-33
Holland AE, Lee AL
Prog Cardiovasc Dis: 30 Dec 1999; 62:29-33 | PMID: 30610880
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Impact:
Abstract

Advances in Health Technology Use and Implementation in the Era of Healthy Living: Implications for Precision Medicine.

Phillips SA, Ali M, Modrich C, Oke S, ... Laddu D, Bond S

Much of the focus of precision medicine has been directed toward genomics, despite the fact that \"lifestyle and behavioral factors\" are included in the description of precision medicine. Numerous structured diet and PA interventions have demonstrated success in preventing and/or reducing chronic-disease risk. The use of personal health technologies has expanded exponentially in the health care arena; there are a number of consumer-based technologies yielding health information to individual users. The explosion in technology use provides an opportunity for broader dissemination of health care services and products. In addition, tracking cardiovascular disease risk and lifestyle and behavioral aspects of healthy living (HL) profiles in those products may be an important leveraging interface for precision medicine. This review will discuss and present an overview of current health technologies, their use in promotion of HL metrics and how this data may be integrated into venues that support HL and precision medicine.

Copyright © 2018. Published by Elsevier Inc.

Prog Cardiovasc Dis: 30 Dec 1999; 62:44-49
Phillips SA, Ali M, Modrich C, Oke S, ... Laddu D, Bond S
Prog Cardiovasc Dis: 30 Dec 1999; 62:44-49 | PMID: 30597149
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Impact:
Abstract

The Contribution of Psychosocial Interventions to Precision Medicine for Heart Health.

Flynn M, Moran C, Rash JA, Campbell TS

This paper reviews the value of incorporating psychosocial interventions into precision medicine for heart health. First, we review the empirical literature on prevalence of common mental health comorbidities among individuals with cardiovascular disease (CVD). We then review transdiagnostic approaches for conceptualization and treatment of mental health in individuals with CVD. We highlight recent studies that have used novel methods to individualize psychosocial interventions. Finally, we propose a preliminary framework intended to support Health Care Providers in individualizing treatment, which includes: 1) assessment of patient risk factors, characteristics, and expectations; 2) consideration of transdiagnostic processes underlying several psychiatric symptoms that contribute to CVD risk; 3) patient engagement in shared decision-making for psychosocial treatment; and 4) ongoing outcome monitoring to evaluate treatment responsiveness. We anticipate that the proposed framework will evolve with the emergence of new empirical evidence; as such, future directions and challenges for research are discussed.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:21-28
Flynn M, Moran C, Rash JA, Campbell TS
Prog Cardiovasc Dis: 30 Dec 1999; 62:21-28 | PMID: 30576681
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Impact:
Abstract

Managing the Economic Challenges in the Treatment of Heart Failure.

Piña IL, Desai NR, Allen LA, Heidenreich P

The economics of heart failure (HF) touches all patients with HF, their families, and the physicians and health systems that care for them. HF is specifically targeted by cost-reduction and care quality initiatives from the Centers for Medicare and Medicaid Services (CMS). The changing quality assessment and payment landscape is, and will continue to be, challenging for hospitals and HF specialists as they provide care for patients with this debilitating disease. Quality-based payment systems with evolving performance metrics are replacing traditional volume-based fee-for-service models. A critical objective of quality-based models is to improve care and reduce cost, but there are few data to support decision-making on how to improve. CMS payment programs and their implications for health systems treating HF were reviewed at a symposium at the Heart Failure Society of America conference in Nashville, Tennessee on September 15, 2018. This article constitutes the proceedings from that symposium.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:476-483
Piña IL, Desai NR, Allen LA, Heidenreich P
Prog Cardiovasc Dis: 30 Dec 1999; 61:476-483 | PMID: 30565564
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Impact:
Abstract

Addressing the Nutritional Phenotype Through Personalized Nutrition for Chronic Disease Prevention and Management.

Laddu D, Hauser M

The primary focus of public health recommendations related to the prevention of food-related chronic disease has been on the adoption of healthy dietary patterns; however, implementation has been challenging. There has been increasing recognition that an individual\'s diet and environment may impact disease susceptibility by affecting the expression of genes involved in critical metabolic pathways. Precision nutrition (PN) has emerged to translate discoveries about diversity in nutrient metabolism between subgroups and the inter-individual variability in the responses to dietary interventions. The overarching goals of PN are to deliver individualized, actionable dietary therapy based on an individual\'s nutritional phenotype, created from the integration of genetics, metabolic profile, and environmental factors in order to prevent and treat chronic disease. This review addresses the developments of genome- and omic-driven PN and how they have been used to prevent and treat disease, as well as how they might be integrated into broader clinical practice.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:9-14
Laddu D, Hauser M
Prog Cardiovasc Dis: 30 Dec 1999; 62:9-14 | PMID: 30553801
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Impact:
Abstract

The Association between the Change in Directly Measured Cardiorespiratory Fitness across Time and Mortality Risk.

Imboden MT, Harber MP, Whaley MH, Finch WH, ... Fleenor BS, Kaminsky LA
Background
The relationship between cardiorespiratory fitness (CRF) and mortality risk has typically been assessed using a single measurement, though some evidence suggests the change in CRF over time influences risk. This evidence is predominantly based on studies using estimated CRF (CRF). The strength of this relationship using change in directly measured CRF over time in apparently healthy men and women is not well understood.
Purpose
To examine the association of change in CRF over time, measured using cardiopulmonary exercise testing (CPX), with all-cause and disease-specific mortality and to compare baseline and subsequent CRF measurements as predictors of all-cause mortality.
Methods
Participants included 833 apparently healthy men and women (42.9 ± 10.8 years) who underwent two maximal CPXs, the second CPX being ≥1 year following the baseline assessment (mean 8.6 years, range 1.0 to 40.3 years). Participants were followed for up to 17.7 (SD 11.8) years for all-cause-, cardiovascular disease- (CVD), and cancer mortality. Cox-proportional hazard models were performed to determine the association between the change in CRF, computed as visit 1 (CPX1) peak oxygen consumption (VO [mL·kg·min]) - visit 2 (CPX2) VO, and mortality outcomes. A Wald-Chi square test of equality was used to compare the strength of CPX1 to CPX2 VO in predicting mortality.
Results
During follow-up, 172 participants died. Overall, the change in CPX-CRF was inversely related to all-cause, CVD, and cancer mortality (p < 0.05). Each 1 mL·kg·min increase was associated with a ~11, 15, and 16% (all p < 0.001) reduction in all-cause, CVD, and cancer mortality, respectively. The inverse relationship between CRF and all-cause mortality was significant (p < 0.05) when men and women were examined independently, after adjusting for years since first CPX, baseline VO, and age. Further, the Wald Chi-square test of equality found CPX2 VO to be a significantly stronger predictor of all-cause mortality than CPX1 VO (p < 0.05).
Conclusion
The change in CRF over time was inversely related to mortality outcomes, and mortality was better predicted by CRF measured at subsequent test than CPX1 CRF. These findings emphasize the importance of adopting lifestyle behaviors that promote CRF, as well as support the need for routine assessment of CRF in clinical practice to better assess risk.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:157-162
Imboden MT, Harber MP, Whaley MH, Finch WH, ... Fleenor BS, Kaminsky LA
Prog Cardiovasc Dis: 30 Dec 1999; 62:157-162 | PMID: 30543812
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Impact:
Abstract

The Role of Government in Precision Medicine, Precision Public Health and the Intersection With Healthy Living.

Whitsel LP, Wilbanks J, Huffman MD, Hall JL

This paper focuses on the significant role of government in promoting precision medicine and public health and the potential intersection with healthy living (HL) and population health. Recent research has highlighted the interplay between genes, environments and different exposures individuals and populations experience over a lifetime. These interactions between longitudinal behaviors, epigenetics, and expression of the human genome have the potential to transform health and well-being, even within a single generation. Precision medicine can elucidate these longitudinal interactions with a granularity that has not been previously possible across the exposome. Understanding the interactions between genes, epigenetics, proteins, metabolites, and the exposome may inform more evidence-based, effective policy, system, and environmental change to optimize individual and population health. Government has an important role in helping to fund primary research in precision medicine and precision public health, as well as creating and enforcing standards related to food systems, air quality, and access to health care, defining and optimizing measures of health care quality and safety, and ensuring data privacy standards and protections, interoperability, and integration with surveillance systems. Government partnership and collaboration with the non-profit and private sectors can optimize precision medicine and precision public health for the benefit of the United States and global population.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:50-54
Whitsel LP, Wilbanks J, Huffman MD, Hall JL
Prog Cardiovasc Dis: 30 Dec 1999; 62:50-54 | PMID: 30529579
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Impact:
Abstract

Precision in Promoting Physical Activity and Exercise With the Overarching Goal of Moving More.

Ozemek C, Arena R

Physical inactivity is strongly associated with an unfavorable health profile, increasing an individual\'s risk for developing cardiovascular disease. Initiating a regular exercise routine contributes to improvements in cardiorespiratory fitness, body composition, resting blood pressure, blood glucose, and circulating lipoproteins. However, the extent to which positive changes occur come with significant inter-individual variability within intervention groups; non-responders and responders have been commonly identified across populations, highlighting that not all exercise regimens are universally effective in all individuals and should therefore not be treated as a \"one-size fits all\" prescription. Recent studies have therefore emphasized reporting the quantity of participants favorably and meaningfully \"responding\" to varying amounts and intensities of exercise, thereby presenting the opportunity to view exercise prescription in the context of precision medicine. This review will address the impact of varying amounts and intensities of physical activity and exercise, highlighting their impact on key health metrics.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:3-8
Ozemek C, Arena R
Prog Cardiovasc Dis: 30 Dec 1999; 62:3-8 | PMID: 30529578
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Impact:
Abstract

Role of Transesophageal Echocardiography in Patients with Ischemic Stroke.

Stewart MH, Gilliland Y

Acute ischemic stroke is a condition with considerable mortality and morbidity. When used appropriately, Transesophageal Echocardiography (TEE) can be an incredibly useful tool to identify potential causes of stroke and guide management. The crucial distinction in this modality lies in separating common incidental findings from those likely to have contributed to ischemic stroke. Furthermore, the management of identified intracardiac causes varies widely from open surgery to antiplatelet therapy. This review seeks to discuss the role of TEE in identifying common etiologies of cardioembolic stroke, review the clinical entities, and the highlight the most recent management recommendations.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:456-467
Stewart MH, Gilliland Y
Prog Cardiovasc Dis: 30 Dec 1999; 61:456-467 | PMID: 30465774
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Impact:
Abstract

Echocardiography in Transcatheter Structural Heart Disease Interventions.

Patel H, Raisinghani A, DeMaria A

Interventional echocardiography is an emerging field with growing interest and applications as therapeutic procedures to address structural heart disease (SHD) continue to evolve and expand. As opposed to coronary interventions, in which the course of catheter movement is constrained within the artery, percutaneous procedures for SHD entail free catheter movement within the heart and great vessels. Imaging guidance in 3-dimensional space is therefore of critical importance to the successful performance of these procedures. The complexity of these procedures requires an imager with a complete knowledge of ultrasound instrumentation and technique, an in-depth knowledge of cardiac anatomy, understanding of the procedural steps involved, and an awareness of potential complications that may arise perioperatively. Echocardiography, especially 3-dimensional transesophageal echocardiography, plays a crucial role in every aspect of percutaneous interventions, from patient selection to final device assessment. This review will focus on the role of echocardiography and the echocardiographer with respect to transcatheter guidance for the spectrum of SHD interventions that have gained worldwide application in recent years.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:423-436
Patel H, Raisinghani A, DeMaria A
Prog Cardiovasc Dis: 30 Dec 1999; 61:423-436 | PMID: 30465773
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Impact:
Abstract

Doppler-Echocardiographic Assessment of Tricuspid Regurgitation.

Topilsky Y, Michelena HI, Messika-Zeitoun D, Enriquez Sarano M

Compared with the vast literature concerning the echocardiographic assessment of mitral, or aortic disease, the data concerning the evaluation of tricuspid regurgitation (TR) is very limited. In this review we summarized the present data concerning the assessment of TR. We review the present knowledge concerning the pathogenesis of TR showing that it is extremely multi-factorial, thus, when assessing patients with TR by echocardiography it is imperative to focus on four major aspects: evaluation of severity of TR, assessment of the etiology of TR, evaluation of the mechanism of TR and suitability for surgical or per-cutaneous repair.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:397-403
Topilsky Y, Michelena HI, Messika-Zeitoun D, Enriquez Sarano M
Prog Cardiovasc Dis: 30 Dec 1999; 61:397-403 | PMID: 30447222
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Impact:
Abstract

Echocardiography in Congenital Heart Disease.

Mcleod G, Shum K, Gupta T, Chakravorty S, ... White M, Shah SB

As the prevalence of adult congenital heart disease continues to grow secondary to advances in surgical and diagnostic techniques, it is important for a physician to supplement their examinations with non-invasive imaging techniques to assess their patients. Although a number of these patients have regular cardiology followup, some may be new patients that do not even know their cardiac history. Echocardiography has proven to be a useful tool for this purpose and its utility has expanded drastically with the development of better technology and newer techniques. In this article, we highlight some of these advancements including 2D echocardiography, agitated saline, contrast echocardiography, stress, and 4D, in addition to how each modality can help assess key aspects of the structure and function of a congenital heart defect.

Copyright © 2018. Published by Elsevier Inc.

Prog Cardiovasc Dis: 30 Dec 1999; 61:468-475
Mcleod G, Shum K, Gupta T, Chakravorty S, ... White M, Shah SB
Prog Cardiovasc Dis: 30 Dec 1999; 61:468-475 | PMID: 30445162
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Impact:
Abstract

Low-Gradient Aortic Stenosis: Solving the Conundrum Using Multi-Modality Imaging.

Messika-Zeitoun D, Oh JK, Topilsky Y, Burwash IG, Michelena HI, Enriquez-Sarano M

Up to 1/3 of patients with both reduced or preserved left ventricular ejection fraction (LVEF), harbor a mean pressure gradient (MPG) < 40 mm Hg (peak velocity (PV) < 4 m/s), suggesting moderate aortic stenosis (AS) and an aortic valve area (AVA) < 1 cm suggesting severe AS raising uncertainties regarding AS severity and appropriate management. In patients with reduced LVEF, increased transvalvular flow and stroke volume ≥ 20% (i.e. contractile reserve) during low-dose dobutamine echocardiography enables distinguishing patients with \"true-severe AS\" (severe AS with secondary LV dysfunction, PV ≥ 4 m/s or MPG > 30-40 mm Hg at peak while AVA remains <1 cm) from patients with \"pseudo-severe AS\" (moderate AS with associated LV dysfunction due to ischemic or dilated cardiomyopathy, AVA at peak ≥1 cm with a MPG < 30-40 mm Hg). However, interpretation of dobutamine stress echocardiography is often challenging, and absence of contractile reserve is observed in 20 to 30% of patients. Measurement of the degree of calcification (AVC) using computed tomography is an accurate and flow-independent method for the assessment of AS severity. A score > 1250 AU in women and >2000 UA in men strongly suggest severe AS. Combination of dobutamine echocardiography and AVC scoring enables assessment of AS severity with high confidence. The subset of patients with discordant grading and preserved LVEF is heterogenous and encompasses various conditions. A minority harbor a low flow state related to a reduced myocardial performance, an increased arterial afterload or combination of both. A low flow state is an important prognostic factor but does not provide any information regarding AS severity. Similarly to patients with reduced LVEF, assessment of the degree of AVC seems the best method to differentiate patients with pseudo-severe AS from patients with true severe AS. The latter should be referred for an intervention if symptomatic whereas the optimal management of the former subset remains uncertain.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:416-422
Messika-Zeitoun D, Oh JK, Topilsky Y, Burwash IG, Michelena HI, Enriquez-Sarano M
Prog Cardiovasc Dis: 30 Dec 1999; 61:416-422 | PMID: 30445161
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Impact:
Abstract

An Update on the Role of Cardiorespiratory Fitness, Structured Exercise and Lifestyle Physical Activity in Preventing Cardiovascular Disease and Health Risk.

Ozemek C, Laddu DR, Lavie CJ, Claeys H, ... Arena R, Blair SN

The cardiovascular disease (CVD) pandemic has placed considerable strain on healthcare systems, quality of life, and physical function, while remaining the leading cause of death globally. Decades of scientific investigations have fortified the protective effects of cardiorespiratory fitness (CRF), exercise training, and physical activity (PA) against the development of CVD. This review will summarize recent efforts that have made significant strides in; 1) the application of novel analytic techniques to increase the predictive utility of CRF; 2) understanding the protective effects of long-term compliance to PA recommendations through large cohort studies with multiple points of assessment; 3) and understanding the potential harms associated with extreme volumes of PA.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:484-490
Ozemek C, Laddu DR, Lavie CJ, Claeys H, ... Arena R, Blair SN
Prog Cardiovasc Dis: 30 Dec 1999; 61:484-490 | PMID: 30445160
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Abstract

Prognostic Implications of Left Ventricular Hypertrophy.

Stewart MH, Lavie CJ, Shah S, Englert J, ... Ventura H, Milani R

Left ventricular hypertrophy (LVH) was one of the earliest studied echocardiographic characteristics of the left ventricle. As the myriad of measurable metrics has multiplied over recent years, this reliable and relevant variable can often be overlooked. In this paper, we discuss appropriate techniques for accurate analysis, underlying pathophysiology, and the contributions from various risk factors. The prognostic implications of LVH on stroke, serious arrhythmias, and sudden cardiac death are reviewed. Finally, we examine the effect of therapy to reduce LVH and the resultant clinical outcomes.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:446-455
Stewart MH, Lavie CJ, Shah S, Englert J, ... Ventura H, Milani R
Prog Cardiovasc Dis: 30 Dec 1999; 61:446-455 | PMID: 30408469
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Abstract

Is Speckle Tracking Imaging Ready for Prime Time in Current Echo Clinical Practice?

Luis SA, Pellikka PA

Accurate assessment of left and right ventricular systolic function plays a fundamental role in the prognostication and management of patients with known or suspected cardiovascular disease. Traditional echocardiographic parameters, including left ventricular ejection fraction, may lack the sensitivity to detect subclinical left ventricular systolic dysfunction. The advent of speckle tracking echocardiography for left and right ventricular systolic function assessment provides a further tool in this evaluation. Speckle tracking echocardiography has been demonstrated to provide incremental prognostic value beyond traditional echocardiographic parameters. This review discusses the clinical application of speckle tracking echocardiography in the evaluation of cardiovascular disease and its implementation within the clinical echocardiography laboratory.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:437-445
Luis SA, Pellikka PA
Prog Cardiovasc Dis: 30 Dec 1999; 61:437-445 | PMID: 30408468
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Abstract

The Bicuspid Aortic Valve Condition: The Critical Role of Echocardiography and the Case for a Standard Nomenclature Consensus.

Michelena HI, Chandrasekaran K, Topilsky Y, Messika-Zeitoun D, ... Enriquez-Sarano M,

The bicuspid aortic valve (BAV) condition is characterized by prominent heterogeneity of its valvular phenotypic expression, of its associated disorders, its complications and its prognosis. Echocardiography serves as the first-line imaging modality in 5 major capacities: (1) BAV diagnosis, (2) valvular phenotyping, (3) assessment of valvular function, (4) measurement of the thoracic aorta and exclusion of aortic coarctation, and (5) assessment of uncommon but serious complications such as infective endocarditis and aortic dissection. This article presents a nosological perspective on the BAV condition, discusses the critical role of echocardiography as it relates to these 5 aforementioned capacities; and makes the case for a unified standard nomenclature for the BAV condition.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:404-415
Michelena HI, Chandrasekaran K, Topilsky Y, Messika-Zeitoun D, ... Enriquez-Sarano M,
Prog Cardiovasc Dis: 30 Dec 1999; 61:404-415 | PMID: 30408467
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Abstract

Determining Cardiorespiratory Fitness With Precision: Compendium of Findings From the FRIEND Registry.

Kaminsky LA, Myers J, Arena R

Healthy living (HL) behaviors and characteristics are central to both preventing and treating a myriad of chronic diseases; a key HL characteristic is cardiorespiratory fitness (CRF). Knowing an individual\'s CRF provides vital information when assessing health status and formulating a plan of care. Normative reference values as well as thresholds that denote varying degrees of health and future risk exist for measures of CRF. However, improving upon the precision of CRF reference standards according to key factors as well as precision in how CRF assessments can be used to assess health status and prognosis is needed. The current review will: 1) provide an overview of current approaches to CRF assessment and interpretations; 2) describe more recent efforts to improve upon the precision of CRF values; and 3) describe the Fitness Registry and the Importance of Exercise: A National Data Base (FRIEND) for the precision of CRF as a clinical measure.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:76-82
Kaminsky LA, Myers J, Arena R
Prog Cardiovasc Dis: 30 Dec 1999; 62:76-82 | PMID: 30385268
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Abstract

Advanced Imaging Techniques for Mitral Regurgitation.

Quien MM, Vainrib AF, Freedberg RS, Bamira DG, ... Williams MR, Saric M

Mitral regurgitation (MR) is one of the most commonly encountered valvular lesions in clinical practice. MR can be either primary (degenerative) or secondary (functional) depending on the etiology of MR and the pathology of the mitral valve (MV). Echocardiography is the primary diagnostic tool for MR and is key in determining this etiology as well as MR severity. While clinicians usually turn to 2 Dimensional echocardiography as first-line imaging, 3 Dimensional echocardiography (3DE) has continually shown to be superior in terms of describing MV anatomy and pathology. This review article elaborates on 3DE techniques, modalities, and advances in software. Furthermore, the article demonstrates how 3DE has reformed MR evaluation and has played a vital role in determining patient management.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:390-396
Quien MM, Vainrib AF, Freedberg RS, Bamira DG, ... Williams MR, Saric M
Prog Cardiovasc Dis: 30 Dec 1999; 61:390-396 | PMID: 30321560
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Abstract

The Importance of School-based Healthy Living Initiatives: Introducing the Health and Wellness Academy Concept.

Strieter L, Laddu DR, Sainsbury J, Arena R

Over the last 15 years, the number of school and community based health-intervention programs in the United States has grown. Many of these programs aim to prevent non-communicable chronic disease diagnoses (e.g., obesity, cardiovascular disease and type-2 diabetes). The Department of Physical Therapy in the College of Applied Health Sciences (CAHS) at the University of Illinois at Chicago (UIC) created a school-based wellness program (SBWP) that focuses on nutrition and physical activity, providing tailored experiences that motivate adolescents to make healthier lifestyle choices. The SBWP began as a camp for children in the surrounding neighborhoods and implemented healthy living practices utilizing students from Departments in the CAHS. From this camp, the Health and Wellness Academy (HWA) evolved. This paper provides a review of school-based initiatives and introduces the UIC HWA, an innovative and reproducible approach that can bring positive environmental change by improving health outcomes for children and their families.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:68-73
Strieter L, Laddu DR, Sainsbury J, Arena R
Prog Cardiovasc Dis: 30 Dec 1999; 62:68-73 | PMID: 30236752
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Abstract

Long Term Consequences of the Fontan Procedure and How to Manage Them.

Kay WA, Moe T, Suter B, Tennancour A, ... Krasuski RA, Zaidi AN

In 1971, Fontan and Baudet described a surgical technique for successful palliation of patients with tricuspid atresia. Subsequently, this technique has been applied to treat most forms of functional single ventricles and has become the current standard of care for long-term palliation of all patients with single ventricle congenital heart disease. Since 1971, the Fontan procedure has undergone several variations. These patients require lifelong management including a thorough knowledge of their anatomic substrate, hemodynamic status, management of rhythm and ventricular function along with multi organ evaluation. As these patients enter middle age, there is increasing awareness regarding the long-term complications and mortality. This review highlights the long-term outcomes of the Fontan procedure and management of late sequelae.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:365-376
Kay WA, Moe T, Suter B, Tennancour A, ... Krasuski RA, Zaidi AN
Prog Cardiovasc Dis: 30 Dec 1999; 61:365-376 | PMID: 30236751
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Abstract

Transcatheter Valve Replacement for Right-sided Valve Disease in Congenital Heart Patients.

Gales J, Krasuski RA, Fleming GA

Pulmonary and/or tricuspid valve dysfunction is common among individuals with congenital heart disease, and surgical intervention often carries prohibitive risks. Transcatheter valve replacement (TVR) of the right-sided cardiac valves has become a viable treatment option over the past two decades, while continued technological development aims to broaden its applicability to an even larger portion of those with repaired congenital heart disease. To date, two transcatheter valves have been approved for use in patients with dysfunctional right ventricular to pulmonary artery conduits as well as those with failing pulmonic bioprosthetic valves, and are also used off-label in the \"native\" RVOT and within surgically repaired/replaced but failing tricuspid valves. TVR has demonstrated comparable safety and short-term outcomes to that of surgical valve replacement. This article aims to review current available devices, focusing on their safety, efficacy and on and off label usage, while briefly describing some of the emerging devices and novel procedural techniques that will likely lead to significant expansion of transcatheter treatment of right sided valve disease in the future.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:347-359
Gales J, Krasuski RA, Fleming GA
Prog Cardiovasc Dis: 30 Dec 1999; 61:347-359 | PMID: 30236750
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Abstract

When Should Adult Congenital Heart Disease Patients be Considered for Transplant and Deciding Which Organs to Transplant.

Lewis M, Rosenbaum M

The number of adult congenital heart disease (ACHD) patients continues to increase. Because of multiple related factors such as aging, residual cardiac lesions and prior palliative procedures, advanced heart failure (HF) is increasingly prevalent in this population. Consequently, there is an emerging need to determine which patients are best suited for advanced cardiac therapies, including heart transplantation (HT) and mechanical circulatory support. Unfortunately, optimizing patient selection for these therapies is complicated by patient heterogeneity, variable HF presentation across lesion-type, and a paucity of outcome data. The lack of patient specific data and the increasing number of ACHD patients with end-stage HF identifies a need to more precisely stratify risk and determine appropriate timing for referral. As such, this article will discuss the clinical recognition and classification of advanced HF in the ACHD patient populations and review current data regarding HT outcomes. Following, key considerations regarding the timing of HT in specific forms of ACHD, the role of device therapy, and when dual organ transplantation should be considered will be reviewed. Finally, existing knowledge gaps and key research needs will be highlighted.

Copyright © 2018. Published by Elsevier Inc.

Prog Cardiovasc Dis: 30 Dec 1999; 61:377-381
Lewis M, Rosenbaum M
Prog Cardiovasc Dis: 30 Dec 1999; 61:377-381 | PMID: 30227188
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Abstract

Meta-analysis of Exercise Training on Left Ventricular Ejection Fraction in Heart Failure with Reduced Ejection Fraction: A 10-year Update.

Tucker WJ, Beaudry RI, Liang Y, Clark AM, ... Ellingsen O, Haykowsky MJ
Background
The role of exercise training modality to attenuate left ventricular (LV) remodeling in heart failure patients with reduced ejection fraction (HFrEF) remains uncertain. The authors performed a systematic review and meta-analysis of published reports on exercise training (moderate-intensity continuous aerobic, high-intensity interval aerobic, and resistance exercise) and LV remodeling in clinically stable HFrEF patients.
Methods
We searched MEDLINE, Cochrane Central Registry of Controlled Trials, CINAHL, and PubMed (2007 to 2017) for randomized controlled trials of exercise training on resting LV ejection fraction (EF) and end-diastolic and end-systolic volumes in HFrEF patients.
Results
18 trials reported LV ejection fraction (LVEF) data, while 8 and 7 trials reported LV end-diastolic and LV end-systolic volumes, respectively. Overall, moderate-intensity continuous training (MICT) significantly increased LVEF (weighted mean difference, WMD = 3.79%; 95% confidence interval, CI, 2.08 to 5.50%) with no change in LV volumes versus control. In trials ≥6 months duration, MICT significantly improved LVEF (WMD = 6.26%; 95% CI 4.39 to 8.13%) while shorter duration (<6 months) trials modestly increased LVEF (WMD = 2.33%; 95% CI 0.84 to 3.82%). High-intensity interval training (HIIT) significantly increased LVEF compared to control (WMD = 3.70%; 95% CI 1.63 to 5.77%) but was not different than MICT (WMD = 3.17%; 95% CI -0.87 to 7.22%). Resistance training performed alone or combined with aerobic training (MICT or HIIT) did not significantly change LVEF.
Conclusions
In clinically stable HFrEF patients, MICT is an effective therapy to attenuate LV remodeling with the greatest benefits occurring with long-term (≥6 months) training. HIIT performed for 2 to 3 months is superior to control, but not MICT, for improvement of LVEF.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:163-171
Tucker WJ, Beaudry RI, Liang Y, Clark AM, ... Ellingsen O, Haykowsky MJ
Prog Cardiovasc Dis: 30 Dec 1999; 62:163-171 | PMID: 30227187
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Abstract

Long-term Outcomes of the Arterial Switch Operation for d-Transposition of the Great Arteries.

Moe TG, Bardo DME

Dextrotransposition of the great arteries (d-TGA) is a relatively rare form of complex childhood congenital heart disease, which occurs in approximately 0.2 in 1000 live births (Long et al, 2010). The most common palliative procedure for this anatomy has become the arterial switch operation (ASO). We will review in this paper the evidence that is currently available regarding the clinical management following the ASO. Individuals with d-TGA who undergo ASO at a young age thus far have excellent long-term outcomes. Long-term complications for the ASO should be monitored for and patients should have routine follow-up with specialists in adult congenital heart disease.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:360-364
Moe TG, Bardo DME
Prog Cardiovasc Dis: 30 Dec 1999; 61:360-364 | PMID: 30227186
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Abstract

Temporal Changes in a Novel Metric of Physical Activity Tracking (Personal Activity Intelligence) and Mortality: The HUNT Study, Norway.

Kieffer SK, Croci I, Wisløff U, Nauman J
Background
Personal Activity Intelligence (PAI) is a novel activity metric that translates heart rate variations during exercise into a weekly score. Weekly PAI scores assessed at a single point in time were found to associate with lower risk of premature cardiovascular disease (CVD) mortality in the general healthy population. However, to date, the associations between long-term longitudinal changes in weekly PAI scores and mortality have not been explored.
Purpose
The aim of the present study was to prospectively examine the association between change in weekly PAI scores estimated 10 years apart, and risk of mortality from CVD and all-causes.
Methods
We performed a prospective cohort study of 11,870 men and 13,010 women without known CVD in Norway. By using data from the Nord-Trøndelag Health Study (HUNT), PAI was estimated twice, ten years apart (HUNT1 1984-86 and HUNT2 1995-97). Mortality was followed-up until December 31, 2015. Adjusted hazard ratios (AHR) and 95% confidence intervals (CI) for death from CVD and all-causes related to temporal changes in PAI were estimated using Cox regression analyses.
Results
During a mean (SD) of 18 (4) years of follow-up, there were 4782 deaths, including 1560 deaths caused by CVD. Multi-adjusted analyses demonstrated that participants achieving a score of ≥100 PAI at both time points had 32% lower risk of CVD mortality (AHR 0.68; CI: 0.54-0.86) for CVD mortality and 20% lower risk of all-cause mortality (AHR 0.80; CI: 71-0.91) compared with participants obtaining <100 weekly PAI at both measurements. For participants having <100 PAI in HUNT1 but ≥100 PAI in HUNT2, the AHRs were 0.87 (CI: 0.74-1.03) for CVD mortality, and 0.86 (CI: 0.79-0.95) for all-cause mortality. We also found an inverse linear relationship between change in PAI and risk of CVD mortality among participants with 0 PAI (P < 0.01), and ≤50 PAI (P = 0.04) in HUNT1, indicating that an increase in PAI over time is associated with lower risk of mortality. Excluding the first three years of follow-up did not substantially alter the findings. Increasing PAI score from <100 PAI in HUNT1 to ≥100 PAI in HUNT2 was associated with 6.6 years gained lifespan.
Conclusion
Among men and women without known CVD, an increase in PAI score and sustained high PAI score over a 10-year period was associated with lower risk of mortality.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 62:186-192
Kieffer SK, Croci I, Wisløff U, Nauman J
Prog Cardiovasc Dis: 30 Dec 1999; 62:186-192 | PMID: 30227185
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Abstract

Epidemiology of ACHD: What Has Changed and What is Changing?

Khan A, Gurvitz M

The worldwide population of adults with congenital heart disease (ACHD) has grown steadily over the last few decades, estimated at approximately 1.4 million people in 2010 (Gilboa et al., 2016). Innovations in surgical and medical treatment of children with congenital heart disease (CCHD) have dramatically improved survival, resulting in a growing population of ACHD patients with unique health needs (Marelli et al., 2014; Khairy et al., 2010). This growth has significant implications for health care providers and health systems, which must adapt to meet the demands of caring for this complex population. Obtaining an accurate estimate of the population prevalence of ACHD is essential to define the population and to better advocate for resources to meet the needs of this group. While there is a general consensus that the prevalence of CCHD at birth is about 8 per 1000 live births, defining the prevalence in the adult population is a more challenging endeavor (van der Linde et al., 2011).

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Prog Cardiovasc Dis: 30 Dec 1999; 61:275-281
Khan A, Gurvitz M
Prog Cardiovasc Dis: 30 Dec 1999; 61:275-281 | PMID: 30125582
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Abstract

Role of Physical Activity and Fitness in the Characterization and Prognosis of the Metabolically Healthy Obesity Phenotype: A Systematic Review and Meta-analysis.

Ortega FB, Cadenas-Sanchez C, Migueles JH, Labayen I, ... Martínez-Vizcaino V, Lavie CJ

The aims of the present article are to systematically review and meta-analyze the existing evidence on: 1) differences in physical activity (PA), sedentary behavior (SB), cardiorespiratory fitness (CRF) and muscular strength (MST) between metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO); and 2) the prognosis of all-cause mortality and cardiovascular disease (CVD) mortality/morbidity in MHO individuals, compared with the best scenario possible, i.e., metabolically healthy normal-weight (MHNW), after adjusting for PA, SB, CRF or MST. Our systematic review identified 67 cross-sectional studies to address aim 1, and 11 longitudinal studies to address aim 2. The major findings and conclusions from the current meta-analysis are: 1) MHO individuals are more active, spend less time in SB, and have a higher level of CRF (yet no differences in MST) than MUO individuals, suggesting that their healthier metabolic profile could be at least partially due to these healthier lifestyle factors and attributes. 2) The meta-analysis of cohort studies which accounted for PA (N = 10 unique cohorts, 100% scored as high-quality) support the notion that MHO individuals have a 24-33% higher risk of all-cause mortality and CVD mortality/morbidity compared to MHNW individuals. This risk was borderline significant/non-significant, independent of the length of the follow-up and lower than that reported in previous meta-analyses in this topic including all type of studies, which could be indicating a modest reduction in the risk estimates as a consequence of accounting for PA. 3) Only one study has examined the role of CRF in the prognosis of MHO individuals. This study suggests that the differences in the risk of all-cause mortality and CVD mortality/morbidity between MHO and MHNW are largely explained by differences in CRF between these two phenotypes.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:190-205
Ortega FB, Cadenas-Sanchez C, Migueles JH, Labayen I, ... Martínez-Vizcaino V, Lavie CJ
Prog Cardiovasc Dis: 30 Dec 1999; 61:190-205 | PMID: 30122522
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Abstract

Neurocognitive Impairment and Its Long-term Impact on Adults With Congenital Heart Disease.

Cohen S, Earing MG

It is well-recognized now that adult survivors with congenital heart disease (ACHD) are at risk for non-cardiac co-morbidities and complications that can impact symptoms and clinical outcomes. Cognitive dysfunction, in particular, is common in this population, but likely an under-recognized and undertreated cause for long-term morbidity. Abnormal cognitive function has a major impact on all aspects of quality of life, including employment opportunities, educational attainment, and the ability to maintain meaningful social relationships, such as marriage. The association and impact of cognitive dysfunction in ACHD is not fully understood and continues to be understudied. Nevertheless, cognitive dysfunction may be a potentially modifiable risk factor in this population that is amenable to intervention, which may in-turn translate to improved outcomes. This review summarizes our current understanding of the prevalence, impact, and management of cognitive dysfunction in ACHD.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:287-293
Cohen S, Earing MG
Prog Cardiovasc Dis: 30 Dec 1999; 61:287-293 | PMID: 30118722
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Abstract

Management of Heart Failure in Adult Congenital Heart Disease.

Opina AD, Franklin WJ

Heart failure (HF) in the adult with congenital heart disease (ACHD) is associated with high morbidity and mortality and has been implicated as the leading cause of death in this patient population. The diagnosis of HF in ACHD involves a combination of clinical suspicion from subjective patient history, anatomic imaging, functional diagnostic studies, and rhythm evaluation. Once diagnosed, the approach to management of HF in this population varies widely and by lesion. Unfortunately, there is a paucity of literature available delineating the optimal management of these patients, making clinical decision-making extremely challenging. In this review, we aim to summarize available evidence to help guide the diagnosis and management of HF in ACHD.

Copyright © 2018. Published by Elsevier Inc.

Prog Cardiovasc Dis: 30 Dec 1999; 61:308-313
Opina AD, Franklin WJ
Prog Cardiovasc Dis: 30 Dec 1999; 61:308-313 | PMID: 30107184
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Abstract

Family Planning and Pregnancy Management in Adults with Congenital Heart Disease.

Shum KK, Gupta T, Canobbio MM, Durst J, Shah SB

With advances in congenital heart disease management, there are an increasing number of women reaching reproductive age. Pregnancy results in a surge of hormones and increased demands on both the cardiovascular (CV) and respiratory systems. Depending on the heart defect and the treatments the mother has undergone, these hemodynamic changes can result in an increased risk of maternal CV events and an increased risk of fetal morbidity and mortality. Thus, it is important to have a comprehensive approach to adult congenital heart disease patients involving pre-pregnancy planning in addition to diligent peri- and post-partum care.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:336-346
Shum KK, Gupta T, Canobbio MM, Durst J, Shah SB
Prog Cardiovasc Dis: 30 Dec 1999; 61:336-346 | PMID: 30102921
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Abstract

When the Heart Is Not to Blame: Managing Lung Disease in Adult Congenital Heart Disease.

Ginde S, Earing MG

It is well-recognized now that adult survivors with congenital heart disease (CHD) are at risk for non-cardiac co-morbidities and complications that can impact symptoms and clinical outcomes. Lung disease, in particular, is common in this population, but likely an under-recognized and undertreated cause for long-term morbidity. Abnormal lung function contributes to exercise intolerance and is associated with a higher risk for mortality in this population. The exact mechanisms that contribute to abnormal measurements of lung function are not entirely known, and are likely multifactorial and variable depending on the underlying CHD. Nevertheless, lung disease is a potentially modifiable risk factor in this patient population, the management of which may result in improved clinical outcomes. This review summarizes our current understanding of the prevalence, impact and management of lung disease in adults with CHD.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:314-319
Ginde S, Earing MG
Prog Cardiovasc Dis: 30 Dec 1999; 61:314-319 | PMID: 30041022
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Abstract

Precise Therapy for Thoracic Aortic Aneurysm in Marfan Syndrome: A Puzzle Nearing Its Solution.

Rurali E, Perrucci GL, Pilato CA, Pini A, ... Nigro P, Pompilio G

Marfan Syndrome (MFS) is a rare connective tissue disorder, resulting from mutations in the fibrillin-1 gene, characterized by pathologic phenotypes in multiple organs, the most detrimental of which affects the thoracic aorta. Indeed, thoracic aortic aneurysms (TAA), leading to acute dissection and rupture, are today the major cause of morbidity and mortality in adult MFS patients. Therefore, there is a compelling need for novel therapeutic strategies to delay TAA progression and counteract aortic dissection occurrence. Unfortunately, the wide phenotypic variability of MFS patients, together with the lack of a complete genotype-phenotype correlation, have represented until now a barrier hampering the conduction of translational studies aimed to predict disease prognosis and drug discovery. In this review, we will illustrate available therapeutic strategies to improve the health of MFS patients. Starting from gold standard surgical overtures and the description of the main pharmacological approaches, we will comprehensively review the state-of-the-art of in vivo MFS models and discuss recent clinical pharmacogenetic results. Finally, we will focus on induced pluripotent stem cells (iPSC) as a technology that, if integrated with preclinical research and pharmacogenetics, could contribute in determining the best therapeutic approach for each MFS patient on the base of individual differences. Finally, we will suggest the integration of preclinical studies, pharmacogenetics and iPSC technology as the most likely strategy to help solve the composite puzzle of precise medicine in this condition.

Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:328-335
Rurali E, Perrucci GL, Pilato CA, Pini A, ... Nigro P, Pompilio G
Prog Cardiovasc Dis: 30 Dec 1999; 61:328-335 | PMID: 30041021
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Abstract

Coronary Disease and Modifying Cardiovascular Risk in Adult Congenital Heart Disease Patients: Should General Guidelines Apply?

Awerbach JD, Krasuski RA, Camitta MGW

There are >1.4 million adult congenital heart disease (CHD; ACHD) patients living in the United States. Coronary artery disease (CAD) is at least as prevalent in ACHD patients as in the general population and has become a leading cause of their mortality. In the majority of cases, CAD in the ACHD population is driven by the presence of traditional cardiovascular disease (CVD) risk factors. 80% of ACHD patients have at least one CVD risk factor. Hypertension (HTN), obesity and physical inactivity are frequently seen in both pediatric and adult patients with CHD. Many ACHD patients demonstrate abnormal glucose metabolism and are at an increased risk for developing diabetes. Current guidelines for CVD risk assessment and prevention do not specifically mention patients with CHD but are likely applicable to most of these patients. Specific CHD populations have \"high-risk\" lesions that are associated with an increased risk of CVD complications and may warrant intensified screening and treatment. These include patients with a history of coarctation of the aorta or with prior coronary artery ostial manipulation (patients with a history of d-transposition of the great arteries or anomalous aortic origin of a coronary artery). The physiology of single ventricle patients is also poorly suited for the effects of superimposed CVD; these patients may benefit from intensified treatment of CVD risk factors, particularly HTN and obesity.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:300-307
Awerbach JD, Krasuski RA, Camitta MGW
Prog Cardiovasc Dis: 30 Dec 1999; 61:300-307 | PMID: 30041020
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Abstract

Transition of Care in Congenital Disease: Allaying Fears for Patients and Specialists.

Cotts TB

Advances in the care of infants and children with congenital heart disease (CHD) have resulted in significantly improved survival of this population into adulthood. Although the majority of patients with CHD have undergone surgical intervention or transcatheter intervention, patients are not \"cured\" and almost all require lifelong cardiac care. In many parts of the world, robust systems of care have been developed for infants and children with CHD. Although there has been progress in the development of programs for the care of adults with CHD, the time of transition and transfer of care remains a time of high risk for lapses in care and becoming lost to follow-up. Transition is a process of education and preparation for young patients to assume their own care as they enter adulthood, while transfer is the actual event of a patient moving their care from a pediatric to an adult environment. The purpose of this review is to summarize what is known of best practices related to the transition and transfer of patients with CHD to adult services and to provide a practical approach to the sometimes daunting task of preparing patients for the transfer of care.

Copyright © 2018. Published by Elsevier Inc.

Prog Cardiovasc Dis: 30 Dec 1999; 61:282-286
Cotts TB
Prog Cardiovasc Dis: 30 Dec 1999; 61:282-286 | PMID: 30031004
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Impact:
Abstract

A Multifaceted Approach to Pulmonary Hypertension in Adults With Congenital Heart Disease.

Fathallah M, Krasuski RA

Advances in the management of congenital heart disease (CHD) in children have resulted in growing numbers of adults with CHD. Pulmonary arterial hypertension related to CHD (PAH-CHD) is a common complication, affecting up to 10% of patients; and can arise even after successful and complete defect repair, with severe and potentially fatal consequences. Careful work-up in these patients is essential, particularly hemodynamic assessment, and can help define the most appropriate therapeutic approach. Management can be challenging, but the therapeutic armamentarium is continually expanding and now includes surgical, transcatheter and medical options. Timely correction of defects along with early treatment with advanced medical therapies appears to improve quality of life and possible even improve survival. Interestingly most studies of PAH-CHD have focused on its most severely afflicted patients, those with Eisenmenger Syndrome, making it less certain how to manage PAH-CHD of milder degrees. This review summarizes our current understanding of PAH-CHD and emphasizes the need for close follow-up in specialized centers of care where close collaboration is common practice.

Copyright © 2018 Elsevier Inc. All rights reserved.

Prog Cardiovasc Dis: 30 Dec 1999; 61:320-327
Fathallah M, Krasuski RA
Prog Cardiovasc Dis: 30 Dec 1999; 61:320-327 | PMID: 30031003
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Impact:

This program is still in alpha version.