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Cigarette smoking during pregnancy is associated with numerous obstetrical, fetal, and developmental complications, as well as an increased risk of adverse health consequences in the adult offspring. Nicotine replacement therapy and electronic nicotine delivery systems (e-cigarettes) have been developed as a pharmacotherapy for smoking cessation and are considered safer alternatives for women to smoke during pregnancy. The safety of nicotine replacement therapy use during pregnancy has been evaluated in a limited number of short-term human trials, but there is currently no information on the long-term effects of developmental nicotine exposure in humans. However, animal studies suggest that nicotine alone may be a key chemical responsible for many of the long-term effects associated with maternal cigarette smoking on the offspring and increases the risk of adverse neurobehavioral outcomes, dysmetabolism, respiratory illness, and cancer. This review will examine the long-term effects of fetal and neonatal nicotine exposure on postnatal health.

The majority of embolic strokes in patients with nonvalvular atrial fibrillation are caused by thrombi in the left atrial appendage. It is projected that strokes related to atrial fibrillation will markedly increase in the future unless effective mitigation strategies are implemented. Systemic anticoagulation has been known to be highly effective in reducing stroke risk in patients with atrial fibrillation. However, bleeding complications and nonadherence are barriers to effective anticoagulation therapy. Surgical and percutaneous left atrial appendage occlusion devices are nonpharmacologic strategies to mitigate the challenges of drug therapy. We present a contemporary review of left atrial appendage occlusion for stroke prevention in nonvalvular atrial fibrillation. A thorough review of the history of surgical and percutaneous left atrial appendage occlusion devices, recent trials, and US Food and Drug Administration milestones of current left atrial appendage occlusion devices are discussed.

Irisin, a novel hormone like polypeptide, is cleaved and secreted by an unknown protease from a membrane‐spanning protein, FNDC5 (fibronectin type III domain‐containing protein 5). The current knowledge on the biological functions of irisin includes browning white adipose tissue, regulating insulin use, and anti‐inflammatory and antioxidative properties. Dysfunction of irisin has shown to be involved in cardiovascular diseases such as hypertension, coronary artery disease, myocardial infarction, and myocardial ischemia–reperfusion injury. Moreover, irisin gene variants are also associated with cardiovascular diseases. In this review, we discuss the current knowledge on irisin‐mediated regulatory mechanisms and their roles in the pathogenesis of cardiovascular diseases.

The congenital heart care community faces a myriad of public health issues that act as barriers toward optimum patient outcomes. In this article, we attempt to define advocacy and policy initiatives meant to spotlight and potentially address these challenges. Issues are organized into the following 3 key facets of our community: patient population, health care delivery, and workforce. We discuss the social determinants of health and health care disparities that affect patients in the community that require the attention of policy makers. Furthermore, we highlight the many needs of the growing adults with congenital heart disease and those with comorbidities, highlighting concerns regarding the inequities in access to cardiac care and the need for multidisciplinary care. We also recognize the problems of transparency in outcomes reporting and the promising application of telehealth. Finally, we highlight the training of providers, measures of productivity, diversity in the workforce, and the importance of patient–family centered organizations in advocating for patients. Although all of these issues remain relevant to many subspecialties in medicine, this article attempts to illustrate the unique needs of this population and highlight ways in which to work together to address important opportunities for change in the cardiac care community and beyond. This article provides a framework for policy and advocacy efforts for the next decade.

Criteria for diagnosis of arrhythmogenic cardiomyopathy (ACM) were first proposed in 1994 and revised in 2010 by a Task Force. Although the Task Force criteria demonstrated a good accuracy for diagnosis of the original right ventricular phenotype (arrhythmogenic right ventricular cardiomyopathy), they lacked sensitivity for identification of the expanding phenotypic spectrum of ACM, which includes left‐sided variants and did not incorporate late‐gadolinium enhancement findings by cardiac magnetic resonance. The 2020 International criteria (“Padua criteria”) have been developed by International experts with the aim to improve the diagnosis of ACM by providing new criteria for the diagnosis of left ventricular phenotypic features. The key upgrade was the incorporation of tissue characterization findings by cardiac magnetic resonance for noninvasive detection of late‐gadolinium enhancement/myocardial fibrosis that are determinants for characterization of arrhythmogenic biventricular and left ventricular cardiomyopathy. The 2020 International criteria are heavily dependent on cardiac magnetic resonance, which has become mandatory to characterize the ACM phenotype and to exclude other diagnoses. New criteria regarding left ventricular depolarization and repolarization ECG abnormalities and ventricular arrhythmias of left ventricular origin were also provided. This article reviews the evolving approach to diagnosis of ACM, going back to the 1994 and 2010 International Task Force criteria and then grapple with the modern 2020 International criteria.

Radiation therapy demonstrates a clear survival benefit in the treatment of several malignancies. However, cancer survivors can develop a wide array of cardiotoxic complications related to radiation. This pathology is often underrecognized by clinicians and there is little known on how to manage this population. Radiation causes fibrosis of all components of the heart and significantly increases the risk of coronary artery disease, cardiomyopathy, valvulopathy, arrhythmias, and pericardial disease. Physicians should treat other cardiovascular risk factors aggressively in this population and guidelines suggest obtaining regular imaging once symptomatology is established. Patients with radiation‐induced cardiovascular disease tend to do worse than their traditional counterparts for the same interventions. However, there is a trend toward fewer complications and lower mortality with catheter‐based rather than surgical approaches, likely because radiation makes these patients poor surgical candidates. When appropriate, these patients should be referred for percutaneous management of valvulopathy and coronary disease.

Delayed cerebral ischemia is a major predictor of poor outcomes in patients who suffer subarachnoid hemorrhage. Treatment options are limited and often ineffective despite many years of investigation and clinical trials. Modern advances in basic science have produced a much more complex, multifactorial framework in which delayed cerebral ischemia is better understood and novel treatments can be developed. Leveraging this knowledge to improve outcomes, however, depends on a holistic understanding of the disease process. We conducted a review of the literature to analyze the current state of investigation into delayed cerebral ischemia with emphasis on the major themes that have emerged over the past decades. Specifically, we discuss microcirculatory dysfunction, glymphatic impairment, inflammation, and neuroelectric disruption as pathological factors in addition to the canonical focus on cerebral vasospasm. This review intends to give clinicians and researchers a summary of the foundations of delayed cerebral ischemia pathophysiology while also underscoring the interactions and interdependencies between pathological factors. Through this overview, we also highlight the advances in translational studies and potential future therapeutic opportunities.

Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. Influenza infection is associated with an increased risk of cardiovascular events (myocardial infarction, stroke, and heart failure exacerbation) and mortality, and all‐cause mortality in patients with CVD. Infection with influenza leads to a systemic inflammatory and thrombogenic response in the host body, which further causes destabilization of atherosclerotic plaques. Influenza vaccination has been shown to be protective against cardiovascular and cerebrovascular events in several observational and prospective studies of at‐risk populations. Hence, many international guidelines recommend influenza vaccination for adults of all ages, especially for individuals with high‐risk conditions such as CVD. Despite these long‐standing recommendations, influenza vaccine uptake among US adults with CVD remains suboptimal. Specifically, vaccination uptake is strikingly low among patients aged

Mitral valve prolapse (MVP) is a commonly occurring heart condition defined by enlargement and superior displacement of the mitral valve leaflet(s) during systole. Although commonly seen as a standalone disorder, MVP has also been described in case reports and small studies of patients with various genetic syndromes. In this review, we analyzed the prevalence of MVP within syndromes where an association to MVP has previously been reported. We further discussed the shared biological pathways that cause MVP in these syndromes, as well as how MVP in turn causes a diverse array of cardiac and noncardiac complications. We found 105 studies that identified patients with mitral valve anomalies within 18 different genetic, developmental, and connective tissue diseases. We show that some disorders previously believed to have an increased prevalence of MVP, including osteogenesis imperfecta, fragile X syndrome, Down syndrome, and Pseudoxanthoma elasticum, have few to no studies that use up‐to‐date diagnostic criteria for the disease and therefore may be overestimating the prevalence of MVP within the syndrome. Additionally, we highlight that in contrast to early studies describing MVP as a benign entity, the clinical course experienced by patients can be heterogeneous and may cause significant cardiovascular morbidity and mortality. Currently only surgical correction of MVP is curative, but it is reserved for severe cases in which irreversible complications of MVP may already be established; therefore, a review of clinical guidelines to allow for earlier surgical intervention may be warranted to lower cardiovascular risk in patients with MVP.

Cangrelor is the only currently available intravenous platelet P2Y 12 receptor inhibitor. It is characterized by potent, predictable, and rapidly reversible antiplatelet effects. Cangrelor has been tested in the large CHAMPION (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) program, where it was compared with different clopidogrel regimens, and it is currently indicated for use in patients with coronary artery disease undergoing percutaneous coronary intervention. However, the uptake of cangrelor use varies across the globe and may also include patients with profiles different from those enrolled in the registration trials. These observations underscore the need to fully examine the safety and efficacy of cangrelor in postregistration studies. There are several ongoing and planned studies evaluating the use of cangrelor in real‐world practice which will provide important insights to this extent. The current article provides a review on the pharmacology, clinical studies, contemporary use of cangrelor in real‐world practice, a description of ongoing studies, and futuristic insights on potential strategies on how to improve outcomes of patients undergoing percutaneous coronary intervention.

Heart failure (HF) remains the most common major cardiovascular complication arising in pregnancy and the postpartum period. Mothers who develop HF have been shown to experience an increased risk of death as well as a variety of adverse cardiac and obstetric outcomes. Recent studies have demonstrated that the risk to neonates is significant, with increased risks in perinatal morbidity and mortality, low Apgar scores, and prolonged neonatal intensive care unit stays. Information on the causal factors of HF can be used to predict risk and understand timing of onset, mortality, and morbidity. A variety of modifiable, nonmodifiable, and obstetric risk factors as well as comorbidities are known to increase a patient's likelihood of developing HF, and there are additional elements that are known to portend a poorer prognosis beyond the HF diagnosis. Multidisciplinary cardio‐obstetric teams are becoming more prominent, and their existence will both benefit patients through direct care and increased awareness and educate clinicians and trainees on this patient population. Detection, access to care, insurance barriers to extended postpartum follow‐up, and timely patient counseling are all areas where care for these women can be improved. Further data on maternal and fetal outcomes are necessary, with the formation of State Maternal Perinatal Quality Collaboratives paving the way for such advances.

Approximately one‐third of ischemic strokes are classified as cryptogenic strokes. The risk of stroke recurrence in these patients is significantly elevated with up to one‐third of patients with cryptogenic stroke experiencing a further stroke within 10 years. While anticoagulation is the mainstay of treatment for secondary stroke prevention in the context of documented atrial fibrillation (AF), it is estimated that up to 25% of patients with cryptogenic stroke have undiagnosed AF. Furthermore, the historical acceptance of a causal relationship between AF and stroke has recently come under scrutiny, with evidence to suggest that embolic stroke risk may be elevated even in the absence of documented atrial fibrillation attributable to the presence of electrical and structural changes constituting an atrial cardiomyopathy. More recently, the term embolic stroke of unknown source has garnered increasing interest as a subset of patients with cryptogenic stroke in whom a minimum set of diagnostic investigations has been performed, and a nonlacunar infarct highly suspicious of embolic etiology is suspected but in the absence of an identifiable secondary cause of stroke. The ongoing ARCADIA (Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke) randomized trial and ATTICUS (Apixiban for Treatment of Embolic Stroke of Undetermined Source) study seek to further define this novel term. This review summarizes the relationship between AF, embolic stroke, and atrial cardiomyopathy and provides an overview of the clinical relevance of cardiac imaging, electrocardiographic, and serum biomarkers in the assessment of AF and secondary stroke risk. The implications of these findings on therapeutic considerations is considered and gaps in the literature identified as areas for future study in risk stratifying this cohort of patients.

Left ventricular assist devices (LVAD) are increasingly being used as destination therapy in patients with Stage D heart failure. It has been reported that a majority of patients who receive a durable LVAD (dLVAD) present in cardiogenic shock due to decompensated heart failure (ADHF‐CS). As it stands, there is no consensus on the optimal management strategy for patients presenting with ADHF. Bridging with intra‐aortic balloon pumps (IABPs) continues to be a therapeutic option in patients with hemodynamic instability due to cardiogenic shock. The majority of data regarding the use of IABP in cardiogenic shock come from studies in patients presenting with acute myocardial infarction with cardiogenic shock and demonstrates that there is no benefit of routine IABP use in this patient population. However, the role of IABPs as a bridge to dLVAD in ADHF‐CS has yet to be determined. The hemodynamic changes seen in acute myocardial infarction with cardiogenic shock are known to be different and more acutely impaired than those presenting with ADHF‐CS as evidenced by differences in pressure/volume loops. Thus, data should not be extrapolated across these 2 very different disease processes. The aim of this review is to describe results from contemporary studies examining the use of IABPs as a bridge to dLVAD in patients with ADHF‐CS. Retrospective evidence from large registries suggests that the use of IABP as a bridge to dLVAD is feasible and safe when compared with other platforms of temporary mechanical circulatory support. However, there is currently a paucity of high‐quality evidence examining this increasingly important clinical question.

Cancer chemopreventive agents inhibit the formation of precursor lesions and/or the progression of these lesions to late stage disease. This approach to disease control has the potential to reduce the physical and financial costs of cancer in society. Several drugs that have been approved by the FDA for other diseases and have been extensively evaluated for their safety and pharmacokinetic/pharmacodynamic characteristics have the potential to be repurposed for use as cancer chemopreventive agents. These agents often mechanistically inhibit signaling molecules that play key roles in the carcinogenic process. The safety profile of agents is a primary concern when considering the administration of drugs for chemoprevention, as the drugs will be given chronically to high-risk, asymptomatic individuals. To decrease drug toxicity while retaining efficacy, several approaches are currently being explored. In this short review, we describe studies that use preclinical in vivo models to assess efficacy of alternative drug dosing strategies and routes of drug administration on chemopreventive drug efficacy. In vivo drug dosing strategies that reduce toxicity while retaining efficacy will pave the way for future cancer prevention clinical trials.

The findings of randomized trials of neurohormonal modulation have been neutral in heart failure with preserved ejection fraction and consistently positive in heart failure with reduced ejection. Left ventricular remodeling promotes the development and progression of heart failure with preserved and reduced ejection fraction. However, different stimuli mediate left ventricular remodeling that is commonly concentric in heart failure with preserved ejection fraction and eccentric in heart failure with reduced ejection. The stimuli that promote concentric left ventricular remodeling may account for the neutral findings of neuhormonal modulation in heart failure with preserved ejection fraction. Low‐grade systemic inflammation‐induced microvascular endothelial dysfunction is currently the leading hypothesis behind the development and progression of heart failure with preserved ejection fraction. The hypothesis provided the rationale for several randomized controlled trials that have led to neutral findings. The trials and their limitations are reviewed.

Drug-induced liver injury (DILI) is a significant clinical issue, affecting 1–1.5 million patients annually, and remains a major challenge during drug development—toxicity and safety concerns are the second-highest reason for drug candidate failure. The future prevalence of DILI can be minimized by developing a greater understanding of the biological mechanisms behind DILI. Both qualitative and quantitative analytical techniques are vital to characterizing and investigating DILI. In vitro assays are capable of characterizing specific aspects of a drug’s hepatotoxic nature and multiplexed assays are capable of characterizing and scoring a drug’s association with DILI. However, an even deeper insight into the perturbations to biological pathways involved in the mechanisms of DILI can be gained through the use of omics-based analytical techniques: genomics, transcriptomics, proteomics, and metabolomics. These omics analytical techniques can offer qualitative and quantitative insight into genetic susceptibilities to DILI, the impact of drug treatment on gene expression, and the effect on protein and metabolite abundance. This review will discuss the analytical techniques that can be applied to characterize and investigate the biological mechanisms of DILI and potential predictive biomarkers.

CD137 (4‐1BB, tumor necrosis factor receptor superfamily 9) is a surface glycoprotein of the tumor necrosis factor receptor family that can be induced on a variety of immunocytes and nonimmune cells, including endothelial cells and smooth muscle cells. The importance of CD137 in immune response has been well recognized; however, the precise biological effects and underlying mechanisms of CD137 in endothelial cells are unclear. A single layer of cells called the endothelium constitutes the innermost layer of blood vessels including larger arteries, veins, the capillaries, and the lymphatic vessels. It not only acts as an important functional interface, but also participates in local inflammatory response. This review covers recent findings to illuminate the role of CD137 in endothelial cells in different pathophysiologic settings.

Pulmonary hypertension (PH) attributable to left heart disease (LHD) is believed to be the most common form of PH and is strongly associated with increased mortality and morbidity in this patient population. Specific therapies for PH‐LHD have not yet been identified and the use of pulmonary artery hypertension‐targeted therapies in PH‐LHD are not recommended. Endothelin receptor antagonists, phosphodiesterase‐5 inhibitors, guanylate cyclase stimulators, and prostacyclins have all been studied in PH‐LHD with conflicting results. Understanding the mechanisms underlying PH‐LHD could potentially provide novel therapeutic targets. Fibrosis, oxidative stress, and metabolic syndrome have been proposed as pathophysiological components of PH‐LHD. Genetic associations have also been identified, offering additional mechanisms with biological plausibility. This review summarizes the evidence and challenges for treatment of PH‐LHD and focuses on underlying mechanisms on the horizon that could develop into potential therapeutic targets for this disease.

Each guideline recommendation from the American Heart Association and the American College of Cardiology includes an indication of the level of supporting evidence and the associated strength of recommendation with “IA” recommendations representing those with the highest quality supporting evidence and the least amount of uncertainty for benefit. In this analysis, study type and funding sources were systematically tabulated across these IA guideline recommendations over the past 5 years. Nearly half of studies supporting IA guideline recommendations were randomized controlled trials (45%). Overall, about one third of studies supporting IA recommendations were publicly funded (34.9%) with slightly more funded through industry sources (43.5%). Funding sources varied based on the type of intervention being studied with randomized controlled trials of device, diagnostic, and pharmacological interventions reflecting predominantly industry‐funded studies. Over time, studies supporting IA cardiology guideline are funded by industry about twice as often as public sources. Thus, data of adequate quality to support cardiovascular guideline recommendations come from a variety of sources.

Cardiac amyloidosis (CA) is an increasingly recognized cause of heart failure, arrhythmias, and sudden cardiac death. While CA was previously rapidly fatal, recent advances in diagnosis and treatment have significantly improved outcomes. Advances in cardiac imaging and biomarkers have critically improved the accuracy and efficiency with which CA is diagnosed, even allowing for the noninvasive diagnosis of transthyretin CA. Cardiac magnetic resonance imaging, technetium nuclear imaging, echocardiography, and blood‐based biomarkers have established important and complementary roles in the management and advancement of care. At the same time, the development of novel targeted amyloid therapies has allowed patients with CA to live longer and potentially achieve better quality of life. Still, despite this significant progress, there remain critical ongoing questions in the field. Accordingly, within this review we will highlight recent advances in cardiac imaging and therapeutics for CA, while focusing on key opportunities for further optimization of care and outcomes among this growing population. Specifically, we will discuss ongoing debates in the diagnosis of CA, including the interpretation of indeterminate cardiac imaging findings, the best technique to screen asymptomatic transthyretin amyloidosis gene mutation carriers for cardiac involvement, and the ideal method for monitoring response to CA treatment. We will additionally focus on recent advances in treatment for transthyretin amyloidosis‐CA, including a discussion of available agents as well as highlighting ongoing clinical trials. Together, these data will allow clinicians to emerge with a greater understanding of the present and future of diagnosis, management, and potentially enhanced outcomes in this rapidly advancing field.

Life‐threatening ventricular arrhythmias and sudden cardiac death are often preceded by cardiac alternans, a beat‐to‐beat oscillation in the T‐wave morphology or duration. However, given the spatiotemporal and structural complexity of the human heart, designing algorithms to effectively suppress alternans and prevent fatal rhythms is challenging. Recently, an antiarrhythmic constant diastolic interval pacing protocol was proposed and shown to be effective in suppressing alternans in 0‐, 1‐, and 2‐dimensional in silico studies as well as in ex vivo whole heart experiments. Herein, we provide a systematic review of the electrophysiological conditions and mechanisms that enable constant diastolic interval pacing to be an effective antiarrhythmic pacing strategy. We also demonstrate a successful translation of the constant diastolic interval pacing protocol into an ECG‐based real‐time control system capable of modulating beat‐to‐beat cardiac electrical activity and preventing alternans. Furthermore, we present evidence of the clinical utility of real‐time alternans suppression in reducing arrhythmia susceptibility in vivo. We provide a comprehensive overview of this promising pacing technique, which can potentially be translated into a clinically viable device that could radically improve the quality of life of patients experiencing abnormal cardiac rhythms.

In the past decades, numerous preclinical studies and several clinical trials have evidenced the feasibility of cell transplantation in treating heart diseases. Over the years, different delivery routes of cell therapy have emerged and broadened the width of the field. However, a common hurdle is shared by all current delivery routes: low cell retention. A myriad of studies confirm that cell retention plays a crucial role in the success of cell‐mediated cardiac repair. It is important for any delivery route to maintain donor cells in the recipient heart for enough time to not only proliferate by themselves, but also to send paracrine signals to surrounding damaged heart cells and repair them. In this review, we first undertake an in‐depth study of primary theories of cell loss, including low efficiency in cell injection, “washout” effects, and cell death, and then organize the literature from the past decade that focuses on cell transplantation to the heart using various cell delivery routes, including intracoronary injection, systemic intravenous injection, retrograde coronary venous injection, and intramyocardial injection. In addition to a recapitulation of these approaches, we also clearly evaluate their strengths and weaknesses. Furthermore, we conduct comparative research on the cell retention rate and functional outcomes of these delivery routes. Finally, we extend our discussion to state‐of‐the‐art bioengineering techniques that enhance cell retention, as well as alternative delivery routes, such as intrapericardial delivery. A combination of these novel strategies and more accurate assessment methods will help to address the hurdle of low cell retention and boost the efficacy of cell transplantation to the heart.

Bioprosthetic mitral structural valve degeneration and failed mitral valve repair (MVr) have traditionally been treated with reoperative mitral valve surgery. Transcatheter mitral valve‐in‐valve (MVIV) and valve‐in‐ring (MVIR) replacement are now feasible, but data comparing these approaches are lacking. We sought to compare the outcomes of (1) reoperative mitral valve replacement (redo‐MVR) and MVIV for structural valve degeneration, and (2) reoperative mitral valve repair (redo‐MVr) or MVR and MVIR for failed MVr. A literature search of PubMed, Embase, and the Cochrane Library was conducted up to July 31, 2020. Thirty‐two studies involving 25 832 patients were included. Redo‐MVR was required in ≈35% of patients after index surgery at 10 years, with 5% to 15% 30‐day mortality. MVIV resulted in >95% procedural success with 30‐day and 1‐year mortality of 0% to 8% and 11% to 16%, respectively. Recognized complications included left ventricular outflow tract obstruction (0%–6%), valve migration (0%–9%), and residual regurgitation (0%–6%). Comparisons of redo‐MVR and MVIV showed no statistically significant differences in mortality (11.3% versus 11.9% at 1 year, P =0.92), albeit higher rates of major bleeding and arrhythmias with redo‐MVR. MVIR resulted in 0% to 34% mortality at 1 year, whereas both redo‐MVr and MVR for failed repairs were performed with minimal mortality and durable long‐term results. MVIV is therefore a viable alternative to redo‐MVR for structural valve degeneration, whereas redo‐MVr or redo‐MVR is preferred for failed MVr given the suboptimal results with MVIR. However, not all patients will be candidates for MVIV/MVIR because anatomical restrictions may preclude transcatheter options from adequately addressing the underlying pathology.

Mitral annular calcification with mitral valve disease is a challenging problem that could necessitate surgical mitral valve replacement (SMVR). Transcatheter mitral valve replacement (TMVR) is emerging as a feasible alternative in high‐risk patients with appropriate anatomy. PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched from inception to December 25, 2019 for studies discussing SMVR or TMVR in patients with mitral annular calcification; 27 of 1539 articles were selected for final review. TMVR was used in 15 studies. Relevant data were available on 82 patients who underwent hybrid transatrial TMVR, and 354 patients who underwent transapical or transseptal TMVR. Outcomes on SMVR were generally reported as small case series (447 patients from 11 studies); however, 1 large study recently reported outcomes in 9551 patients. Patients who underwent TMVR had a shorter median follow‐up of 9 to 12 months (range, in‐hospital‒19 months) compared with patients with SMVR (54 months; range, in‐hospital‒120 months). Overall, those undergoing TMVR were older and had higher Society of Thoracic Surgeons risk scores. SMVR showed a wide range of early (0%–27%; median 6.3%) and long‐term mortality (0%–65%; median at 1 year, 15.8%; 5 years, 38.8%, 10 years, 62.4%). The median in‐hospital, 30‐day, and 1‐year mortality rates were 16.7%, 22.7%, and 43%, respectively, for transseptal/transapical TMVR, and 9.5%, 20.0%, and 40%, respectively, for transatrial TMVR. Mitral annular calcification is a complex disease and TMVR, with a versatile option of transatrial approach in patients with challenging anatomy, offers a promising alternative to SMVR in high‐risk patients. However, further studies are needed to improve technology, patient selection, operative expertise, and long‐term outcomes.

Bioprosthetic heart valves (BHVs) largely circumvent the need for long‐term anticoagulation compared with mechanical valves but are increasingly susceptible to deterioration and reduced durability with reoperation rates of ≈10% and 30% at 10 and 15 years, respectively. Structural valve degeneration is a common, unpreventable, and untreatable consequence of BHV implantation and is frequently characterized by leaflet calcification. However, 25% of BHV reoperations attributed to structural valve degeneration occur with minimal leaflet mineralization. This review discusses the noncalcific mechanisms of BHV structural valve degeneration, highlighting the putative roles and pathophysiological relationships between protein infiltration, glycation, oxidative and mechanical stress, and inflammation and the structural consequences for surgical and transcatheter BHVs.

Cardiac fibroblasts are the primary cell type responsible for deposition of extracellular matrix in the heart, providing support to the contracting myocardium and contributing to a myriad of physiological signaling processes. Despite the importance of fibrosis in processes of wound healing, excessive fibroblast proliferation and activation can lead to pathological remodeling, driving heart failure and the onset of arrhythmias. Our understanding of the mechanisms driving the cardiac fibroblast activation and proliferation is expanding, and evidence for their direct and indirect effects on cardiac myocyte function is accumulating. In this review, we focus on the importance of the fibroblast‐to‐myofibroblast transition and the cross talk of cardiac fibroblasts with cardiac myocytes. We also consider the current use of models used to explore these questions.

Objective/hypothesis The purpose of this review is to summarize evidence-based data regarding the ototoxic effects of potential COVID-19 therapeutics to treat patients suffering from SARS-CoV-2. Methods Medications under investigation as novel therapeutics to treat COVID-19 were identified using the search term coronavirus therapeutics, COVID therapeutics, and SARS-CoV-2 therapeutics on ClinicalTrials.gov and the PubMed Database. A literature review was performed using the PubMed Database for each proposed COVID-19 therapeutic to identify relevant articles. Search criteria included Medical Subject Headings (MeSH) and key word search terms for ototoxicity, vestibulotoxicity, hearing disorders, and vertigo. Results Six proposed COVID-19 therapeutics were identified as possessing ototoxic side effects including chloroquine and hydroxychloroquine, azithromycin, lopinavir-ritonavir, interferon, ribavirin, and ivermectin. Conclusions Available evidence suggests that ototoxic effects may be improved or mitigated by stopping the offending agent. Recognition of hearing loss, tinnitus, or imbalance/vertigo is therefore crucial to facilitate early intervention and prevent long-term damage. Hospitals should consider the inclusion of audiologic monitoring protocols for patients receiving COVID-19 therapeutics with known ototoxicity, especially in high-risk patient groups such as the elderly and hearing impaired. Laryngoscope, 131:1626-1632, 2021.

The failure of adult cardiomyocytes to reproduce themselves to repair an injury results in the development of severe cardiac disability leading to death in many cases. The quest for an understanding of the inability of cardiac myocytes to repair an injury has been ongoing for decades with the identification of various factors which have a temporary effect on cell‐cycle activity. Fetal cardiac myocytes are continuously replicating until the time that the developing fetus reaches a stage of maturity sufficient for postnatal life around the time of birth. Recent reports of the ability for early neonatal mice and pigs to completely repair after the severe injury has stimulated further study of the regulators of the cardiomyocyte cell cycle to promote replication for the remuscularization of injured heart. In all mammals just before or after birth, single‐nucleated hyperplastically growing cardiomyocytes, 1X2N, undergo ≥1 additional DNA replications not followed by cytokinesis, resulting in cells with ≥2 nuclei or as in primates, multiple DNA replications (polyploidy) of 1 nucleus, 2X2(+)N or 1X4(+)N. All further growth of the heart is attributable to hypertrophy of cardiomyocytes. Animal studies ranging from zebrafish with 100% 1X2N cells in the adult to some strains of mice with up to 98% 2X2N cells in the adult and other species with variable ratios of 1X2N and 2X2N cells are reviewed relative to the time of conversion. Various structural, physiologic, metabolic, genetic, hormonal, oxygenation, and other factors that play a key role in the inability of post‐neonatal and adult myocytes to undergo additional cytokinesis are also reviewed.

It is important for both the patient and physician communities to have timely access to information recognizing rapid progress in the diagnosis and treatment of familiar but relatively uncommon cardiovascular diseases. Patients with 3 cardiovascular diseases (ie, hypertrophic cardiomyopathy, pulmonary arterial hypertension, and transthyretin (TTR) cardiac amyloidosis (ATTR)]), once considered rare without effective management options and associated with malignant prognosis, have now benefited substantially from the development of a variety of innovative therapeutic strategies. In addition, in each case, enhanced diagnostic testing has expanded the patient population and allowed for more widespread administration of contemporary treatments. In hypertrophic cardiomyopathy, introduction of implantable defibrillators to prevent sudden death as well as high‐benefit:low‐risk septal reduction therapies to reverse heart failure have substantially reduced morbidity and disease‐related mortality (to 0.5% per year). For pulmonary arterial hypertension, a disease once characterized by a particularly grim prognosis, prospective randomized drug trials with aggressive single (or combined) pharmacotherapy have measurably improved survival and quality of life for many patients. In cardiac amyloidosis, development of disease‐specific drugs can for the first time reduce morbidity and mortality, prominently with breakthrough ATTR‐protein–stabilizing tafamidis. In conclusion, in less common and visible cardiovascular diseases, it is crucial to recognize substantial progress and achievement, given that penetration of such information into clinical practice and the patient community can be inconsistent. Diseases such as hypertrophic cardiomyopathy, pulmonary arterial hypertension, and ATTR cardiac amyloidosis, once linked to a uniformly adverse prognosis, are now associated with the opportunity for patients to experience satisfactory quality of life and extended longevity.

Digital, Acquired tuberculosis continues to be a challenge worldwide. Although tuberculosis has been considered a global public health emergency, it remains poorly controlled in many countries. Despite being primarily a pulmonary disease, tu-berculosis could involve the heart. This systematic review is part of the "Neglected Tropical Diseases and Other Infectious Diseases Involving the Heart" (the NET-Heart Project) initiative from the Interamerican Society of Cardiology. This project aims to review the cardiovascular involvement of these heterogeneous diseases, advancing original algorithms to help healthcare providers diagnose and manage cardiovascular complications. In tuberculosis, pericardium involvement is relatively common, especially in AIDS, and tuberculosis is the most common cause of constrictive pericarditis in endemic countries. Myocarditis and aortitis by tuberculosis are rare. Clinical manifestations of cardiovascular involvement by tuberculosis differ from those typically found for bacteria or viruses. Prevailing systemic symptoms and the pericarditis diagnostic index should be taken into account. An echocardiogram is the first step for diagnosing cardiovascular involvement; however, several image modalities can be used, depending on the suspected site of infection. Adenosine deaminase levels, gamma interferon, or polymerase chain reaction testing could be used to confirm tuberculosis infection; each has a high diagnostic performance. Antituberculosis chemotherapy and corticosteroids are treatment mainstays that significantly reduce mortality, constriction, and hospitaliza-tions, especially in patients with HIV. In conclusion, tuberculosis cardiac involvement is frequent and could lead to heart failure, constrictive pericarditis, or death. Early detection of complications should be a cornerstone of overall management., Ciencias Médicas y de la Salud

Despite many improvements in its prevention and management, acute coronary syndrome (ACS) remains a major cause of morbidity and mortality in the developed world. Lipid management is an important part of secondary prevention after ACS, but many patients currently remain undertreated and do not attain guideline‐recommended levels of low‐density lipoprotein cholesterol reduction. This review details the current state of evidence on lipid management in patients presenting with ACS, provides directions for identification of patients who may benefit from early escalation of lipid‐lowering therapy, and discusses novel lipid‐lowering medication that is currently under investigation in clinical trials. Moreover, a treatment algorithm aimed at attaining guideline‐recommended low‐density lipoprotein cholesterol levels is proposed. Despite important advances in the initial treatment and secondary prevention of ACS, ≈20% of ACS survivors experience a subsequent ischemic cardiovascular event within 24 months, and 5‐year mortality ranges from 19% to 22%. Knowledge of the current state of evidence‐based lipid management after ACS is of paramount importance to improve outcomes after ACS.

Venous thromboembolism (VTE) is an important vascular disease and public health problem. Prevention of VTE has focused mainly on using thromboprophylaxis to avoid provoked VTE or recurrent VTE, with little attention paid to the possibility of preventing the one third to one half of VTEs that are unprovoked. We review growing research suggesting that unhealthy lifestyle risk factors may cause a considerable proportion of unprovoked VTE. Using epidemiologic data to calculate population attributable risks, we estimate that in the United States obesity may contribute to 30% of VTEs, physical inactivity to 4%, current smoking to 3%, and Western dietary pattern to 11%. We also review possibilities for VTE primary prevention either through a high‐risk individual approach or a population‐wide approach. Interventions for outpatients at high VTE risk but without VTE provoking factors have not been fully tested; yet, improving patient awareness of risk and symptoms, lifestyle counseling, and possibly statins or direct oral anticoagulants may prove useful in primary prevention of unprovoked VTE. A population approach to prevention would bolster awareness of VTE and aim to shift lifestyle risk factors downward in the whole population using education, environmental changes, and policy. Assuming the epidemiological associations are accurate, causal, and independent of each other, a reduction of obesity, physical inactivity, current smoking, and Western diet by 25% in the general population might reduce the incidence of unprovoked VTE by 12%. We urge further research and consideration that primary prevention of unprovoked VTE may be a worthwhile public health aim.

Patients diagnosed with the same subtype of atrial fibrillation according to our current classification system may differ in symptom severity, severity of the arrhythmogenic substrate, and response to antiarrhythmic therapy. Hence, there is a need for an electrical biomarker as an indicator of the arrhythmogenic substrate underlying atrial fibrillation enabling patient‐tailored therapy. The aim of this review is to investigate whether atrial refractoriness, a well‐known electrophysiological parameter that is affected by electrical remodeling, can be used as an electrical biomarker of the arrhythmogenic substrate underlying atrial fibrillation. We discuss methodologies of atrial effective refractory period assessment, identify which changes in refractoriness‐related parameters reflect different degrees of electrical remodeling, and explore whether these parameters can be used to predict clinical outcomes.

Coronavirus disease 2019 (COVID‐19) is an infectious disease caused by severe acute respiratory syndrome coronavirus‐2, which has posed a significant threat to global health. Although the infection is frequently asymptomatic or associated with mild symptoms, in a small proportion of patients it can produce an intense inflammatory and prothrombotic state that can lead to acute respiratory distress syndrome, multiple organ failure, and death. Angiotensin‐converting enzyme 2, highly expressed in the respiratory system, has been identified as a functional receptor for severe acute respiratory syndrome coronavirus‐2. Notably, angiotensin‐converting enzyme 2 is also expressed in the cardiovascular system, and there are multiple cardiovascular implications of COVID‐19. Cardiovascular risk factors and cardiovascular disease have been associated with severe manifestations and poor prognosis in patients with COVID‐19. More important, patients with COVID‐19 may have thrombotic and coagulation abnormalities, promoting a hypercoagulable state and resulting in an increased rate of thrombotic and thromboembolic events. This review will describe the pathophysiological characteristics of the cardiovascular involvement following infection by severe acute respiratory syndrome coronavirus‐2, with a focus on thrombotic and thromboembolic manifestations and implications for antithrombotic management.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is characterized by asymmetric septal thickening and diastolic dysfunction. More than 1500 mutations in genes encoding sarcomere proteins are associated with HCM. However, the genotype‐phenotype relationship in HCM is incompletely understood and involves modification by additional disease hits. Recent cohort studies identify obesity as a major adverse modifier of disease penetrance, severity, and clinical course. In this review, we provide an overview of these clinical findings. Moreover, we explore putative mechanisms underlying obesity‐induced sensitization and aggravation of the HCM phenotype. We hypothesize obesity‐related stressors to impact on cardiomyocyte structure, metabolism, and homeostasis. These may impair cardiac function by directly acting on the primary mutation‐induced myofilament defects and by independently adding to the total cardiac disease burden. Last, we address important clinical and pharmacological implications of the involvement of obesity in HCM disease modification.

Various congenital heart diseases are associated with malalignment of a part of the ventricular septum. Most commonly, the outlet septum is malaligned toward the right or left ventricle. Less commonly, the whole or a major part of the ventricular septum is malaligned in relation to the atrial septal plane. Although the pathological conditions associated with ventricular septal malalignment have been well recognized, the descriptions are often confusing and sometimes incorrect. In this pictorial essay, we introduce our systematic approach to the assessment of malalignment type ventricular septal defects with typical case examples. The systematic approach comprises description of the essential features of malalignment, including the following: (1) the malaligned part of the ventricular septum, (2) the reference structure, (3) the mechanism of malalignment, (4) the direction of malalignment, and (5) the severity of malalignment.

Depression in patients with cardiovascular disease is independently associated with progression of heart disease, major adverse cardiac events, and mortality. A wide variety of depression treatment strategies have been studied in randomized controlled trials as the field works to identify optimal depression treatments in this population. A contemporary scoping review of the literature can help to consolidate and synthesize the growing and disparate literature on depression treatment trials in people with cardiovascular disease. We conducted a scoping review utilizing a systematic search of the literature via 4 databases (PubMed, PsycINFO, EMBASE, and Google Scholar) from database inception to March 2020. We identified 42 relevant randomized controlled trials of depression treatment interventions in patients with cardiac disease (n=9181 patients with coronary artery disease, n=1981 patients with heart failure). Selective serotonin reuptake inhibitors appear to be safe in patients with cardiac disease and to have beneficial effects on depression (and some suggestion of cardiac benefit) in patients with coronary artery disease, with less evidence of their efficacy in heart failure. In contrast, psychotherapy appears to be effective for depression in coronary artery disease and heart failure, but with less evidence of cardiac benefit. Newer multimodal depression care management approaches that utilize flexible approaches to patients' care have been less studied but appear promising across cardiac patient groups. Selective serotonin reuptake inhibitors may be preferred in the treatment of patients with coronary artery disease, psychotherapy may be preferred in heart failure, and more flexible depression care management approaches have shown promise by potentially using both approaches based on patient needs.

Seizure liability remains a significant cause of attrition in drug discovery and development, leading to loss of competitiveness, delays, and increased costs. Current detection methods rely on observations made in in vivo studies intended to support clinical trials, such as tremors or other abnormal movements. These signs could be missed or misinterpreted; thus, definitive confirmation of drug-induced seizure requires a follow-up electroencephalogram study. There has been progress in in vivo detection of seizure using automated video systems that record and analyze animal movements. Nonetheless, it would be preferable to have earlier prediction of seizurogenic risk that could be used to eliminate liabilities early in discovery while there are options for medicinal chemists making potential new drugs. Attrition due to cardiac adverse events has benefited from routine early screening; could we reduce attrition due to seizure using a similar approach? Specifically, microelectrode arrays could be used to detect potential seizurogenic signals in stem-cell-derived neurons. In addition, there is clear evidence implicating neuronal voltage-gated and ligand-gated ion channels, GPCRs and transporters in seizure. Interactions with surrounding glial cells during states of stress or inflammation can also modulate ion channel function in neurons, adding to the challenge of seizure prediction. It is timely to evaluate the opportunity to develop an in vitro assessment of seizure linked to a panel of ion channel assays that predict seizure, with the aim of influencing structure-activity relationship at the design stage and eliminating compounds predicted to be associated with pro-seizurogenic state.

Improvements in cardiovascular disease (CVD) rates among young adults in the past 2 decades have been offset by increasing racial/ethnic and gender disparities, persistence of unhealthy lifestyle habits, overweight and obesity, and other CVD risk factors. To enhance the promotion of cardiovascular health among young adults 18 to 39 years old, the medical and broader public health community must understand the biological, interpersonal, and behavioral features of this life stage. Therefore, the National Heart, Lung, and Blood Institute, with support from the Office of Behavioral and Social Science Research, convened a 2‐day workshop in Bethesda, Maryland, in September 2017 to identify research challenges and opportunities related to the cardiovascular health of young adults. The current generation of young adults live in an environment undergoing substantial economic, social, and technological transformations, differentiating them from prior research cohorts of young adults. Although the accumulation of clinical and behavioral risk factors for CVD begins early in life, and research suggests early risk is an important determinant of future events, few trials have studied prevention and treatment of CVD in participants

The implantation of bioprosthetic heart valves (BHVs) is increasingly becoming the treatment of choice in patients requiring heart valve replacement surgery. Unlike mechanical heart valves, BHVs are less thrombogenic and exhibit superior hemodynamic properties. However, BHVs are prone to structural valve degeneration (SVD), an unavoidable condition limiting graft durability. Mechanisms underlying SVD are incompletely understood, and early concepts suggesting the purely degenerative nature of this process are now considered oversimplified. Recent studies implicate the host immune response as a major modality of SVD pathogenesis, manifested by a combination of processes phenocopying the long‐term transplant rejection, atherosclerosis, and calcification of native aortic valves. In this review, we summarize and critically analyze relevant studies on (1) SVD triggers and pathogenesis, (2) current approaches to protect BHVs from calcification, (3) obtaining low immunogenic BHV tissue from genetically modified animals, and (4) potential strategies for SVD prevention in the clinical setting.

OBJECTIVE/HYPOTHESIS: Review the published literature of telemedicine's use within otorhinolaryngology (ORL), highlight its successful implementation, and document areas with need of future research. STUDY DESIGN: State of the Art Review. METHODS: Three independent, comprehensive searches for articles published on the subject of telemedicine in ORL were conducted of literature available from January 2000 to April 2020. Search terms were designed to identify studies which examined telemedicine use within ORL. Consensus among authors was used to include all relevant articles. RESULTS: While several, small reports document clinical outcomes, patient satisfaction, and the cost of telemedicine, much of the literature on telemedicine in ORL is comprised of preliminary, proof-of-concept reports. Further research will be necessary to establish its strengths and limitations. CONCLUSIONS: Particularly during the coronavirus disease of 2019 pandemic, telemedicine can, and should, be used within ORL practice. This review can assist in guiding providers in implementing telemedicine that has been demonstrated to be successful, and direct future research. Laryngoscope, 2020.

OBJECTIVES: During a public health crisis, it is important for medical journals to share information in a timely manner while maintaining a robust peer-review process. This review reports and analyzes The Laryngoscope's publication trends and practices during the COVID-19 pandemic, before the COVID-19 pandemic, and during previous pandemics. METHODS: Comprehensive review of two databases (PubMed and The Laryngoscope) was performed. COVID-19 manuscripts (published in The Laryngoscope during the first 4 months of the pandemic) were identified and compared to manuscripts pertaining to historic pandemics (published in The Laryngoscope during the first 2 years of each outbreak). Keywords included "The Laryngoscope," "flu," "pandemic," "influenza," "SARS," "severe acute respiratory syndrome," "coronavirus," "COVID-19," and "SARS-CoV-2." Data were obtained from The Laryngoscope to characterize publication trends during and before the COVID-19 pandemic. RESULTS: From March 1, 2020 to June 30, 2020, The Laryngoscope had 203 COVID-19 submissions. As of July 8, 2020, 20 (9.9%) were accepted, 117 (57.6%) under review, and 66 (32.5%) rejected. During the first 4 months of the pandemic, 18 COVID-19 manuscripts were published. Mean number of days from submission to online publication was 45, compared to 170 in 2018 and 196 in 2019. A total of 4 manuscripts concerning previous pandemics were published during the initial 2 years of each outbreak. CONCLUSIONS: The Laryngoscope rapidly disseminated quality publications during the COVID-19 pandemic by upholding a robust peer-review process while expediting editorial steps, highlighting relevant articles online, and providing open access to make COVID-19-related publications available as quickly as possible. This article is protected by copyright. All rights reserved.

Despite consensus that excessive circulating concentrations of apoB‐lipoproteins is a key driver for the atherosclerotic process and that treatments that low‐density lipoprotein cholesterol lowering by up‐regulation of low‐density lipoprotein cholesterol receptor expression reduces that risk, divergent viewpoints on interpretation of study data have resulted in substantial differences in European and American lipid guideline recommendations. This article explores those differences and highlights the importance of understanding guideline‐based lipid management to improve patient care and reduce the risk of clinical atherosclerotic cardiovascular disease.

Aortic stenosis (AS) is a common valvular heart disease in the aging population that is characterized by a variable period of asymptomatic phase before development of symptoms and severe AS. Mortality and morbidity is substantial even after aortic valve replacement, in part related to persistent left ventricular hypertrophy, diastolic dysfunction, and heart failure. Renin‐angiotensin system (RAS) blockade therapy is associated with modulation of adverse left ventricular remodeling, reduction in myocardial hypertrophy, and fibrosis, resulting in clinical improvements in patients with congestive heart failure There are emerging data to suggest benefit of RAS blockade in patients with AS before and after AVR with regard to potentially slower progression of aortic valve calcification, left ventricular mass and survival benefit in favor of RAS blockade group before AVR, and also survival benefit in patients after AVR. We review the available data to understand the role of RAS blockade before AVR and in patients undergoing surgical AVR and transcatheter AVR. There are significant survival advantages of RAS inhibition in patients with AS undergoing surgical AVR or transcatheter AVR. On the basis of existing literature, adequately powered randomized trials are needed to evaluate the role of RAS inhibition in patients with AS.

Atherosclerotic cardiovascular disease (ASCVD) has posed an increasing burden on Americans and the United States healthcare system for decades. In addition, ASCVD has had a substantial economic impact, with national expenditures for ASCVD projected to increase by over 2.5‐fold from 2015 to 2035. This rapid increase in costs associated with health care for ASCVD has consequences for payers, healthcare providers, and patients. The issues to patients are particularly relevant in recent years, with a growing trend of shifting costs of treatment expenses to patients in various forms, such as high deductibles, copays, and coinsurance. Therefore, the issue of“financial toxicity” of health care is gaining significant attention. The term encapsulates the deleterious impact of healthcare expenditures for patients. This includes the economic burden posed by healthcare costs, but also the unintended consequences it creates in form of barriers to necessary medical care, quality of life as well tradeoffs related to non‐health–related necessities. While the societal impact of rising costs related to ASCVD management have been actively studied and debated in policy circles, there is lack of a comprehensive assessment of the current literature on the financial impact of cost sharing for ASCVD patients and their families. In this review we systematically describe the scope and domains of financial toxicity, the instruments that measure various facets of healthcare‐related financial toxicity, and accentuating factors and consequences on patient health and well‐being. We further identify avenues and potential solutions for clinicians to apply in medical practice to mitigate the burden and consequences of out‐of‐pocket costs for ASCVD patients and their families.

Approximately 50% of patients with heart failure have preserved ejection fraction. Although a wide variety of conditions cause or contribute to heart failure with preserved ejection fraction, elevated left ventricular filling pressures, particularly during exercise, are common to all causes. Acute elevation in left‐sided filling pressures promotes lung congestion and symptoms of dyspnea, while chronic elevations often lead to pulmonary vascular remodeling, right heart failure, and increased risk of mortality. Pharmacologic therapies, including neurohormonal modulation and drugs that modify the nitric oxide/cyclic GMP‐protein kinase G pathway have thus far been limited in reducing symptoms or improving outcomes in patients with heart failure with preserved ejection fraction. Hence, alternative means of reducing the detrimental rise in left‐sided heart pressures are being explored. One proposed method of achieving this is to create an interatrial shunt, thus unloading the left heart at rest and during exercise. Currently available studies have shown 3‐ to 5‐mm Hg decreases of pulmonary capillary wedge pressure during exercise despite increased workload. The mechanisms underlying the hemodynamic changes are just starting to be understood. In this review we summarize results of recent studies aimed at elucidating the potential mechanisms of improved hemodynamics during exercise tolerance following interatrial shunt implantation and the current interatrial shunt devices under investigation.

Prosthetic valve endocarditis (PVE) after surgical aortic valve replacement and transcatheter aortic valve replacement (TAVR) carries significant morbidity/mortality. Our review aims to compare incidence, predisposing factors, microbiology, diagnosis, management, and outcomes of PVE in surgical aortic valve replacement/TAVR patients. We searched PubMed and Embase to identify published studies from January 1, 2015 to March 13, 2020. Key words were indexed for original reports, clinical studies, and reviews. Reports were evaluated by 2 authors against a priori inclusion/exclusion criteria. Studies were included if they reported incidence and outcomes related to surgical aortic valve replacement/TAVR PVE and excluded if they were published pre‐2015 or included a small population. We followed the Cochrane methodology and Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines for all stages of the design and implementation. Study quality was based on the Newcastle‐Ottawa Scale. Thirty‐three studies with 311 to 41 025 patients contained relevant information. The majority found no significant difference in incidence of surgical aortic valve replacement/TAVR PVE (reported as 0.3%–1.2% per patient‐year versus 0.6%–3.4%), but there were key differences in pathogenesis. TAVR has a specific set of infection risks related to entry site, procedure, and device, including nonstandardized protocols for infection control, valve crimping injury, paravalvular leak, neo‐leaflet stress, intact/calcified native leaflets, and intracardiac hardware. With the expansion of TAVR to lower risk and younger patients, a better understanding of pathogenesis, patient presentation, and guideline‐directed treatment is paramount. When operative intervention is necessary, mortality remains high at 20% to 30%. Unique TAVR infection risks present opportunities for PVE prevention, therefore, further investigation is imperative.

Compared with the extensive data on left‐sided infective endocarditis ( IE ), there is much less published information on the features and management of right‐sided IE . Right‐sided IE accounts for 5% to 10% of all IE cases, and compared with left‐sided IE , it is more often associated with intravenous drug use, intracardiac devices, and central venous catheters, all of which has become more prevalent over the past 20 years. In this manuscript on right‐sided IE we provide an up‐to‐date overview on the epidemiology, etiology, microbiology, potential locations of infection in the right heart, diagnosis, imaging, common complications, management, and prognosis. We present updated information on the treatment of pacemaker and device infections, infected fibrin sheaths that appear to be an easily missed source of infection after central line as well as pacemaker removal. We review current data on the AngioVac percutaneous aspiration device, which can obviate the need for surgery in patients with infected pacemaker leads and fibrin sheaths. We also focused on advanced diagnostic modalities, such as positron emission tomography/computed tomography. All of these are supported by specific case examples with detailed echocardiographic imaging from our experience.

Sodium‐glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure. Initially, these drugs were believed to have a profile similar to diuretics or hemodynamically active drugs, but they do not rapidly reduce natriuretic peptides or cardiac filling pressures, and they exert little early benefit on symptoms, exercise tolerance, quality of life, or signs of congestion. Clinically, the profile of SGLT2 inhibitors resembles that of neurohormonal antagonists, whose benefits emerge gradually during sustained therapy. In experimental models, SGLT2 inhibitors produce a characteristic pattern of cellular effects, which includes amelioration of oxidative stress, mitigation of mitochondrial dysfunction, attenuation of proinflammatory pathways, and a reduction in myocardial fibrosis. These cellular effects are similar to those produced by angiotensin converting enzyme inhibitors, β‐blockers, mineralocorticoid receptor antagonists, and neprilysin inhibitors. At a molecular level, SGLT2 inhibitors induce transcriptional reprogramming of cardiomyocytes that closely mimics that seen during nutrient deprivation. This shift in signaling activates the housekeeping pathway of autophagy, which clears the cytosol of dangerous cytosolic constituents that are responsible for cellular stress, thereby ameliorating the development of cardiomyopathy. Interestingly, similar changes in cellular signaling and autophagic flux have been seen with inhibitors of the renin‐angiotensin system, β‐blockers, mineralocorticoid receptor antagonists, and neprilysin inhibitors. The striking parallelism of these molecular, cellular, and clinical profiles supports the premise that SGLT2 inhibitors should be regarded as neurohormonal antagonists when prescribed for the treatment of heart failure with a reduced ejection fraction.

Heart failure is a complex clinical syndrome, represented as an impairment in ventricular filling and myocardial blood ejection. As such, heart failure is one of the leading causes of death in the United States. With a mortality rate of 1 per 8 individuals and a prevalence of 6.2 million Americans, it has been projected that heart failure prevalence will increase by 46% by 2030. Cardiac remodeling (a general determinant of heart failure) is regulated by an extensive network of intertwined intracellular signaling pathways. The ability of signalosomes (molecular signaling complexes) to compartmentalize several cellular pathways has been recently established. These signalosome signaling complexes provide an additional level of specificity to general signaling pathways by regulating the association of upstream signals with downstream effector molecules. In cardiac myocytes, the AKAP12 (A‐kinase anchoring protein 12) scaffolds a large signalosome that orchestrates spatiotemporal signaling through stabilizing pools of phosphatases and kinases. Predominantly upon β‐AR (β 2 ‐adrenergic‐receptor) stimulation, the AKAP12 signalosome is recruited near the plasma membrane and binds tightly to β‐AR. Thus, one major function of AKAP12 is compartmentalizing PKA (protein kinase A) signaling near the plasma membrane. In addition, it is involved in regulating desensitization, downregulation, and recycling of β‐AR. In this review, the critical roles of AKAP12 as a scaffold protein in mediating signaling downstream GPCRs (G protein–coupled receptor) are discussed with an emphasis on its reported and potential roles in cardiovascular disease initiation and progression.