Physicians' perspectives on percutaneous left atrial appendage occlusion for patients with atrial fibrillation.

BACKGROUND: There has been an increasing uptake of transcatheter left atrial appendage occlusion (LAAO) for stroke reduction in atrial fibrillation. OBJECTIVES: To investigate the perceptions and approaches among a nationally representative sample of physicians. METHODS: Using the American Medical Association Physician Masterfile, we selected a random sample of 500 physicians from each of the specialties: general cardiologists, interventional cardiologists, electrophysiologists, and vascular neurologists. The participants received the survey by mail up to three times from November 9, 2021 to January 14, 2022. In addition to the questions about experiences, perceptions, and approaches, physicians were randomly assigned to 1 of the 4 versions of a patient vignette: white man, white woman, black man, and black woman, to investigate potential bias in decision-making. RESULTS: The top three reasons for considering LAAO were: a history of intracranial bleeding (94.3%), a history of major extracranial bleeding (91.8%), and gastrointestinal lesions (59.0%), whereas the top three reasons for withholding LAAO were: other indications for long-term oral anticoagulation (87.7%), a low bleeding risk (77.0%), and a low stroke risk (65.6%). For the reasons limiting recommendations for LAAO, 59.8% mentioned procedural risks, 42.6% mentioned "limiting efficacy data comparing LAAO to NOAC" and 32.8% mentioned "limited safety data comparing LAAO to NOAC." There was no difference in physicians' decision-making by patients' race, gender, or the concordance between patients' and physicians' race or gender. CONCLUSIONS: In the first U.S. national physician survey of LAAO, individual physicians' perspectives varied greatly, which provided information that will help customize future educational activities for different audiences. CONDENSED ABSTRACT: Although diverse practice patterns of LAAO have been documented, little is known about the reasoning or perceptions that drive these variations. Unlike prior surveys that were directed to Centers that performed LAAO, the current survey obtained insights from individual physicians, not only those who perform the procedures (interventional cardiologists and electrophysiologists) but also those who are closely involved in the decision-making and referral process (general cardiologists and vascular neurologists). The findings identify key evidence gaps and help prioritize future studies to establish a consistent and evidence-based best practice for AF stroke prevention.

Restructuring the Heart From Failure to Success: Role of Structural Interventions in the Realm of Heart Failure.

Heart failure through the spectrum of reduced (HFrEF), mid-range (or mildly reduced or HFmEF), and preserved ejection fraction (HFpEF), continues to plague patients' quality of life through recurrent admissions and high mortality rates. Despite tremendous innovation in medical therapy, patients continue to experience refractory congestive symptoms due to adverse left ventricular remodeling, significant functional mitral regurgitation (FMR), and right-sided failure symptoms due to significant functional tricuspid regurgitation (FTR). As most of these patients are surgically challenging for open cardiac surgery, the past decade has seen the development and evolution of different percutaneous structural interventions targeted at improving FMR and FTR. There is renewed interest in the sphere of left ventricular restorative devices to effect reverse remodeling and thereby improve effective stroke volume and patient outcomes. For patients suffering from HFpEF, there is still a paucity of disease-modifying effective medical therapies, and these patients continue to have recurrent heart failure exacerbations due to impaired left ventricular relaxation and high filling pressures. Structural therapies involving the implantation of inter-atrial shunt devices to decrease left atrial pressure and the development of implantable devices in the pulmonary artery for real-time hemodynamic monitoring would help redefine treatment and outcomes for patients with HFpEF. Lastly, there is pre-clinical data supportive of soft robotic cardiac sleeves that serve to improve cardiac function, can assist contraction as well as relaxation of the heart, and have the potential to be customized for each patient. In this review, we focus on the role of structural interventions in heart failure as it stands in current clinical practice, evaluate the evidence amassed so far, and review promising structural therapies that may transform the future of heart failure management.

Patterns of care for first-detected atrial fibrillation: Insights from the Get With The Guidelines® - Atrial Fibrillation registry.

BACKGROUND: Despite multiple trials comparing rate with rhythm control, there is no consensus on the optimal management of first-detected atrial fibrillation (AF). OBJECTIVE: We analyzed current patterns of care for first-detected AF in the nationwide Get With The Guidelines® - Atrial Fibrillation registry. METHODS: Patients hospitalized with first-detected AF from 2013 to 2019 were included, and a descriptive analysis was performed comparing planned rate with rhythm control. Multivariable logistic regression analysis was performed to identify predictors for choosing rhythm over rate control. RESULTS: Of the 86,759 patients with AF, 17.8% (15,473) had first-detected AF; 11,685 patients were included from 126 sites. Overall, 51.3% (5999) of patients were treated with rate control and 48.7% (5686) with rhythm control at admission. Patients with planned rhythm control had a shorter length of stay and were more likely to be discharged home than a facility. A higher percentage of patients with planned rhythm control were discharged on anticoagulation than those with planned rate control (75.6% vs 70.9%) despite a higher underlying stroke risk in the rate control group (higher median CHA2DS2-VASc score 4; Q1-Q3 2-5 for rate control vs 3; Q1-Q3 2-4 for rhyhtm control; P < .001). While Hispanic ethnicity, Medicaid insurance, age >70 years, and liver disease decreased the likelihood of rhythm control, factors such as heart failure, stroke, or prior bleeding diathesis had no association with the chosen treatment strategy. CONCLUSION: Less than half of the patients with first-detected AF receive rhythm control at admission. Given recent trial results, further studies should assess the long-term impact of rhythm control on patients' symptoms and quality of life, cardiovascular morbidity, and mortality.

What Is the Status of Regenerative Therapy in Heart Failure?

PURPOSE OF REVIEW: Heart failure remains a major public health concern with high burden of morbidity and mortality despite advances in pharmacotherapy, device therapy, and surgical and percutaneous techniques. Cardiac regeneration may have a role to play in these patients with a huge unmet need for these therapies in patients with chronic ischemic heart disease, post-infarct heart failure, dilated cardiomyopathy, and heart failure with preserved ejection fraction. RECENT FINDINGS: In this review, we focus on the pre-clinical and translational basis for different modes of cardiac regenerative medicine and then critically appraise the clinical evidence amassed from pivotal clinical trials focused on cardiac regeneration for ischemic and non-ischemic cardiomyopathies. Cardiac regenerative medicine is rapidly evolving with novel approaches involving cell-based, cell-free, tissue engineering, and hybrid therapies to achieve myocardial regeneration and repair. Further studies are warranted with a robust comparison arm with optimal contemporary medical therapy to translate regenerative therapies to a clinical reality.

Cardiac sarcoidosis masquerading as ventricular tachycardia storm: a challenging diagnosis.

A 67-year-old African-American woman with remote history of complete heart block (s/p pacemaker 3 years ago) and recent onset of ventricular tachycardia (VT) (s/p VT ablation and cardiac resynchronisation therapy defibrillator upgrade 3 months ago) presented to the hospital with VT storm. Workup showed newly reduced left ventricular ejection fraction with global hypokinesis (20%) and restrictive physiology. Positive technetium pyrophosphate scan was suspicious for TTR amyloid while serological workup revealed a monoclonal gammopathy. Cardiac MRI was contraindicated given remote brain aneurysm clip. Given clinical suspicion for cardiac sarcoidosis and divergent non-invasive workup, endomyocardial biopsy was performed which showed non-necrotising granulomas consistent with cardiac sarcoidosis. She was started on steroids with clinical improvement. Cardiac sarcoidosis is a challenging clinical diagnosis, particularly in patients without extracardiac manifestations. This case highlights the importance of a detailed and thorough workup of non-ischaemic cardiomyopathy and being cognizant of infiltrative disease as it can change patient management and outcomes.

Effect of institutional transcatheter aortic valve replacement volume on mortality: A systematic review and meta-analysis.

OBJECTIVE: We sought to conduct a systematic review and network meta-analysis to examine the association between institutional transcatheter aortic valve replacement (TAVR) volume and all-cause mortality. BACKGROUND: Since inception in 2011, there has been an exponential increase in the number of TAVR centers across the world. Multiple studies have questioned if a relationship exists between institutional TAVR volume and patient outcomes. METHODS: We performed a systematic literature search for relevant articles using a combination of free text terms in the title/abstract related to volume, TAVR, and patient outcomes. Two reviewers independently screened all titles/abstracts for eligibility based on pre-specified criteria. All-cause mortality data was pooled from eligible studies and centers were categorized as low-(30-50 cases), intermediate-, or high-volume (75-130 cases) based on their annual TAVR volumes. RESULTS: Our search yielded an initial list of 11,153 citations, 120 full text studies were reviewed and 7 studies met all inclusion and exclusion criteria, yielding a total of 1,93,498 TAVRs. Categorized according to center's annual volume; 25,062 TAVRs were performed in low-, 77,093 in intermediate- and 91,343 in high-volume centers. Network meta-analysis showed a relative reduction in mortality rates of 37%, 23% and 19%, for high volume versus low volume centers, high volume versus intermediate volume centers and intermediate versus low volume centers, respectively. CONCLUSIONS: Existing research clearly shows an inverse relationship between annual TAVR procedural volume and all-cause mortality. We need to focus on development of strong referral networks and consolidation rather than expansion of existing TAVR centers to improve patient outcomes, while ensuring adequate access-to-care.

Takotsubo cardiomyopathy caused by emotional stressors in the coronavirus disease 2019 (COVID-19) pandemic era.

The COVID-19 pandemic has had far-reaching consequences beyond the disease itself, including economic, social, political, religious, and psychological implications. This novel coronavirus has been shown to have cardiovascular manifestations in the form of arrhythmias, conduction disturbances, myocarditis, stress cardiomyopathy, myocardial injury and myocardial ischemia or infarction from increased microvascular and/or macrovascular coagulopathy. However, in addition to these direct effects, we are now starting to recognize indirect cardiovascular effects of COVID-19 in the form of increased incidence of Takutsobo cardiomyopathy in patients without any evidence of coronavirus infection presumably due to the increased psychological stress of social isolation and societal turbulence. In this case series, we present two post-menopausal women, presenting with chest pain and acute coronary syndrome, who are finally diagnosed with stress cardiomyopathy, triggered by increased emotional stress-related to the pandemic. There is data from a retrospective cohort analysis showing a fourfold increase in the incidence of acute coronary syndrome resulting from stress cardiomyopathy during the pandemic period compared to similar times periods before the pandemic. Hence, health care providers need to be cognizant of the emotional ramifications of the ongoing pandemic in the form of increased risk of Takotsubo cardiomyopathy. Moreover, urgent measures need to be taken to help the at-risk population cope with the ongoing stressors to help decrease the incidence of this cardiomyopathy.

Heart Brake: An Unusual Cardiac Manifestation of COVID-19.

A 49-year-old man presented with worsening high-grade fevers, dry cough, and shortness of breath. He tested positive for severe acute respiratory syndrome-coronavirus-2 and was noted to have bradycardia with intermittent high-degree atrioventricular block. However, cardiac biomarkers and echocardiographic findings were normal, thus making this an unusual and interesting manifestation of myocardial involvement of this novel coronavirus. (Level of Difficulty: Beginner.).

Regulation of angiogenesis by microRNAs in cardiovascular diseases.

Non-coding RNAs are functional RNA molecules comprising the majority of human transcriptome. Only about 1.5% of the human genome is transcribed into messenger RNAs (mRNA) that are translated into proteins. Among the non-coding RNAs, miRNAs are extensively studied and miR targets in endothelial cells, perivascular cells, and angiogenic signaling are relatively well defined. MicroRNAs not only regulate transcripts in situ but also function as paracrine mediators in affecting angiogenesis at distant sites. Exosomal miRs are implicated in modulating endothelial cell function and angiogenesis. Thus miRs have been shown to affect tissue microenvironment in a multitude of ways. A comprehensive analysis of the role of miRs in modulation of angiogenesis and their impact on cardiovascular diseases is presented in this review.

Cell-permeable iron inhibits vascular endothelial growth factor receptor-2 signaling and tumor angiogenesis.

Angiogenesis is important for tumor growth and metastasis. Hypoxia in tumors drives this angiogenic response by stabilizing Hypoxia Inducible Factors (HIF) and target genes like Vascular Endothelial Growth Factor (VEGF). HIF stability is regulated by Prolylhydroxylases (PHD)-mediated modification. Iron is an important cofactor in regulating the enzymatic activity of PHDs. Reducing intracellular iron, for instance, mimics hypoxia and induces a pro-angiogenic response. It is hypothesized that increasing the intracellular iron levels will have an opposite, anti-angiogenic effect. We tested this hypothesis by perturbing iron homeostasis in endothelial cells using a unique form of iron, Ferric Ammonium Citrate (FAC). FAC is a cell-permeable form of iron, which can passively enter into cells bypassing the transferrin receptor mediated uptake of transferrin-bound iron. Our studies show that FAC does not decrease the levels of HIF-1α and HIF-2α in endothelial cells but inhibits the autocrine stimulation of VEGF-Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) system by blocking receptor tyrosine kinase phosphorylation. FAC inhibits VEGF-induced endothelial cell proliferation, migration, tube formation and sprouting. Finally, systemic administration of FAC inhibits VEGF and tumor cell-induced angiogenesis in vivo. In conclusion, our studies show that cell-permeable iron attenuates VEGFR-2 mediated signaling and inhibits tumor angiogenesis.

Minnelide Overcomes Oxaliplatin Resistance by Downregulating the DNA Repair Pathway in Pancreatic Cancer.

INTRODUCTION: Oxaliplatin is part of pancreatic cancer therapy in the FOLFIRINOX or GEMOX/XELOX regimen. DNA damage repair is one of the factors responsible for oxaliplatin resistance that eventually develops in this cancer. Triptolide/Minnelide has been shown to be effective against pancreatic cancer in preclinical trials. In this study, we evaluated the efficacy of combination of triptolide and oxaliplatin against pancreatic cancer. METHODS: Highly aggressive pancreatic cancer cells (MIA PaCa-2 and PANC-1) were treated with oxaliplatin (0-10 µM), low-dose triptolide (50 nM), or a combination of both for 24-48 h. Cell viability, apoptosis, and DNA damage were evaluated by appropriate methods. Nucleotide excision repair pathway components were quantitated using qPCR and Western blot. Combination of low doses of Minnelide and oxaliplatin was tested in an orthotopic murine model of pancreatic cancer. RESULTS: Proliferation of pancreatic cancer cells was markedly inhibited by combination treatment. Triptolide potentiated apoptotic cell death induced by oxaliplatin and sensitized cancer cells towards oxaliplatin-induced DNA damage by suppressing the oxaliplatin-induced DNA damage repair pathway. Combination of low doses of Minnelide and oxaliplatin inhibited tumor progression by inducing significant apoptotic cell death in these tumors. CONCLUSIONS: Combination of low doses of Minnelide and oxaliplatin has immense potential to emerge as a novel therapeutic strategy against pancreatic cancer.

Control of Apoptosis in Treatment and Biology of Pancreatic Cancer.

Pancreatic cancer is estimated to be the 12th most common cancer in the United States in 2014 and yet this malignancy is the fourth leading cause of cancer-related death in the United States. Late detection and resistance to therapy are the major causes for its dismal prognosis. Apoptosis is an actively orchestrated cell death mechanism that serves to maintain tissue homoeostasis. Cancer develops from normal cells by accruing significant changes through one or more mechanisms, leading to DNA damage and mutations, which in a normal cell would induce this programmed cell death pathway. As a result, evasion of apoptosis is one of the hallmarks of cancer cells. PDAC is notoriously resistant to apoptosis, thereby explaining its aggressive nature and resistance to conventional treatment modalities. The current review is focus on understanding different intrinsic and extrinsic pathways in pancreatic cancer that may affect apoptosis in this disease.

Hypoxia Differentially Regulates Arterial and Venous Smooth Muscle Cell Migration.

OBJECTIVE: Intimal hyperplasia (IH) is a clinical concern leading to failure of up to 50% of vein grafts and 10% of arterial grafts after 10 years with no known current treatment. Recent studies have shown that hypoxia differentially regulates proliferation of vein derived smooth muscle cells (V-SMC) compared to artery derived smooth muscle cells (A-SMC). The objective of this study is to evaluate the effect of hypoxia on cellular migration and the mechanisms underlying the differential effects of hypoxia on A-SMC and V-SMC migration. METHODS AND RESULTS: Hypoxic treatment (3-5% O2) of Smooth Muscle Cells (SMC) resulted in differential migration in scratch wound and electric cell substrate impedance sensing (ECIS) assays. Hypoxia led to greater migration compared to normoxia with venous derived wound closure (V-SMC 30.8% Normoxia to 67% Hypoxia) greater than arterial wound closure (A-SMC 6.2% Normoxia to 24.7% Hypoxia). Paracrine factors secreted by hypoxic endothelial cells induced more migration in SMC compared to factors secreted by normoxic endothelial cells. Migration of V-SMC was greater than A-SMC in the presence of paracrine factors. Neutralizing antibody to Vascular Endothelial Growth Factor Receptor -1 (VEGFR-1) completely inhibited V-SMC migration while there was only partial inhibition of A-SMC migration. A-SMC migration was completely inhibited by Platelet Derived Growth Factor BB (PDGF-BB) neutralizing antibody. p38 Mitogen Activated Protein kinase (p38 MAPK) inhibitor pre-incubation completely inhibited migration induced by paracrine factors in both A-SMC and V-SMC. CONCLUSION: Our study determines that SMC migration under hypoxia occurs via both an autocrine and paracrine mechanism and is dependent on Vascular Endothelial Growth Factor-A (VEGF-A) in V-SMC and PDGF-BB in A-SMC. Migration of both A-SMC and V-SMC is inhibited by p38 MAPK inhibitor. These studies suggest that pharmacotherapeutic strategies directed at modulating p38 MAPK activity can be exploited to prevent IH in vascular grafts.

Health Related Quality of Life in Indian Children with Cystic Fibrosis.

OBJECTIVE: This study was devised to translate Cystic Fibrosis Questionnaire-Revised to Hindi and administer it to Indian children and adolescents diagnosed with cystic fibrosis. DESIGN: Cross-sectional study. SETTING: This study was carried out in cystic fibrosis patients attending Pediatric Chest Clinic of a tertiary-care hospital in Northern India from July 2012 to December 2012. PARTICIPANTS: 45 children (6-13 years) and their parents, and 14 adolescents. Patients with unstable health in the past two weeks were excluded. INTERVENTION: Cystic Fibrosis Questionnaire- Revised translated in Hindi was administered. Clinical evaluation and scoring, throat swab cultures and spirometry were also done during the same visit. MAIN OUTCOME MEASURES: Health Related Quality of Life scores were the primary measures, and clinical scores, swab cultures and spirometry were secondary measures. RESULTS: Cronbachs alpha ranged from 0.020-0.863.The Factor analysis indicated that most test-items correlated more with competing scales than the intended scales. Convergence between self and proxy-rating was found to be dependent on the domain. The Cystic Fibrosis Questionnaire- Revised scores correlated well with clinical scores (r=0.65,P=0.011), Pseudomonas spp culture data and pulmonary function tests. There was an inverse relation between Health Related Quality of Life scores and age at diagnosis (r=-0.339, P=0.02). CONCLUSIONS: Hindi versions of Cystic Fibrosis Questionnaire- Revised: Child, Adolescent and Parents instruments will act as an important step towards data on Health Related Quality of Life of Indian patients with cystic fibrosis.