Cardiac Rehabilitation During COVID-19 Pandemic: Highlighting the Value of Home-Based Programs.

Cardiac rehabilitation (CR) is a class I treatment for cardiovascular disease, however, underutilization of these services remains. Home-based CR (HBCR) models have been implemented as a potential solution to addressing access barriers to CR services. Home-based models have been shown to be effective, however, there continues to be large variation of protocols and minimal evidence of effectiveness in higher risk populations. In addition, lack of reimbursement models has discouraged the widespread adoption of HBCR. During the coronavirus 2019 (COVID-19) pandemic, an even greater gap in CR care has been present due to decreased availability of on-site services. The COVID-19 pandemic presents a time to highlight the value and experiences of home-based models as clinicians search for ways to continue to provide care. Continued review and standardization of HBCR models are essential to provide care for a wider range of patients and circumstances.

Creating and disseminating a home-based cardiac rehabilitation program: experience from the Veterans Health Administration.

BACKGROUND: Cardiac rehabilitation (CR) programs provide significant benefit for people with cardiovascular disease. Despite these benefits, such services are not universally available. We designed and evaluated a national home-based CR (HBCR) program in the Veterans Health Administration (VHA). The primary aim of the study was to examine barriers and facilitators associated with site-level implementation of HBCR. METHODS: This study used a convergent parallel mixed-methods design with qualitative data to analyze the process of implementation, quantitative data to determine low and high uptake of the HBCR program, and the integration of the two to determine which facilitators and barriers were associated with adoption. Data were drawn from 16 VHA facilities, and included semi-structured interviews with multiple stakeholders, document analysis, and quantitative analysis of CR program attendance codes. Qualitative data were analyzed using the Consolidated Framework for Implementation Research codes including three years of document analysis and 22 interviews. RESULTS: Comparing high and low uptake programs, readiness for implementation (leadership engagement, available resources, and access to knowledge and information), planning, and engaging champions and opinion leaders were key to success. High uptake sites were more likely to seek information from the external facilitator, compared to low uptake sites. There were few adaptations to the design of the program at individual sites. CONCLUSION: Consistent and supportive leadership, both clinical and administrative, are critical elements to getting HBCR programs up and running and sustaining programs over time. All sites in this study had external funding to develop their program, but high adopters both made better use of those resources and were able to leverage existing resources in the setting. These data will inform broader policy regarding use of HBCR services.

Spontaneous Aortic Regurgitation and Valvular Cardiomyopathy in Mice.

OBJECTIVE: We studied the mechanistic links between fibrocalcific changes in the aortic valve and aortic valve function in mice homozygous for a hypomorphic epidermal growth factor receptor mutation (Wave mice). We also studied myocardial responses to aortic valve dysfunction in Wave mice. APPROACH AND RESULTS: At 1.5 months of age, before development of valve fibrosis and calcification, aortic regurgitation, but not aortic stenosis, was common in Wave mice. Aortic valve fibrosis, profibrotic signaling, calcification, osteogenic markers, lipid deposition, and apoptosis increased dramatically by 6 and 12 months of age in Wave mice. Aortic regurgitation remained prevalent, however, and aortic stenosis was rare, at all ages. Proteoglycan content was abnormally increased in aortic valves of Wave mice at all ages. Treatment with pioglitazone prevented abnormal valve calcification, but did not protect valve function. There was significant left ventricular volume overload, hypertrophy, and fetal gene expression, at all ages in Wave mice with aortic regurgitation. Left ventricular systolic function was normal until 6 months of age in Wave mice, but became impaired by 12 months of age. Myocardial transverse tubules were normal in the presence of left ventricular hypertrophy at 1.5 and 3 months of age, but became disrupted by 12 months of age. CONCLUSIONS: We present the first comprehensive phenotypic and molecular characterization of spontaneous aortic regurgitation and volume-overload cardiomyopathy in an experimental model. In Wave mice, fibrocalcific changes are not linked to valve dysfunction and are epiphenomena arising from structurally incompetent myxomatous valves.

Oxidized Ca(2+)/calmodulin-dependent protein kinase II triggers atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is a growing public health problem without adequate therapies. Angiotensin II and reactive oxygen species are validated risk factors for AF in patients, but the molecular pathways connecting reactive oxygen species and AF are unknown. The Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) has recently emerged as a reactive oxygen species-activated proarrhythmic signal, so we hypothesized that oxidized CaMKIIδ could contribute to AF. METHODS AND RESULTS: We found that oxidized CaMKII was increased in atria from AF patients compared with patients in sinus rhythm and from mice infused with angiotensin II compared with mice infused with saline. Angiotensin II-treated mice had increased susceptibility to AF compared with saline-treated wild-type mice, establishing angiotensin II as a risk factor for AF in mice. Knock-in mice lacking critical oxidation sites in CaMKIIδ (MM-VV) and mice with myocardium-restricted transgenic overexpression of methionine sulfoxide reductase A, an enzyme that reduces oxidized CaMKII, were resistant to AF induction after angiotensin II infusion. CONCLUSIONS: Our studies suggest that CaMKII is a molecular signal that couples increased reactive oxygen species with AF and that therapeutic strategies to decrease oxidized CaMKII may prevent or reduce AF.

Aortic valve sclerosis in mice deficient in endothelial nitric oxide synthase.

Risk factors for fibrocalcific aortic valve disease (FCAVD) are associated with systemic decreases in bioavailability of endothelium-derived nitric oxide (EDNO). In patients with bicuspid aortic valve (BAV), vascular expression of endothelial nitric oxide synthase (eNOS) is decreased, and eNOS(-/-) mice have increased prevalence of BAV. The goal of this study was to test the hypotheses that EDNO attenuates profibrotic actions of valve interstitial cells (VICs) in vitro and that EDNO deficiency accelerates development of FCAVD in vivo. As a result of the study, coculture of VICs with aortic valve endothelial cells (vlvECs) significantly decreased VIC activation, a critical early phase of FCAVD. Inhibition of VIC activation by vlvECs was attenuated by N(G)-nitro-l-arginine methyl ester or indomethacin. Coculture with vlvECs attenuated VIC expression of matrix metalloproteinase-9, which depended on stiffness of the culture matrix. Coculture with vlvECs preferentially inhibited collagen-3, compared with collagen-1, gene expression. BAV occurred in 30% of eNOS(-/-) mice. At age 6 mo, collagen was increased in both bicuspid and trileaflet eNOS(-/-) aortic valves, compared with wild-type valves. At 18 mo, total collagen was similar in eNOS(-/-) and wild-type mice, but collagen-3 was preferentially increased in eNOS(-/-) mice. Calcification and apoptosis were significantly increased in BAV of eNOS(-/-) mice at ages 6 and 18 mo. Remarkably, these histological changes were not accompanied by physiologically significant valve stenosis or regurgitation. In conclusion, coculture with vlvECs inhibits specific profibrotic VIC processes. In vivo, eNOS deficiency produces fibrosis in both trileaflet and BAVs but produces calcification only in BAVs.

Coronary collateral circulation: its relevance.

The interest in coronary collateral circulation (CCC) as "natural bypasses" is growing, especially in patients in whom the extent of coronary atherosclerosis is too severe to allow for conventional revascularization. The anatomic foundation of CCC has been recognized for long time. Recently, reliable methods have become available for the assessment of the adequacy of collateral flow. However, the debate regarding the importance of CCC in the different clinical settings continues. In this article, we present the recent progress in the understanding of anatomy and physiology of the CCC and focus on the studies addressing their functional significance in acute, subacute, and chronic coronary artery disease. In addition, we provide a focused update on the essential role of collateral circulation in the management of coronary chronic total occlusions.

Mitral Valve Echodensities in a Young-Adult Female with Relapsing Polychondritis, Transiently Positive Lupus Anticoagulant, and Systemic Embolism.

Background: Valvular strands seen on echocardiography carry a wide differential diagnosis and may not always have a clear etiology despite taking clinical context into account. The decision of whether to provide anticoagulation for these lesions can be challenging. Case Presentation. A young adult female with an extensive rheumatologic history involving relapsing polychondritis and positive lupus anticoagulant presents to the emergency department with a discolored and painful right toe, as well as right auricular pain and swelling. Initial work-up revealed a possible splenic infarct, vasculitis of the right lower extremity, and mitral valve echodensities on echocardiography, without evidence of infective endocarditis. Due to concern that nonbacterial thrombotic endocarditis may be the cause of the patient's thromboembolic event, her valvular lesions were treated with low molecular weight heparin while awaiting serial imaging. When follow-up echocardiography showed no change in the size of her mitral valve lesions, which would be most consistent with Lambl's excrescences, the care team still faced a decision about which long-term anticoagulation to prescribe. This patient of childbearing age wished to avoid the teratogenicity and long-term monitoring associated with warfarin therapy. Although warfarin was the preferred agent for the patient's rheumatologic comorbidities, she elected to receive enoxaparin therapy for long-term thromboembolism prophylaxis. Conclusions: Even when accounting for clinical context, valvular lesions seen on echocardiography often have uncertain etiology and may require time and serial imaging to determine which treatment to pursue. When long-term anticoagulation is provided for females of childbearing age, shared decision-making with consideration of the patient's personal priorities and comorbidities is essential.

Acute Left Atrial Appendage Thrombus Formation During Transcatheter Mitral Valve Edge-to-Edge Repair.

We present a case of a 75-year-old man who developed an acute left atrial appendage thrombus immediately following mitral valve transcatheter edge to edge repair despite adequate intraprocedural anticoagulation. The patient was managed with enoxaparin to warfarin bridging with no obvious thromboembolic events on follow-up. Attention to anticoagulation is important to reduce thromboembolic risk during mitral valve transcatheter edge to edge repair. (Level of Difficulty: Intermediate.).

Home-Based Cardiac Rehabilitation: EXPERIENCE FROM THE VETERANS AFFAIRS.

PURPOSE: The conceptual utility of home-based cardiac rehabilitation (HBCR) is widely acknowledged. However, data substantiating its effectiveness and safety are limited. This study evaluated effectiveness and safety of the Veterans Affairs (VA) national HBCR program. METHODS: Veterans completed a 12-wk HBCR program over 18 mo at 25 geographically dispersed VA hospitals. Pre- to post-changes were compared using paired t tests. Patient satisfaction and adverse events were also summarized descriptively. RESULTS: Of the 923 Veterans with a mean age of 67.3 ± 10.6 yr enrolled in the HBCR program, 572 (62%) completed it. Findings included significant improvements in exercise capacity (6-min walk test distance: 355 vs 398 m; P < .05; Duke Activity Status Index: 27.1 vs 33.5; P < .05; self-reported steps/d: 3150 vs 4166; P < .05); depression measured by Patient Health Questionnaire (6.4 vs 4.9; P < .0001); cardiac self-efficacy (33.1 vs 39.2; P < .0001); body mass index (31.5 vs 31.1 kg/m2; P = .0001); and eating habits measured by Rate Your Plate, Heart (47.2 vs 51.1; P < .05). No safety issues were related to HBCR participation. Participants were highly satisfied. CONCLUSIONS: The VA HBCR program demonstrates strong evidence of effectiveness and safety to a wide range of patients, including those with high clinical complexity and risk. HBCR provides an adjunct to site-based programs and access to cardiac rehabilitation. Additional research is needed to assess long-term effects, cost-effectiveness, and sustainability of the model.

Obstructive bioprosthetic mitral valve thrombosis.

Bioprosthetic valve thrombosis (BPVT) is not uncommon but can be under diagnosed due to the lack of awareness and technical limitations of echocardiography. When suspecting BPVT, it is imperative to consider multimodality imaging to establish the diagnosis as early treatment can alter the clinical course. Here we present a case series of two patients with a history of rheumatic heart disease status post bioprosthetic mitral valve replacement who presented with acute heart failure symptoms. In both cases, supplemental imaging with real-time 3D echocardiography was critical in establishing a diagnosis of BPVT, resulting in timely treatment. These cases support updating current guidelines for the management of patients with bioprosthetic valve replacement to include more frequent surveillance imaging even if patients are asymptomatic.

Meta-Analysis Evaluating Calcium Channel Blockers and the Risk of Peripheral Arterial Disease in Patients With Hypertension.

Clinical studies have shown that calcium channel blockers (CCB) can mitigate the progression of atherosclerosis. Their role in the primary prevention of peripheral artery disease (PAD) is unclear. We conducted a meta-analysis of randomized control trials (RCT) to compare the impact of CCB on the incidence of PAD in patients with hypertension. A comprehensive review of the literature was performed in PubMed and Cochrane registry. Studies were included if they were RCT and had outcome data on PAD with a follow-up duration of at least 6 months. CCB formed the intervention group, whereas the control group was constituted by either placebo or active treatment with any of the other antihypertensive medications. A random-effects meta-analysis was performed, and we report odds ratio as a measure of treatment effect. Our search identified 934 trials, of which 7 RCTs with 71,971 patients fulfilled the inclusion criteria. The mean duration of follow-up was 3.8 years. In patients receiving CCB, PAD events occurred in 547 out of 27,502 patients (2%) compared with 1,263 out of 42,659 patients in the control group (3%). Based on the random-effect model, the odds for development of PAD in hypertensive patients treated with CCB compared with the control group was 0.70 (95% confidence interval of 0.58 to 0.86, p = 0.0005). In conclusion, this meta-analysis of RCTs of hypertensive patients, we found that treatment with CCB was strongly associated with a decrease in the PAD compared with other antihypertensive agents or placebo.

Effect of ß-blocker therapy in diabetic patients with stable coronary heart disease: a meta-analysis.

BACKGROUND: ß-blocker (BB) therapy is a cornerstone for the treatment of coronary heart disease (CHD). The evidence of the benefit from long-term BB therapy in diabetic patients with stable CHD is scarce. This meta-analysis summarizes the evidence relating to the BB therapy in diabetic patients with stable CHD. METHODS: A meta-analysis was performed according to PRISMA and MOOSE guidelines for reporting of systematic reviews of observational studies. PubMed, Embase, and Cochrane central were searched and two authors independently screened studies for eligibility. The quality of studies was assessed with the Newcastle Ottawa scale. The primary outcome of interest was all-cause mortality, cardiovascular (CV) mortality and major adverse cardiovascular events (MACE) in diabetic patients with and without BB therapy. A generic inverse variance model was used to pool odds ratio or hazards ratio from included studies to calculate the overall effect estimate. The significance threshold was set at P-value < 0.05. Heterogeneity was assessed by I 2. RESULTS: Four non-randomized studies with 9515 participants were selected for the analyses. Four studies were post-hoc analyses of randomized controlled trials, and one article was an analysis of a nationally representative survey. In a fixed effects model, BB therapy in diabetic patients with stable CHD was found to be associated with increased risk of CV mortality, and MACE (27% and 32% respectively; P-value < 0.05) and was not associated with a reduction in all-cause mortality (HR 1.12; 95% CI: 0.94-1.33; P-value = 0.22). CONCLUSION: BB therapy in diabetic patients with stable CHD appears to be linked to higher mortality. Large randomized trials are needed in this population to confirm these findings.

Pulmonary hypertension in beta-thalassemia major and the role of L-carnitine therapy.

Cardiac complications, such as pulmonary hypertension (PHT), are the leading cause of death in beta-thalassemia patients. L-Carnitine, due to its role in fatty acid oxidation, might help control the elevation in pulmonary artery systolic pressure (PASP). The objectives of this study were to assess the prevalence of PHT in beta-thalassemia major patients, identify clinical predictors for its development, and determine the potential effects of L-carnitine. In total, 32 patients with beta-thalassemia major were recruited; 16 age- and sex-matched children constituted the control group. Cardiac evaluation was performed by using echocardiography. The patients with PHT received 50 mg/kg/day L-carnitine orally for 3 months and were then reevaluated. Based on PASP, the patients were divided into group A without PHT and group B with PHT. The prevalence of PHT was 37.5%. The other echocardiographic measurements were not significantly different between groups A and B. PASP did not have any significant correlation with the following variables: age, total number of blood units received, splenic status, serum ferritin level, and ejection fraction. Following the administration of L-carnitine, there was a significant decrease in the mean PASP from 33.96 +/- 7.85 to 24.11 +/- 7.61. All cardiac dimensions decreased following L-carnitine, but the changes were not statistically significant. Even though beta-thalassemia major resulted in an elevation in the PASP in only a fraction of the patients, it seems to have an impact on the heart dimensions and function of all patients. No clinical predictors were identified. Oral administration of L-carnitine appears to significantly improve PASP.

Discovery of an Experimental Model of Unicuspid Aortic Valve.

BACKGROUND: The epithelial growth factor receptor family of tyrosine kinases modulates embryonic formation of semilunar valves. We hypothesized that mice heterozygous for a dominant loss-of-function mutation in epithelial growth factor receptor, which are EgfrVel/+ mice, would develop anomalous aortic valves, valve dysfunction, and valvular cardiomyopathy. METHODS AND RESULTS: Aortic valves from EgfrVel/+ mice and control mice were examined by light microscopy at 2.5 to 4 months of age. Additional EgfrVel/+ and control mice underwent echocardiography at 2.5, 4.5, 8, and 12 months of age, followed by histologic examination. In young mice, microscopy revealed anatomic anomalies in 79% of EgfrVel/+ aortic valves, which resembled human unicuspid aortic valves. Anomalies were not observed in control mice. At 12 months of age, histologic architecture was grossly distorted in EgfrVel/+ aortic valves. Echocardiography detected moderate or severe aortic regurgitation, or aortic stenosis was present in 38% of EgfrVel/+ mice at 2.5 months of age (N=24) and in 74% by 8 months of age. Left ventricular enlargement, hypertrophy, and reversion to a fetal myocardial gene expression program occurred in EgfrVel/+ mice with aortic valve dysfunction, but not in EgfrVel/+ mice with near-normal aortic valve function. Myocardial fibrosis was minimal or absent in all groups. CONCLUSIONS: A new mouse model uniquely recapitulates salient functional, structural, and histologic features of human unicuspid aortic valve disease, which are phenotypically distinct from other forms of congenital aortic valve disease. The new model may be useful for elucidating mechanisms by which congenitally anomalous aortic valves become critically dysfunctional.

Thalidomide and thrombosis. A meta-analysis.

With the increase in the number of reports and trials on the use of thalidomide as a part of the treatment of different medical conditions, particularly multiple myeloma (MM), it was observed that this drug might be associated with an increase in the risk of venous thromboembolic (VTE) events. It was the objective of this study to assess this risk, to check whether it might be affected by the concomitant administration of other medications, specifically dexamethasone, and to study the effect of anticoagulation and anti-platelet medications. A literature search for articles describing the use of thalidomide and the resultant VTE events was performed, and 50 articles were reviewed. A sample consisting of 3,322 patients resembling the above-mentioned studies was designed, and multivariate logistic regression was conducted. While thalidomide, dexamethasone and their combination were found to significantly increase the risk of VTE events among MM patients by 2.6, 2.8 and eight times, respectively, "adequate" anticoagulation significantly reduced the risk. In conclusion, patients receiving thalidomide should be carefully monitored for thromboembolic events, and those receiving concomitantly dexamethasone or other chemotherapy should be followed even more closely. Administering prophylactic doses of low-molecular-weight heparin or warfarin with therapeutic International Normalized Ratio reduces the risk of thromboembolic events among MM patients.

Effect of L-carnitine on the physical fitness of thalassemic patients.

Poor physical fitness is a common problem among thalassemic patients. L-Carnitine plays an essential role in fatty acid beta-oxidation, a process especially important in the organs that preferentially use fatty acid as a source of energy such as the myocardium and the skeletal muscles. The main objective of this study is to assess the effect of the administration of oral L-carnitine on exercise tolerance and physical fitness in patients with thalassemia major. Thirty patients followed up at the New Cairo University Children Hospital were included in this study. Clinical, laboratory, and cardiopulmonary exercise testing were performed before and after 6 months of oral L-carnitine therapy (50 mg/kg/day). The oxygen consumption, cardiac output, and oxygen pulse at maximal exercise significantly increased after L-carnitine therapy (p<0.001, p=0.002 and p<0.001, respectively). However, there was no significant change in minute ventilation and ventilatory equivalent of carbon dioxide (p=0.07 and p=0.06, respectively). A weak but positive correlation between the age of the patients and the degree of improvement in exercise parameters was noted. There was also significant increase in the blood transfusion intervals after L-carnitine administration (p=0.008). However, there was no significant change in hemoglobin concentration (p=0.4). L-Carnitine seems to be a safe and effective adjunctive therapeutic approach in thalassemic patients. It improves their cardiac performance and physical fitness. The younger the patients are, the higher is the degree of improvement in their exercise parameters.

A review of the off-label use of recombinant activated factor VII in a developing country tertiary care center.

Recombinant activated factor VII (rFVIIa) was first approved for treatment of congenital hemophilia. It could, however, also have a role in management of patients without pre-existing coagulopathies who undergo surgical procedures, have life-threatening hemorrhages, or sustain traumas associated with major blood loss. A retrospective chart review was performed for all cases given rFVIIa at American University of Beirut Medical Center (AUB MC). Patients with a previous medical history of thrombophilia were excluded. There were four pediatric patients with a mean age younger than 1 year. Adult patients' mean age was 64.5 +/- 17.4 years. The most common off-label uses for rFVIIa are control of hemorrhage during the repair of aortic dissection (4/17 cases) or following intracerebral hemorrhage (4/17 case). One trauma patient received the medication. Complications included cerebral ischemia in one patient. Three of the patients died but their death was not related to the bleeding or the medication. Based on the prognostic score proposed by Biss and Hanley, seven patients were low risk, four intermediate risk, and six high risk. Although off-label use of rFVIIa at AUB MC was supported by published reports, and associated with few complications, guidelines are required to control use of this medication.