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.

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.

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.

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.

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.

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.

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.

Chronic vitamin K antagonist therapy and bleeding risk in ST elevation myocardial infarction patients.

OBJECTIVES: Acute management of ST elevation myocardial infarction (STEMI) patients on chronic vitamin K antagonist (VKA) therapy is uncertain. This study aims to estimate in-hospital major bleeding risk among STEMI patients on chronic VKA treated with primary percutaneous coronary intervention (PCI); and determine the relationship between bleeding and acute treatments stratified by international normalised ratio (INR) values. METHODS: We retrospectively examined 120,270 STEMI patients treated with primary PCI at 586 national registry hospitals (2007-2012). RESULTS: Overall, 3101 patients (2.6%) were on VKA which was associated with increased in-hospital major bleeding risk when compared with patients not on VKA (17.0%, vs 10.1%; adjusted OR 1.26, 95% CI 1.13 to 1.40). In patients on VKA, admission INR ≥2.0 was not associated with an increase in bleeding risk compared to INR <2.0. Patients on VKA were more likely to receive clopidogrel or bivalirudin within 24 h of presentation (acute), but less likely to receive prasugrel, heparin, or glycoprotein IIb/IIIa inhibitors (GPI). In those patients, acute GPI was associated with increased bleeding risk (adjusted OR 1.92, 95% CI 1.54 to 2.40) while bivalirudin was associated with decreased risk (adjusted OR 0.69, 95% CI 0.55 to 0.86); bleeding risk associated with heparin, bivalirudin, ADP-receptor blockers, or GPI was similar between INR ≥2.0 and <2.0. CONCLUSIONS: In STEMI patients treated with primary PCI, chronic VKA therapy was associated with a significant increase in in-hospital major bleeding risk compared to no VKA therapy, irrespective of whether admission INR was ≥2.0 or not. In patients on VKA, GPI was associated with increased bleeding risk while bivalirudin was associated with decreased risk.

Outcome comparison of 600 mg versus 300 mg loading dose of clopidogrel for patients with ST-elevation myocardial infarction: a meta-analysis.

BACKGROUND: A 600-mg loading dose (LD) of clopidogrel has been shown to be superior to a 300-mg LD in inhibiting platelet function. However, data for clinical superiority are limited, and there is a paucity of adequately powered randomized trials investigating this issue. This meta-analysis was performed to determine the optimal LD of clopidogrel in ST-elevation myocardial infarction patients treated with primary percutaneous coronary intervention. METHODS: A meta-analysis of controlled trials and observational studies was performed comparing 600-mg with 300-mg LDs of clopidogrel. The primary efficacy end point was a major adverse cardiac event (MACE), and the primary safety end point was major bleeding. Data were extracted on an intention to treat basis. The X2 test was used to evaluate heterogeneity. A random effects model was used, and odds ratios (OR) were calculated using the Mantel-Haenszel method. RESULTS: Nine studies involving 18 623 patients were included in the efficacy analysis. Mean duration of follow-up was 8 months. Four studies were eligible for the safety analysis. The MACE risk was lower with a 600-mg LD (7.0% [650/9231]) than with a 300-mg LD (9.2% [867/9392]; OR, 0.75; 95% CI, 0.63-0.91). On the other hand, there was no significant difference in the major bleeding events between the 2 groups (2.5% [89/3551] with 600 mg vs 2.3% [63/2796] with 300 mg; OR, 0.84; 95% CI, (0.60-1.16). CONCLUSIONS: In ST-elevation myocardial infarction patients treated with primary percutaneous coronary intervention, administration of a 600-mg LD of clopidogrel is associated with a lower risk of MACE than is administration of a 300-mg LD, without increasing the risk of major bleeding.

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.

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.

The multifunctional Ca²âº/calmodulin-dependent kinase IIδ (CaMKIIδ) regulates arteriogenesis in a mouse model of flow-mediated remodeling.

OBJECTIVE: Sustained hemodynamic stress mediated by high blood flow promotes arteriogenesis, the outward remodeling of existing arteries. Here, we examined whether Ca²âº/calmodulin-dependent kinase II (CaMKII) regulates arteriogenesis. METHODS AND RESULTS: Ligation of the left common carotid led to an increase in vessel diameter and perimeter of internal and external elastic lamina in the contralateral, right common carotid. Deletion of CaMKIIδ (CaMKIIδ-/-) abolished this outward remodeling. Carotid ligation increased CaMKII expression and was associated with oxidative activation of CaMKII in the adventitia and endothelium. Remodeling was abrogated in a knock-in model in which oxidative activation of CaMKII is abolished. Early after ligation, matrix metalloproteinase 9 (MMP9) was robustly expressed in the adventitia of right carotid arteries of WT but not CaMKIIδ-/- mice. MMP9 mainly colocalized with adventitial macrophages. In contrast, we did not observe an effect of CaMKIIδ deficiency on other proposed mediators of arteriogenesis such as expression of adhesion molecules or smooth muscle proliferation. Transplantation of WT bone marrow into CaMKIIδ-/- mice normalized flow-mediated remodeling. CONCLUSION: CaMKIIδ is activated by oxidation under high blood flow conditions and is required for flow-mediated remodeling through a mechanism that includes increased MMP9 expression in bone marrow-derived cells invading the arterial wall.

Osteoprotegerin inhibits aortic valve calcification and preserves valve function in hypercholesterolemic mice.

BACKGROUND: There are no rigorously confirmed effective medical therapies for calcific aortic stenosis. Hypercholesterolemic Ldlr (-/-) Apob (100/100) mice develop calcific aortic stenosis and valvular cardiomyopathy in old age. Osteoprotegerin (OPG) modulates calcification in bone and blood vessels, but its effect on valve calcification and valve function is not known. OBJECTIVES: To determine the impact of pharmacologic treatment with OPG upon aortic valve calcification and valve function in aortic stenosis-prone hypercholesterolemic Ldlr (-/-) Apob (100/100) mice. METHODS: Young Ldlr (-/-) Apob (100/100) mice (age 2 months) were fed a Western diet and received exogenous OPG or vehicle (N = 12 each) 3 times per week, until age 8 months. After echocardiographic evaluation of valve function, the aortic valve was evaluated histologically. Older Ldlr (-/-) Apob (100/100) mice were fed a Western diet beginning at age 2 months. OPG or vehicle (N = 12 each) was administered from 6 to 12 months of age, followed by echocardiographic evaluation of valve function, followed by histologic evaluation. RESULTS: In Young Ldlr (-/-) Apob (100/100) mice, OPG significantly attenuated osteogenic transformation in the aortic valve, but did not affect lipid accumulation. In Older Ldlr (-/-) Apob (100/100) mice, OPG attenuated accumulation of the osteoblast-specific matrix protein osteocalcin by ∼80%, and attenuated aortic valve calcification by ∼ 70%. OPG also attenuated impairment of aortic valve function. CONCLUSIONS: OPG attenuates pro-calcific processes in the aortic valve, and protects against impairment of aortic valve function in hypercholesterolemic aortic stenosis-prone Ldlr (-/-) Apob (100/100) mice.