Cardiac stasis imaging, stroke, and silent brain infarcts in patients with nonischemic dilated cardiomyopathy.

Cardioembolic stroke is one of the most devastating complications of nonischemic dilated cardiomyopathy (NIDCM). However, in clinical trials of primary prevention, the benefits of anticoagulation are hampered by the risk of bleeding. Indices of cardiac blood stasis may account for the risk of stroke and be useful to individualize primary prevention treatments. We performed a cross-sectional study in patients with NIDCM and no history of atrial fibrillation (AF) from two sources: 1) a prospective enrollment of unselected patients with left ventricular (LV) ejection fraction <45% and 2) a retrospective identification of patients with a history of previous cardioembolic neurological event. The primary end point integrated a history of ischemic stroke or the presence intraventricular thrombus, or a silent brain infarction (SBI) by imaging. From echocardiography, we calculated blood flow inside the LV, its residence time (TR) maps, and its derived stasis indices. Of the 89 recruited patients, 18 showed a positive end point, 9 had a history of stroke or transient ischemic attack (TIA) and 9 were diagnosed with SBIs in the brain imaging. Averaged TR, [Formula: see text] performed well to identify the primary end point [AUC (95% CI) = 0.75 (0.61-0.89), P = 0.001]. When accounting only for identifying a history of stroke or TIA, AUC for [Formula: see text] was 0.92 (0.85-1.00) with odds ratio = 7.2 (2.3-22.3) per cycle, P < 0.001. These results suggest that in patients with NIDCM in sinus rhythm, stasis imaging derived from echocardiography may account for the burden of stroke.NEW & NOTEWORTHY Patients with nonischemic dilated cardiomyopathy (NIDCM) are at higher risk of stroke than their age-matched population. However, the risk of bleeding neutralizes the benefit of preventive oral anticoagulation. In this work, we show that in patients in sinus rhythm, the burden of stroke is related to intraventricular stasis metrics derived from echocardiography. Therefore, stasis metrics may be useful to personalize primary prevention anticoagulation in these patients.

Increased Chamber Resting Tone Is a Key Determinant of Left Ventricular Diastolic Dysfunction.

BACKGROUND: Twitch-independent tension has been demonstrated in cardiomyocytes, but its role in heart failure (HF) is unclear. We aimed to address twitch-independent tension as a source of diastolic dysfunction by isolating the effects of chamber resting tone (RT) from impaired relaxation and stiffness. METHODS: We invasively monitored pressure-volume data during cardiopulmonary exercise in 20 patients with hypertrophic cardiomyopathy, 17 control subjects, and 35 patients with HF with preserved ejection fraction. To measure RT, we developed a new method to fit continuous pressure-volume measurements, and first validated it in a computational model of loss of cMyBP-C (myosin binding protein-C). RESULTS: In hypertrophic cardiomyopathy, RT (estimated marginal mean [95% CI]) was 3.4 (0.4-6.4) mm Hg, increasing to 18.5 (15.5-21.5) mm Hg with exercise (P<0.001). At peak exercise, RT was responsible for 64% (53%-76%) of end-diastolic pressure, whereas incomplete relaxation and stiffness accounted for the rest. RT correlated with the levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide; R=0.57; P=0.02) and with pulmonary wedge pressure but following different slopes at rest and during exercise (R2=0.49; P<0.001). In controls, RT was 0.0 mm Hg and 1.2 (0.3-2.8) mm Hg in HF with preserved ejection fraction patients and was also exacerbated by exercise. In silico, RT increased in parallel to the loss of cMyBP-C function and correlated with twitch-independent myofilament tension (R=0.997). CONCLUSIONS: Augmented RT is the major cause of LV diastolic chamber dysfunction in hypertrophic cardiomyopathy and HF with preserved ejection fraction. RT transients determine diastolic pressures, pulmonary pressures, and functional capacity to a greater extent than relaxation and stiffness abnormalities. These findings support antimyosin agents for treating HF.

A comparison of the clinical efficacy of echocardiography and magnetic resonance for chronic aortic regurgitation.

AIMS: Timing surgery in chronic aortic regurgitation (AR) relies mostly on echocardiography. However, cardiac magnetic resonance (CMR) may be more accurate for quantifying regurgitation and left ventricular (LV) remodelling. We aimed to compare the technical and clinical efficacies of echocardiography and CMR to account for the severity of the disease, the degree of LV remodelling, and predict AR-related outcomes. METHODS AND RESULTS: We studied 263 consecutive patients with isolated AR undergoing echocardiography and CMR. After a median follow-up of 33 months, 76 out of 197 initially asymptomatic patients reached the primary endpoint of AR-related events: 6 patients (3%) were admitted for heart failure, and 70 (36%) underwent surgery. Adjusted survival models based on CMR improved the predictions of the primary endpoint based on echocardiography: R2 = 0.37 vs. 0.22, χ2 = 97 vs. 49 (P < 0.0001), and C-index = 0.80 vs. 0.70 (P < 0.001). This resulted in a net classification index of 0.23 (0.00-0.46, P = 0.046) and an integrated discrimination improvement of 0.12 (95% confidence interval 0.08-0.58, P = 0.02). CMR-derived regurgitant fraction (<28, 28-37, or >37%) and LV end-diastolic volume (<83, 183-236, or >236 mL) adequately stratified patients with normal EF. The agreement between techniques for grading AR severity and assessing LV dilatation was poor, and CMR showed better reproducibility. CONCLUSIONS: CMR improves the clinical efficacy of ultrasound for predicting outcomes of patients with AR. This is due to its better reproducibility and accuracy for grading the severity of the disease and its impact on the LV. Regurgitant fraction, LV ejection fraction, and end-diastolic volume obtained by CMR most adequately predict AR-related events.

Transvalvular jet velocity, aortic valve area, mortality, and cardiovascular outcomes.

AIMS: The interplay between aortic stenosis (AS), cardiovascular events, and mortality is poorly understood. In addition, how echocardiographic indices compare for predicting outcomes remains unexplored for the full range of AS severity. METHODS AND RESULTS: We prospectively calculated peak jet velocity (Vmax) and aortic valve area (AVA) in 5994 adult subjects with and without AS. We linked ultrasound data to 5-year mortality and clinical events obtained from electronic medical records. Proportional-hazard and negative binomial regression models were adjusted for relevant covariables such as age, sex, comorbidities, stroke-volume, LV ejection fraction, left valve regurgitation, aortic valve sclerosis or calcification, and valve replacement. We observed a strong linear relationship between Vmax and all-cause mortality (hazard ratio: 1.26, 95% confidence interval: 1.19-1.33 per 100 cm/s), cardiovascular events, as well as incidental and recurrent heart failure (HF). Adjusted risks were highly significant even at Vmax values in the range of 150-200 cm/s, risk curves separating very early after the index exam. Vmax was not associated with coronary, arrhythmic, cerebrovascular, or non-cardiovascular events. Although risks were confirmed when AVA was entered in place of Vmax, the risks estimated for categories based on the two indices were mismatched, even in patients with normal flow. An external cohort comprising 112 690 patients confirmed augmented risks of all-cause and cardiovascular mortality starting at values of Vmax and AVA in the range of mild AS. CONCLUSIONS: Aortic stenosis is strongly associated to all-cause mortality, cardiovascular mortality, and cardiac events, specifically HF. Risks increase in parallel to the degree of outflow obstruction but are apparent very early in patients with mild disease. Criteria for grading AS based on Vmax and AVA are mismatched in terms of outcomes.

Data from acellular human heart matrix.

Perfusion decellularization of cadaveric hearts removes cells and generates a cell-free extracellular matrix scaffold containing acellular vascular conduits, which are theoretically sufficient to perfuse and support tissue-engineered heart constructs. This article contains additional data of our experience decellularizing and testing structural integrity and composition of a large series of human hearts, "Acellular human heart matrix: a critical step toward whole heat grafts" (Sanchez et al., 2015) [1]. Here we provide the information about the heart decellularization technique, the valve competence evaluation of the decellularized scaffolds, the integrity evaluation of epicardial and myocardial coronary circulation, the pressure volume measurements, the primers used to assess cardiac muscle gene expression and, the characteristics of donors, donor hearts, scaffolds and perfusion decellularization process.

Potential drug-drug interactions in oncological adult inpatients at a Spanish hospital: epidemiology and risk factors.

BACKGROUND: Oncological patients are at high risk for drug-drug interactions (DDIs), which may contribute to therapeutic failure or lead to serious adverse events. OBJECTIVE: To determine the prevalence of potential DDIs in medication lists, to describe the most frequent DDIs and to investigate the possible risk factors associated with them. A prospective cohort study was performed at the Oncology Department of a tertiary hospital over a 12-week period. Twice a week, every inpatient's treatment sheet was collected and screened through two databases: Micromedex™ and Drug Interaction Facts™. All identified potential DDIs with a moderate or higher severity rating were recorded. Multivariate analysis was used to identify risk factors associated with DDIs. RESULT: A total of 1956 DDIs were detected in 699 treatment sheets. The prevalence of treatment sheets with DDIs was 81.0 % and 32.6 % by Micromedex™ and Drug Interaction Facts™, respectively. Central nervous depressant agents and antiemetics were the most commonly involved groups in DDIs. A higher number of non-antineoplastic drugs was related with potential DDIs [adjusted-OR 1.398 and 1.613 by Micromedex™ and Drug Interaction Facts™, respectively]. CONCLUSION The prevalence of potential DDIs was widely variable among databases. The main risk factor associated with DDIs was a higher number of non-antineoplastic medicines.

Acellular human heart matrix: A critical step toward whole heart grafts.

The best definitive treatment option for end-stage heart failure currently is transplantation, which is limited by donor availability and immunorejection. Generating an autologous bioartificial heart could overcome these limitations. Here, we have decellularized a human heart, preserving its 3-dimensional architecture and vascularity, and recellularized the decellularized extracellular matrix (dECM). We decellularized 39 human hearts with sodium-dodecyl-sulfate for 4-8 days. Cell removal and architectural integrity were determined anatomically, functionally, and histologically. To assess cytocompatibility, we cultured human cardiac-progenitor cells (hCPC), bone-marrow mesenchymal cells (hMSCs), human endothelial cells (HUVECs), and H9c1 and HL-1 cardiomyocytes in vitro on dECM ventricles up to 21 days. Cell survival, gene expression, organization and/or electrical coupling were analyzed and compared to conventional 2-dimensional cultures. Decellularization removed cells but preserved the 3-dimensional cardiac macro and microstructure and the native vascular network in a perfusable state. Cell survival was observed on dECM for 21 days. hCPCs and hMSCs expressed cardiocyte genes but did not adopt cardiocyte morphology or organization; HUVECs formed a lining of endocardium and vasculature; differentiated cardiomyocytes organized into nascent muscle bundles and displayed mature calcium dynamics and electrical coupling in recellularized dECM. In summary, decellularization of human hearts provides a biocompatible scaffold that retains 3-dimensional architecture and vascularity and that can be recellularized with parenchymal and vascular cells. dECM promotes cardiocyte gene expression in stem cells and organizes existing cardiomyocytes into nascent muscle showing electrical coupling. These findings represent a first step toward manufacturing human heart grafts or matrix components for treating cardiovascular disease.

Pharmacoepidemiological study of drug-drug interactions in onco-hematological pediatric patients.

BACKGROUND: Onco-hematological patients are particularly susceptible to drug-drug interactions (DDIs) because they often undergo multiple combined treatments. Some studies have analyzed the frequency of DDIs in adult patients with cancer; however, the prevalence of DDIs in children, and especially among pediatric cancer patients, remains unknown. OBJECTIVE: To determine the prevalence of DDIs in treatment sheets comparing two commonly used drug interaction databases, to describe the most common clinically relevant DDIs (CR-DDIs) and to investigate the risk factors associated with them. SETTING: An onco-hematological pediatric unit from a tertiary hospital in Spain. METHOD: A prospective, observational and descriptive study was carried out from November 2012 to February 2013. Twice a week, every patient's treatment sheet was collected. Each medication list was screened through two databases: Thomson Micromedex™ and Drug Interaction Facts™. All identified DDIs were graded by their level of severity. Summary statistics were used to describe patient and disease characteristics, most often prescribed drugs, and frequency, types and classification of CR-DDIs. Multivariate analysis was used to identify risk factors associated with CRDDIs. MAIN OUTCOME MEASURE: Prevalence of CR-DDIs was measured as percentage. RESULTS: A total of 506 potential DDIs were detected in 150 treatment sheets. The prevalence of CR-DDIs by Micromedex database and Drug Interaction Facts database were 44.7 and 51.3% respectively. Amikacin, azole antifungals, antiemetics and cyclosporine were the most frequent drugs involved in CR-DDIs. In multivariate analysis, the main risk factor associated with increased odds for CR-DDIs was a higher number of drugs. CONCLUSION: The frequency of potential DDIs was related to a higher number of drugs, being immunosuppressant and azole antifungal agents the most commonly involved drugs. The lack of agreement between different databases enhances the complexity to detect drug interactions in clinical practice.

Kounis syndrome secondary to amoxicillin use in an asthmatic patient.

A sixty-four year old man with a past history of hypercholesterolemia, asthma, food allergy, epilepsy and myocardial infarction was admitted to the emergency department because of a generalized erythema, nausea, vomiting, and chest pain after taking an oral dose of amoxicillin. Electrocardiography showed ST segment elevation in anterior leads. After coronary angiography, type 2 variant of Kounis syndrome was diagnosed. We present the first case of oral amoxicillin induced Kounis syndrome in an asthmatic patient with severe anaphylactic shock. The present report also shows that atopic people expressing an amplified mast cell degranulation may have more serious hemodynamic decompensation during hypersensitivity reactions. Case selective mast cell surface membrane stabilization should be considered a potential therapeutic strategy for people with food induced allergy, for atopic patients and for patients who have already experienced a first Kounis syndrome.