A novel risk model for predicting potentially life-threatening arrhythmias in non-ischemic dilated cardiomyopathy (DCM-SVA risk).

BACKGROUND: Non-ischemic dilated cardiomyopathy (DCM) can be complicated by sustained ventricular arrhythmias (SVA) and sudden cardiac death (SCD). By now, left-ventricular ejection fraction (LV-EF) is the main guideline criterion for primary prophylactic ICD implantation, potentially leading either to overtreatment or failed detection of patients at risk without severely impaired LV-EF. The aim of the European multi-center study DETECTIN-HF was to establish a clinical risk calculator for individualized risk stratification of DCM patients. METHODS: 1393 patients (68% male, mean age 50.7 ± 14.3y) from four European countries were included. The outcome was occurrence of first potentially life-threatening ventricular arrhythmia. The model was developed using Cox proportional hazards, and internally validated using cross validation. The model included seven independent and easily accessible clinical parameters sex, history of non-sustained ventricular tachycardia, history of syncope, family history of cardiomyopathy, QRS duration, LV-EF, and history of atrial fibrillation. The model was also expanded to account for presence of LGE as the eight8h parameter for cases with available cMRI and scar information. RESULTS: During a mean follow-up period of 57.0 months, 193 (13.8%) patients experienced an arrhythmic event. The calibration slope of the developed model was 00.97 (95% CI 0.90-1.03) and the C-index was 0.72 (95% CI 0.71-0.73). Compared to current guidelines, the model was able to protect the same number of patients (5-year risk ≥8.5%) with 15% fewer ICD implantations. CONCLUSIONS: This DCM-SVA risk model could improve decision making in primary prevention of SCD in non-ischemic DCM using easily accessible clinical information and will likely reduce overtreatment.

Generation of iPSC line from MYH7 R403L mutation carrier with severe hypertrophic cardiomyopathy and isogenic CRISPR/Cas9 corrected control.

MYH7 is a major gene responsible for hypertrophic cardiomyopathy (HCM). From patient's skin fibroblasts, we derived an iPSC line (CDGEN1.16) harboring the heterozygous MYH7 R403L mutation, a hot-spot codon in HCM. We subsequently corrected the mutated codon using CRISPR/Cas9 editing and obtained the isogenic control line (CDGEN1.16.40.5) preserving the genomic background of the patient. Both lines were pluripotent and could be efficiently committed to beating cardiomyocytes (CM) suitable for subsequent cell or pseudo-tissue study of HCM pathology.

Psychosocial Impact of Predictive Genetic Testing in Hereditary Heart Diseases: The PREDICT Study.

Predictive genetic testing (PGT) is offered to asymptomatic relatives at risk of hereditary heart disease, but the impact of result disclosure has been little studied. We evaluated the psychosocial impacts of PGT in hereditary heart disease, using self-report questionnaires (including the State-Trait Anxiety Inventory) in 517 adults, administered three times to the prospective cohort (PCo: n = 264) and once to the retrospective cohort (RCo: n = 253). The main motivations for undergoing PGT were "to remove doubt" and "for their children". The level of anxiety increased between pre-test and result appointments (p <0.0001), returned to baseline after the result (PCo), and was moderately elevated at 4.4 years (RCo). Subjects with a history of depression or with high baseline anxiety were more likely to develop anxiety after PGT result (p = 0.004 and p <0.0001, respectively), whatever it was. Unfavourable changes in professional and/or family life were observed in 12.4% (PCo) and 18.7% (RCo) of subjects. Few regrets about PGT were expressed (0.8% RCo, 2.3% PCo). Medical benefit was not the main motivation, which emphasises the role of pre/post-test counselling. When PGT was performed by expert teams, the negative impact was modest, but careful management is required in specific categories of subjects, whatever the genetic test result.

Platelet reactivity in human immunodeficiency virus infected patients on dual antiplatelet therapy for an acute coronary syndrome: the EVERE2ST-HIV study.

AIM: To explore platelet reactivity on dual antiplatelet therapy (DAPT) of acute coronary syndrome (ACS) patients infected with HIV. METHODS AND RESULTS: Acute coronary syndrome patients infected with HIV (n = 80) were matched to ACS patients without HIV (n = 160) on age, sex, diabetes, and DAPT (aspirin 100%, clopidogrel 68%, prasugrel 31%, ticagrelor 1%). Platelet reactivity was evaluated after ACS (>30 days) by measuring residual platelet aggregation (RPA) to aspirin and to P2Y12 inhibitors with light transmission aggregometry (LTA), VerifyNow aspirin assay (ARU), and P2Y12 assay (PRU) and with the VASP platelet reactivity index (VASP-PRI). Proportion of patients with high residual platelet reactivity (HPR) was evaluated. HIV-infected ACS patients had higher levels of platelet reactivity in response to P2Y12 inhibitors (RPA: 23.8 ± 2.7% vs. 15.3 ± 1.3%; P = 0.001; PRU: 132 ± 10 vs. 107.4 ± 6.6; P = 0.04; and VASP-PRI: 45.2 ± 2.6% vs. 32.0 ± 2.0%; P < 0.001) and to aspirin (RPA: 3.6 ± 1.5% vs. 0.4 ± 0.1%; P = 0.004 and ARU: 442 ± 11 vs. 407 ± 5; P = 0.002) compared with non-HIV. HIV-infection was independently associated with increased platelet reactivity regardless of the test used (RPA: P = 0.005; PRU: P < 0.001 and VASP-PRI: P < 0.001) and a higher proportion of HPR (OR = 7.6; P < 0.001; OR = 2.06; P = 0.06; OR = 2.91; P = 0.004, respectively) in response to P2Y12 inhibitors. Similar results were found with aspirin. Protease inhibitors use was associated with increased platelet reactivity and higher rate of HPR. CONCLUSIONS: Acute coronary syndrome patients infected with HIV have increased levels of platelet reactivity and higher prevalence of HPR to P2Y12 inhibitors and aspirin than non-HIV patients. These results could provide potential explanations for the observed increase risk of recurrent ischemic events in the HIV-infected population.

Phase II Trial of Lenalidomide in HIV-Infected Patients with Previously Treated Kaposi's Sarcoma: Results of the ANRS 154 Lenakap Trial.

Lenalidomide, an oral immunomodulating agent, has shown promising activity in HIV-infected individuals with Kaposi's sarcoma (KS). This single-arm, multicenter, open-label, Gehan's two-stage phase II trial evaluated the efficacy and safety of lenalidomide in HIV-infected patients with progressive KS despite previous chemotherapy (NCT01282047, ANRS 154 Lenakap trial). The primary endpoint was the rate of partial response (PR) or complete response (CR) at week 24, evaluated by both the study investigators and the patients using the Physical Global Assessment (PGA). AIDS Clinical Trials Group (ACTG) criteria for KS treatment evaluation were used as a secondary endpoint. The data and safety monitoring board recommended that enrollments be halted on April 24, 2013, because of lack of responses. We enrolled 12 antiretroviral-treated HIV-infected men with progressive KS despite previous chemotherapy. Their HIV plasma viral load was <50 copies/ml and their median CD4 cell count 444/mm3. One patient stopped taking lenalidomide because of hives at week 1 and a second patient died at week 7. The remaining 10 patients were assessable at week 24, when none had PGA-defined CR or PR and one had ACTG-defined PR. There were no additional PGA responses at week 48, but an additional three patients had ACTG responses, for a total of four patients with ACTG PR at week 48 (40%; 95% confidence interval: 12.2-73.8). Fourteen grade 3-4 adverse events were considered at least possibly related to lenalidomide during a total of 101 cycles. Lenalidomide was well tolerated in antiretroviral experienced patients with progressive KS previously treated with chemotherapy. The ACTG-defined response rate at week 48 was 40%, while it was 0% using PGA criteria.

Aortic stiffness aging is influenced by past profound immunodeficiency in HIV-infected individuals: results from the EVAS-HIV (EValuation of Aortic Stiffness in HIV-infected individuals).

OBJECTIVE: We compared aortic stiffness between HIV-infected and HIV-uninfected individuals and examined the determinants of vascular aging during HIV infection. METHODS: Aortic stiffness using carotid-femoral pulse wave velocity (cf-PWV) was evaluated cross-sectionally between HIV-infected individuals and uninfected controls frequency-matched for age and sex, and longitudinally in a subgroup of HIV-infected individuals. Determinants of elevated cf-PWV levels were assessed using logistic regression. Changes in cf-PWV levels during follow-up (mixed-effect linear regression) and risk factors for achieving cf-PWV below (Group 1) or above the median (Group 2) at last follow-up visit were evaluated only in HIV-infected individuals. RESULTS: A total of 133 HIV-infected and 135 HIV-uninfected individuals (mean age: 47.7 ±â€Š8.9 years, 91% men) were enrolled. Median cf-PWV at baseline was similar between HIV-infected individuals and controls [7.5 m/s (interquartile range = 6.7-8.4) vs. 7.5 m/s (interquartile range = 6.6-8.4), respectively; P = 0.64]. In multivariable analysis, only mean arterial pressure showed significant association with elevated cf-PWV in the overall population (P = 0.036). In HIV-infected individuals, elevated cf-PWV was associated with current smoking (P = 0.042), and nadir CD4 T-cell count less than 200 cells/µl (P = 0.048). Ninety-one HIV-infected individuals were followed for a mean 7.6 ±â€Š2.0 years. cf-PWV progression was associated with age (P = 0.018), mean arterial pressure (P = 0.020), and nadir CD4 T-cell count (P = 0.005). Patients from Group 2 had higher baseline waist circumference, pulse pressure, and nadir CD4 T-cell count less than 200 cells/µl. CONCLUSION: We observed no difference in aortic stiffness between HIV-infected and controls. Moreover, aortic stiffness aging was independently associated with past severe immunodeficiency, along with other traditional risk factors. Our results call for early antiretroviral initiation.

Longitudinal and integrative biomodeling of effector and memory immune compartments after inactivated influenza vaccination.

Most vaccines, including those against influenza, were developed by focusing solely on humoral response for protection. However, vaccination activates different adaptive compartments that might play a role in protection. We took advantage of the pandemic 2009 A(H1N1) influenza vaccination to conduct a longitudinal integrative multiparametric analysis of seven immune parameters in vaccinated subjects. A global analysis underlined the predominance of induction of humoral and CD4 T cell responses, whereas pandemic 2009 A(H1N1)-specific CD8 responses did not improve after vaccination. A principal component analysis and hierarchical clustering of individuals showed a differential upregulation of influenza vaccine-specific immunity including hemagglutination inhibition titers, IgA(+) and IgG(+) Ab-secreting cells, effector CD4 or CD8 T cell frequencies at day 21 among individuals, suggesting a fine-tuning of the immune parameters after vaccination. This is related to individual factors including the magnitude and quality of influenza-specific immune responses before vaccination. We propose a graphical delineation of immune determinants that would be essential for a better understanding of vaccine-induced immunity in vaccination strategies.