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Vascular Smooth Muscle-Specific Progerin Expression Accelerates Atherosclerosis and Death in a Mouse Model of Hutchinson-Gilford Progeria Syndrome [Original Research Article]

Lun, 16/07/2018 - 19:44
Background:Progerin, an aberrant protein that accumulates with age, causes the rare genetic disease Hutchinson-Gilford progeria syndrome (HGPS). Patients who have HGPS exhibit ubiquitous progerin expression, accelerated aging and atherosclerosis, and die in their early teens, mainly of myocardial infarction or stroke. The mechanisms underlying progerin-induced atherosclerosis remain unexplored, in part, because of the lack of appropriate animal models.Methods:We generated an atherosclerosis-prone model of HGPS by crossing apolipoprotein E–deficient (Apoe–/–) mice with LmnaG609G/G609G mice ubiquitously expressing progerin. To induce progerin expression specifically in macrophages or vascular smooth muscle cells (VSMCs), we crossed Apoe–/–LmnaLCS/LCS mice with LysMCre and SM22?Cre mice, respectively. Progerin expression was evaluated by polymerase chain reaction and immunofluorescence. Cardiovascular alterations were determined by immunofluorescence and histology in male mice fed normal chow or a high-fat diet. In vivo low-density lipoprotein retention was assessed by intravenous injection of fluorescently labeled human low-density lipoprotein. Cardiac electric defects were evaluated by electrocardiography.Results:Apoe–/–LmnaG609G/G609G mice with ubiquitous progerin expression exhibited a premature aging phenotype that included failure to thrive and shortened survival. In addition, high-fat diet–fed Apoe–/–LmnaG609G/G609G mice developed a severe vascular pathology, including medial VSMC loss and lipid retention, adventitial fibrosis, and accelerated atherosclerosis, thus resembling most aspects of cardiovascular disease observed in patients with HGPS. The same vascular alterations were also observed in Apoe–/–LmnaLCS/LCSSM22?Cre mice expressing progerin specifically in VSMCs, but not in Apoe–/–LmnaLCS/LCSLysMCre mice with macrophage-specific progerin expression. Moreover, Apoe–/–LmnaLCS/LCSSM22?Cre mice had a shortened lifespan despite the lack of any overt aging phenotype. Aortas of ubiquitously and VSMC-specific progerin-expressing mice exhibited increased retention of fluorescently labeled human low-density lipoprotein, and atheromata in both models showed vulnerable plaque features. Immunohistopathological examination indicated that Apoe–/–LmnaLCS/LCSSM22?Cre mice, unlike Apoe–/–LmnaG609G/G609G mice, die of atherosclerosis-related causes.Conclusions:We have generated the first mouse model of progerin-induced atherosclerosis acceleration, and demonstrate that restricting progerin expression to VSMCs is sufficient to accelerate atherosclerosis, trigger plaque vulnerability, and reduce lifespan. Our results identify progerin-induced VSMC death as a major factor triggering atherosclerosis and premature death in HGPS.

Health Literacy and Cardiovascular Disease: Fundamental Relevance to Primary and Secondary Prevention: A Scientific Statement From the American Heart Association [AHA Scientific Statements]

Lun, 09/07/2018 - 19:44
Health literacy is the degree to which individuals are able to access and process basic health information and services and thereby participate in health-related decisions. Limited health literacy is highly prevalent in the United States and is strongly associated with patient morbidity, mortality, healthcare use, and costs. The objectives of this American Heart Association scientific statement are (1) to summarize the relevance of health literacy to cardiovascular health; (2) to present the adverse associations of health literacy with cardiovascular risk factors, conditions, and treatments; (3) to suggest strategies that address barriers imposed by limited health literacy on the management and prevention of cardiovascular disease; (4) to demonstrate the contributions of health literacy to health disparities, given its association with social determinants of health; and (5) to propose future directions for how health literacy can be integrated into the American Heart Association’s mandate to advance cardiovascular treatment and research, thereby improving patient care and public health. Inadequate health literacy is a barrier to the American Heart Association meeting its 2020 Impact Goals, and this statement articulates the rationale to anticipate and address the adverse cardiovascular effects associated with health literacy.

Inflammatory and Cholesterol Risk in the FOURIER Trial [Original Research Article]

Lun, 09/07/2018 - 19:44
Background:In the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk), the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk. It is not known whether the efficacy of evolocumab is modified by baseline inflammatory risk. We explored the efficacy of evolocumab stratified by baseline high-sensitivity C-reactive protein (hsCRP). We also assessed the importance of inflammatory and residual cholesterol risk across the range of on-treatment LDL-C concentrations.Methods:Patients (n=27?564) with stable atherosclerotic cardiovascular disease and LDL-C ?70 mg/dL on a statin were randomly assigned to evolocumab versus placebo and followed for a median of 2.2 years (1.8–2.5). The effects of evolocumab on the primary end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina or coronary revascularization, and the key secondary end point of cardiovascular death, myocardial infarction, or stroke were compared across strata of baseline hsCRP (<1, 1–3, and >3 mg/dL). Outcomes were also assessed across values for baseline hsCRP and 1-month LDL-C in the entire trial population. Multivariable models adjusted for variables associated with hsCRP and 1-month LDL-C were evaluated.Results:A total of 7981 (29%) patients had a baseline hsCRP<1 mg/L, 11?177 (41%) had a hsCRP 1 to 3 mg/L, and 8337 (30%) had a hsCRP >3 mg/L. Median (interquartile range) baseline hsCRP was 1.8 (0.9–3.6) mg/L and levels were not altered by evolocumab (change at 48 weeks of –0.2 mg/dL [–1.0 to 0.4] in both treatment arms). In the placebo arm, patients in higher baseline hsCRP categories experienced significantly higher 3-year Kaplan-Meier rates of the primary and key secondary end points: 12.0%, 13.7%, and 18.1% for the primary end point (Ptrend<0.0001) and 7.4%, 9.1%, and 13.2% for the key secondary end point (Ptrend<0.0001) for categories of <1, 1 to 3, and >3 mg/dL, respectively. The relative risk reductions for the primary end point and key secondary end point with evolocumab were consistent across hsCRP strata (P-interactions>0.15 for both). In contrast, the absolute risk reductions with evolocumab tended to be greater in patients with higher hsCRP: 1.6%, 1.8%, and 2.6% and 0.8%, 2.0%, and 3.0%, respectively, for the primary and key secondary end points across hsCRP strata. In adjusted analyses of the association between LDL-C and hsCRP levels and cardiovascular risk, both LDL-C and hsCRP were independently associated with the primary outcome (P<0.0001 for each).Conclusions:LDL-C reduction with evolocumab reduces cardiovascular events across hsCRP strata with greater absolute risk reductions in patients with higher-baseline hsCRP. Event rates were lowest in patients with the lowest hsCRP and LDL-C.Clinical Trial Registration:URL: Unique identifier: NCT01764633.

Residual Inflammatory Risk on Treatment With PCSK9 Inhibition and Statin Therapy [Original Research Article]

Lun, 09/07/2018 - 19:44
Background:The combination of statin therapy and PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition markedly lowers low-density lipoprotein cholesterol (LDL-C) and reduces cardiovascular event rates. Whether residual inflammatory risk as measured by on-treatment high sensitivity C-reactive protein (hsCRP) remains an important clinical issue in such patients is uncertain.Methods:We evaluated residual inflammatory risk among 9738 patients participating in the SPIRE-1 and SPIRE-2 cardiovascular outcomes trials (Studies of PCSK9 Inhibition and the Reduction in Vascular Events), who were receiving both statin therapy and bococizumab, according to on-treatment levels of hsCRP (hsCRPOT) and LDL-COT measured 14 weeks after drug initiation. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death.Results:At 14 weeks, the mean percentage change in LDL-C among statin-treated patients who additionally received bococizumab was ?60.5% (95% confidence interval [CI], ?61.2 to ?59.8; P<0.001; median change, ?65.4%) as compared to 6.6% (95% CI, ?1.0 to 14.1; P=0.09; median change, 0.0%) for hsCRP. Incidence rates for future cardiovascular events for patients treated with both statin therapy and bococizumab according to hsCRPOT <1, 1 to 3, and >3 mg/L were 1.96, 2.50, and 3.59 events per 100 person-years, respectively, corresponding to multivariable adjusted hazard ratios of 1.0, 1.16 (95% CI, 0.81–1.66), and 1.62 (95% CI, 1.14–2.30) (P-trend=0.001) after adjustment for traditional cardiovascular risk factors and LDL-COT. Comparable adjusted hazard ratios for LDL-COT (<30, 30–50, >50 mg/dL) were 1.0, 0.87, and 1.21, respectively (P-trend=0.16). Relative risk reductions with bococizumab were similar across hsCRPOT groups (P-interaction=0.87).Conclusions:In this post hoc analysis of the SPIRE trials of bococizumab in a stable outpatient population, evidence of residual inflammatory risk persisted among patients treated with both statin therapy and proprotein convertase subtilisin-kexin type 9 inhibition.Clinical Trial Registration:URL: Unique identifiers: NCT01975376, NCT01975389.

How Do Resuscitation Teams at Top-Performing Hospitals for In-Hospital Cardiac Arrest Succeed? [Original Research Article]

Lun, 09/07/2018 - 19:44
Background:In-hospital cardiac arrest (IHCA) is common, and outcomes vary substantially across US hospitals, but reasons for these differences are largely unknown. We set out to better understand how top-performing hospitals organize their resuscitation teams to achieve high survival rates for IHCA.Methods:We calculated risk-standardized IHCA survival to discharge rates across American Heart Association Get With The Guidelines–Resuscitation registry hospitals between 2012 and 2014. We identified geographically and academically diverse hospitals in the top, middle, and bottom quartiles of survival for IHCA and performed a qualitative study that included site visits with in-depth interviews of clinical and administrative staff at 9 hospitals. With the use of thematic analysis, data were analyzed to identify salient themes of perceived performance by informants.Results:Across 9 hospitals, we interviewed 158 individuals from multiple disciplines including physicians (17.1%), nurses (45.6%), other clinical staff (17.1%), and administration (20.3%). We identified 4 broad themes related to resuscitation teams: (1) team design, (2) team composition and roles, (3) communication and leadership during IHCA, and (4) training and education. Resuscitation teams at top-performing hospitals demonstrated the following features: dedicated or designated resuscitation teams; participation of diverse disciplines as team members during IHCA; clear roles and responsibilities of team members; better communication and leadership during IHCA; and in-depth mock codes.Conclusions:Resuscitation teams at hospitals with high IHCA survival differ from non–top-performing hospitals. Our findings suggest core elements of successful resuscitation teams that are associated with better outcomes and form the basis for future work to improve IHCA.

Single-Cell Sequencing of the Healthy and Diseased Heart Reveals Cytoskeleton-Associated Protein 4 as a New Modulator of Fibroblasts Activation [Original Research Article]

Lun, 09/07/2018 - 19:44
Background:Genome-wide transcriptome analysis has greatly advanced our understanding of the regulatory networks underlying basic cardiac biology and mechanisms driving disease. However, so far, the resolution of studying gene expression patterns in the adult heart has been limited to the level of extracts from whole tissues. The use of tissue homogenates inherently causes the loss of any information on cellular origin or cell type-specific changes in gene expression. Recent developments in RNA amplification strategies provide a unique opportunity to use small amounts of input RNA for genome-wide sequencing of single cells.Methods:Here, we present a method to obtain high-quality RNA from digested cardiac tissue from adult mice for automated single-cell sequencing of both the healthy and diseased heart.Results:After optimization, we were able to perform single-cell sequencing on adult cardiac tissue under both homeostatic conditions and after ischemic injury. Clustering analysis based on differential gene expression unveiled known and novel markers of all main cardiac cell types. Based on differential gene expression, we could identify multiple subpopulations within a certain cell type. Furthermore, applying single-cell sequencing on both the healthy and injured heart indicated the presence of disease-specific cell subpopulations. As such, we identified cytoskeleton-associated protein 4 as a novel marker for activated fibroblasts that positively correlates with known myofibroblast markers in both mouse and human cardiac tissue. Cytoskeleton-associated protein 4 inhibition in activated fibroblasts treated with transforming growth factor ? triggered a greater increase in the expression of genes related to activated fibroblasts compared with control, suggesting a role of cytoskeleton-associated protein 4 in modulating fibroblast activation in the injured heart.Conclusions:Single-cell sequencing on both the healthy and diseased adult heart allows us to study transcriptomic differences between cardiac cells, as well as cell type-specific changes in gene expression during cardiac disease. This new approach provides a wealth of novel insights into molecular changes that underlie the cellular processes relevant for cardiac biology and pathophysiology. Applying this technology could lead to the discovery of new therapeutic targets relevant for heart disease.

Cardioprotective Role of Myeloid-Derived Suppressor Cells in Heart Failure [Original Research Article]

Lun, 09/07/2018 - 19:44
Background:Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand in cancer, inflammation, and infection and negatively regulate inflammation and the immune response. Heart failure (HF) is a complex clinical syndrome wherein inflammation induction and incomplete resolution can potentially contribute to HF development and progression. However, the role of MDSCs in HF remains unclear.Methods:The percentage of MDSCs in patients with HF and in mice with pressure overload–induced HF using isoproterenol infusion or transverse aortic constriction (TAC) was detected by flow cytometry. The effects of MDSCs on isoproterenol- or TAC-induced HF were observed on depleting MDSCs with 5-fluorouracil (50 mg/kg) or gemcitabine (120 mg/kg), transferring purified MDSCs, or enhancing endogenous MDSCs with rapamycin (2 mg·kg?1·d?1). Hypertrophic markers and inflammatory factors were detected by ELISA, real-time polymerase chain reaction, or Western blot. Cardiac functions were determined by echocardiography and hemodynamic analysis.Results:The percentage of human leukocyte antigen-D–related (HLA-DR)?CD33+CD11b+ MDSCs in the blood of patients with HF was significantly increased and positively correlated with disease severity and increased plasma levels of cytokines, including interleukin-6, interleukin-10, and transforming growth factor–?. Furthermore, MDSCs derived from patients with HF inhibited T-cell proliferation and interferon-? secretion. Similar results were observed in TAC- and isoproterenol-induced HF in mice. Pharmaceutical depletion of MDSCs significantly exacerbated isoproterenol- and TAC-induced pathological cardiac remodeling and inflammation, whereas adoptive transfer of MDSCs prominently rescued isoproterenol- and TAC-induced HF. Consistently, administration of rapamycin significantly increased endogenous MDSCs by suppressing their differentiation and improved isoproterenol- and TAC-induced HF, but MDSC depletion mostly blocked beneficial rapamycin-mediated effects. Mechanistically, MDSC-secreted molecules suppressed isoproterenol-induced hypertrophy and proinflammatory gene expression in cardiomyocytes in a coculture system. Neutralization of interleukin-10 blunted both monocytic MDSC- and granulocytic MDSC–mediated anti-inflammatory and antihypertrophic effects, but treatment with a nitric oxide inhibitor only partially blocked the antihypertrophic effect of monocytic MDSCs.Conclusions:Our findings revealed a cardioprotective role of MDSCs in HF by their antihypertrophic effects on cardiomyocytes and anti-inflammatory effects through interleukin-10 and nitric oxide. Pharmacological targeting of MDSCs by rapamycin constitutes a promising therapeutic strategy for HF.

Sex Differences in Cardiovascular Pathophysiology [Primer]

Lun, 09/07/2018 - 19:44
Consistent epidemiological data demonstrate that patients with heart failure with preserved ejection fraction (HFpEF) are more likely to be women than men. Exploring mechanisms behind this sex difference in heart failure epidemiology may enrich the understanding of underlying HFpEF pathophysiology and phenotypes, with the ultimate goal of identifying therapeutic approaches for the broader HFpEF population. In this review we evaluate the influence of sex on the key domains of cardiac structure and function, the systemic and pulmonary circulation, as well as extracardiac factors and comorbidities that may explain the predisposition of women to HFpEF. We highlight the potential role of factors exclusive to or more prevalent in women such as pregnancy, preeclampsia, and iron deficiency. Finally, we discuss existing controversies and gaps in knowledge, as well as the clinical importance of known sex differences in the context of the potential need for sex-specific diagnostic criteria, improved risk stratification models, and targeted therapies.