To estimate the population burden of heart failure and the influence of modifiable risk factors.
Heart failure is a common, costly, and fatal disorder, yet few studies have evaluated the population-level influence of modifiable risk factors.
From 14,709 Atherosclerosis Risk in Communities study participants we estimated incidence rate differences (IRD) for the association between five modifiable risk factors (cigarette smoking, diabetes, elevated low density lipoproteins, hypertension, and obesity) and heart failure. Potential impact fractions were used to measure expected changes in the heart failure incidence assuming achievement of a 5% proportional decrement in the prevalence of each risk factor.
Over an average of 17.6 years of follow-up, 1 in 3 African American and 1 in 4 Caucasian participants were hospitalized with heart failure, defined as the first hospitalization with ICD-9 discharge codes of 428.x. Of the five modifiable risk factors, the largest IRD was observed for diabetes, which was associated with 1,058 (95% CI: 787–1,329) and 660 (95% CI: 514–805) incident hospitalizations of heart failure/100,000 person-years among African American and Caucasian participants, respectively. A 5% proportional reduction in the prevalence of diabetes would result in approximately 53 and 33 fewer incident heart failure hospitalizations per 100,000 person-years in African American and Caucasian ARIC participants, respectively. When applied to U.S. populations, this reduction may prevent approximately 30,000 incident cases of heart failure annually.
Modest decrements in the prevalence of modifiable heart failure risk factors such as diabetes may substantially decrease the incidence of this major disease.
heart failure; epidemiology; diabetes
To provide the spectrum and prevalence of mutations in the 12 Brugada Syndrome (BrS)-susceptibility genes discovered to date, in a single large BrS cohort.
BrS is a potentially lethal heritable arrhythmia syndrome diagnosed electrocardiographically by coved-type ST segment elevation in the right precordial leads (V1-V3; type-1 Brugada ECG pattern) and the presence of a personal/family history of cardiac events.
Using PCR, DHPLC, and DNA sequencing, comprehensive mutational analysis of BrS1-12-susceptibility genes was performed in 129 unrelated patients with possible/probable BrS [46 with clinically diagnosed BrS (ECG pattern plus personal/family history of a cardiac event) and 83 with type 1 ECG pattern only].
Overall, 27 (21%) patients had a putative pathogenic mutation, absent in 1400 Caucasian reference alleles, including 21 patients with an SCN5A mutation, 2 CACNB2B, 1 KCNJ8, 1 KCND3, 1 SCN1Bb, and 1 HCN4. The overall mutation yield was 23% in type 1 ECG pattern only patients versus 17% in clinically diagnosed BrS patients, was significantly greater among young men < 20 years of age with clinically diagnosed BrS, and among patients who had a prolonged PQ interval.
We identified putative pathogenic mutations in ~20% of our BrS cohort, with BrS2-12 accounting for < 5%. Importantly, the yield was similar between patients with only a type 1 BrS ECG pattern and those with clinically established BrS. The yield approaches 40% for SCN5A-mediated BrS (BrS1) when the PQ interval exceeds 200ms. Calcium channel-mediated BrS is extremely unlikely in the absence of a short QT interval.
Brugada Syndrome; Genetic Testing; Ventricular Arrhythmias; Cardiac Arrest; ST segment elevation
Enhancement of human cardiac progenitor cell (hCPC) reparative and regenerative potential by genetic modification for treatment of myocardial infarction.
Regenerative potential of stem cells to repair acute infarction is limited. Improved hCPC survival, proliferation and differentiation into functional myocardium will increase efficacy and advance translational implementation of cardiac regeneration.
hCPCs isolated from myocardium of heart failure patients undergoing left ventricular assist device (LVAD) implantation are engineered to express green fluorescent protein (GFP; hCPCe) or Pim-1-GFP (hCPCeP). Functional tests of hCPC regenerative potential are performed with immunocompromised mice by intramyocardial adoptive transfer injection after infarction. Myocardial structure and function is monitored by echocardiographic and hemodynamic assessment for 20 weeks following delivery. hCPCe and hCPCeP expressing luciferase are followed by bioluminesence imaging (BLI) to non-invasively track persistence.
hCPCeP exhibit augmentation of reparative potential relative to hCPCe control cells as demonstrated by significantly increased proliferation coupled with amelioration of infarction injury and increased hemodynamic performance at 20 weeks post-transplantation. Concurrent with enhanced cardiac structure and function, hCPCeP demonstrate increased cellular engraftment and differentiation with improved vasculature and reduced infarct size. Enhanced persistence of hCPCeP versus hCPCe is revealed by BLI at up to 8 weeks post delivery.
Genetic engineering of hCPCs with Pim-1 enhances repair of damaged myocardium. Ex vivo gene delivery to modify stem cells has emerged as a viable option addressing current limitations in the field. This study demonstrates that efficacy of human CPCs from the failing myocardium can be safely and significantly enhanced through expression of Pim-1 kinase, setting the stage for use of engineered cells in preclinical settings.
human cardiac progenitor cells; Pim-1 kinase; heart repair
We sought to examine the relation of galectin-3 (Gal-3), a marker of cardiac fibrosis, with incident heart failure (HF) in the community.
Gal-3 is an emerging prognostic biomarker in HF, and experimental studies suggest that Gal-3 is an important mediator of cardiac fibrosis. Whether elevated Gal-3 concentrations precede the development of HF is unknown.
Gal-3 concentrations were measured in 3,353 participants in the Framingham Offspring Cohort (mean age 59 years, 53% women). The relation of Gal-3 to incident HF was assessed using proportional hazards regression.
Gal-3 was associated with increased left ventricular mass in age- and sex-adjusted analyses (P=0.001); this association was attenuated in multivariable analyses (P=0.06). A total of 166 participants developed incident HF and 468 died during a mean follow-up of 8.1 years. Gal-3 was associated with risk of incident HF (HR 1.28 per 1 standard deviation increase in log-Gal-3, 95% CI 1.14–1.43, P<0.0001), and remained significant after adjustment for clinical variables and B-type natriuretic peptide (HR 1.23, 95% CI 1.04–1.47, P=0.02). Gal-3 was also associated with risk of all-cause mortality (multivariable-adjusted HR 1.15, 95% CI 1.04–1.28, P=0.01). The addition of Gal-3 to clinical factors resulted in negligible changes to the c-statistic and minor improvements in the net reclassification index.
Higher concentration of Gal-3, a marker of cardiac fibrosis, is associated with increased risk of incident HF and mortality. Future studies evaluating the role of Gal-3 in cardiac remodeling may provide further insights into the role of Gal-3 in the pathophysiology of HF.
heart failure; epidemiology; biomarker; prognosis
The aim of the current study was to test the hypothesis that vascular and endothelial functional responses to acute mental stress are abnormal in patients with apical ballooning syndrome (ABS).
Apical ballooning syndrome is a transient cardiomyopathy that occurs predominantly in post-menopausal women and may be triggered by acute mental stress. The mechanism for ABS is unknown.
Reactive hyperemia as a parameter of endothelial function and vascular responses to acute mental stress were measured using peripheral arterial tonometry (PAT) at baseline and following 3 acute mental stress tests in female patients with ABS (n = 12, at least 6 months after being hospitalized or diagnosed with ABS), post-menopausal female controls (n = 12), and female patients with myocardial infarction (MI) (n = 4). Plasma catecholamine levels were measured at baseline and following the 3 mental stress tests.
Reactive hyperemia PAT scores following mental stress were significantly lower in patients with ABS compared with post-menopausal controls (p < 0.05). The PAT scores during mental stress were significantly lower in patients with ABS compared with patients with MI and post-menopausal controls (p < 0.05). There were no differences in PAT scores during acute mental stress in patients with MI versus post-menopausal controls. Furthermore, catecholamine levels were significantly increased in patients with ABS, compared with post-menopausal controls, following acute mental stress testing (p < 0.05).
There is increased vascular reactivity and decreased endothelial function in response to acute mental stress in patients with a prior episode of ABS. The findings implicate vasomotor dysfunction as a potential mechanism involved in the pathogenesis of this unique cardiomyopathy.
endothelium; stress-induced cardiomyopathy; Tako-Tsubo cardiomyopathy; vasculature; women
To characterize operative outcomes for ascending aorta and arch replacement on a national scale and develop risk models for mortality and major morbidity.
Contemporary outcomes for ascending aorta and arch replacement in North America are unknown.
We queried the Society of Thoracic Surgeons Database for patients undergoing ascending aorta (+/− root) +/− arch replacement from 2004 to 2009. The database captured 45,894 cases, including 12,702 root, 22,048 supracoronary ascending alone, 6,786 ascending+arch, and 4,358 root+arch. Baseline characteristics and clinical outcomes were analyzed. A parsimonious multivariable logistic regression model was constructed to predict risks of mortality and major morbidity.
Operative mortality was 3.4% for elective and 15.4% for non-elective cases. A risk model for operative mortality [c-index 0.81] revealed a risk-adjusted odds ratio (OR) for death following emergent vs. elective operation of 5.9 [95% confidence interval (CI) 5.3, 6.6]. Among elective patients, end stage renal disease and re-operative status were the strongest predictors of mortality (adjusted OR 4.0 [95% CI 2.6, 6.4] and 2.3 [95% CI 1.9, 2.7] respectively, p<0.0001).
Current outcomes for ascending aorta and arch replacement in North America are excellent for elective repair; however, results deteriorate for non-elective status, suggesting that increased screening and/or lowering thresholds for elective intervention could potentially improve outcomes. The predictive models presented may serve clinicians in counseling patients.
aortic disease; aortic surgery outcomes; aortic aneurysm and dissection
To assess the efficacy of exercise and antidepressant medication in reducing depressive symptoms and improving cardiovascular biomarkers in depressed patients with coronary heart disease (CHD).
Although there is good evidence that clinical depression is associated with poor prognosis, optimal therapeutic strategies are currently not well-defined.
101 outpatients with CHD and elevated depressive symptoms underwent assessment of depression including a psychiatric interview and the Hamilton Rating Scale for Depression (HAM-D). Participants were randomized to 4 months of aerobic exercise (3 times/week), sertraline (50-200 mg/day), or placebo. Additional assessments of cardiovascular biomarkers included measures of heart rate variability (HRV), endothelial function, baroreflex sensitivity, inflammation, and platelet function.
After 16 weeks, all groups showed improvement on HAM-D scores. Participants in both aerobic exercise (M= −7.5 [95% CI = −9.8, −5.0]) and sertraline (M= −6.1 [95% CI = −8.4, −3.9] achieved larger reductions in depressive symptoms compared to placebo (M= −4.5 [95% CI = −7.6, −1.5]; p = .034); exercise and sertraline were equally effective in reducing depressive symptoms (p = .607). Exercise and medication tended to result in greater improvements in HRV compared to placebo (p = .052); exercise tended to result in greater improvements in HRV compared to sertraline (p =.093)
Both exercise and sertraline resulted in greater reductions in depressive symptoms compared to placebo in CHD patients. Evidence that active treatments may also improve cardiovascular biomarkers suggests that they may have a beneficial effect on clinical outcomes as well as quality of life.
Depression; Exercise; Sertraline; Heart rate variability; Inflammation; Biomarkers; antidepressant medication; SSRI
The aim of this study was to evaluate the links between connexin43 (Cx43) expression, myocardial conduction velocity, and ventricular tachycardia in a model of healed myocardial infarction.
Post-infarction ventricular arrhythmias frequently cause sudden death. Impaired myocardial conduction has previously been linked to ventricular arrhythmias. Altered connexin expression is a potential source of conduction slowing identified in healed scar border tissues. The functional effect of increasing border-zone Cx43 has not been previously evaluated.
Twenty-five Yorkshire pigs underwent anterior infarction by transient left anterior descending coronary artery occlusion, followed by weekly testing for arrhythmia inducibility. Twenty animals with reproducibly inducible sustained monomorphic ventricular tachycardia were randomized 2:1:1 to receive AdCx43, Adβgal, or no gene transfer. One week later, animals underwent follow-up electrophysiologic study and tissue assessment for several functional and molecular measures.
Animals receiving AdCx43 had less electrogram fractionation and faster conduction velocity in the anterior-septal border zone. Only 40% of AdCx43 animals remained inducible for ventricular tachycardia, while 100% of controls were inducible after gene transfer. AdCx43 animals had 2-fold higher Cx43 protein levels in the anterior-septal infarct border, with similar percents of phosphorylated and intercalated disk-localized Cx43 compared with controls.
These data mechanistically link Cx43 expression to slow conduction and arrhythmia susceptibility in the healed scar border zone. Targeted manipulation of Cx43 levels improved conduction velocity and reduced ventricular tachycardia susceptibility. Cx43 gene transfer represents a novel treatment strategy for post-infarction arrhythmias.
connexin; gene therapy; myocardial infarction; ventricular tachycardia
To assess the associations between renal artery calcification (RAC) and mortality in a healthy outpatient cohort without known cardiovascular disease (CVD).
Studies in individuals with known diabetes and kidney disease have suggested that RAC confers additional mortality risk independent of coronary artery calcification, but this has not been explored in healthier populations.
We assessed RAC by CT scan in 4450 healthy outpatients without known CVD. We used Cox proportional-hazards models to examine the association of RAC with mortality.
The mean age of participants was 57; 42.6% were women. RAC was present in 622 of 4,450 (14%) participants. Over a median follow-up of 8.2 years, 178 deaths occurred. After adjustment for age, gender, diabetes, smoking, cholesterol and family history of CVD, the presence of RAC conferred a more than 60% increased hazard for all-cause mortality (HR 1.63, 95% CI 1.17–2.29). Adjustment for calcification in other vascular beds attenuated this association (HR 1.40, 95% CI 0.99–1.97). Adjustment for hypertension, a potential mediator of the association, did not substantially change the results (HR 1.44, 95% CI, 1.02–2.03). Adding RAC to a model including Framingham risk and CAC improved the predictive ability of the model, from 0.73 to 0.77 (p 0.0002); the net reclassification index was 14.4% for addition of RAC. Results for cardiovascular mortality were not significant, limited by a small number of cardiovascular deaths.
We found that RAC is associated with an increased risk of subsequent all-cause mortality in healthy outpatient individuals, independent of traditional cardiac risk factors. The risk was modestly attenuated by adjustment for vascular calcification in other vascular beds, suggesting partial confounding by systemic calcified atherosclerosis. The effect did not appear to be mediated by hypertension.
The primary aim of this systematic review is to objectively evaluate the test performance characteristics of three-dimensional echocardiography (3DE) in measuring left ventricular (LV) volumes and ejection fraction (EF).
Despite its growing use in clinical laboratories, the accuracy of 3DE has not been studied on a large scale. It is unclear if this technology offers an advantage over traditional two-dimensional (2D) methods.
We searched for studies that compared LV volumes and EF measured by 3DE and cardiac magnetic resonance (CMR) imaging. A subset of those also compared standard 2D methods with CMR. We used meta-analyses to determine the overall bias and limits of agreement of LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF measured by 3DE and 2D echocardiography (2DE).
Twenty-three studies (1,638 echocardiograms) were included. The pooled biases ± 2 SDs for 3DE were −19.1 ± 34.2 ml, −10.1 ± 29.7 ml, and − 0.6 ± 11.8% for EDV, ESV, and EF, respectively. Nine studies also included data from 2DE, where the pooled biases were −48.2 ± 55.9 ml, −27.7 ± 45.7 ml, and 0.1 ± 13.9% for EDV, ESV, and EF, respectively. In this subset, the difference in bias between 3DE and 2D volumes was statistically significant (p = 0.01 for both EDV and ESV). The difference in variance was statistically significant (p < 0.001) for all 3 measurements.
Three-dimensional echocardiography underestimates volumes and has wide limits of agreement, but compared with traditional 2D methods in these carefully performed studies, 3DE is more accurate for volumes and more precise in all 3 measurements.
ejection fraction; left ventricular volumes; meta-analysis; real-time three-dimensional echocardiography; systematic review
Our objective was to determine the prognostic value of plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) for death and cardiovascular events among subjects without risk factors for heart failure (HF), which we term healthy normal.
Previous studies report that plasma NT-proBNP has prognostic value for cardiovascular events in the general population even in the absence of HF. It is unclear if NT-proBNP retains predictive value in healthy normal subjects.
We identified a community-based cohort of 2,042 subjects in Olmsted County, Minnesota. Subjects with symptomatic (stage C/D) HF were excluded. The remaining 1,991 subjects underwent echocardiography and NT-proBNP measurement. We further defined healthy normal (n = 703) and stage A/B HF (n = 1,288) subgroups. Healthy normal was defined as the absence of traditional clinical cardiovascular risk factors and echocardiographic structural cardiac abnormalities. Subjects were followed for death, HF, cerebrovascular accident, and myocardial infarction with median follow-up of 9.1, 8.7, 8.8, and 8.9 years, respectively.
NT-proBNP was not predictive of death or cardiovascular events in the healthy normal subgroup. Similar to previous reports, in stage A/B HF, plasma NT-proBNP values greater than age-/sex-specific 80th percentiles were associated with increased risk of death, HF, cerebrovascular accident, and myocardial infarction (p < 0.001 for all) even after adjustment for clinical risk factors and structural cardiac abnormalities.
These findings do not support the use of NT-proBNP as a cardiovascular biomarker in healthy normal subjects and have important implications for NT-proBNP–based strategies for early detection and primary prevention of cardiovascular disease.
natriuretic peptide; predictive; mortality; heart failure; myocardial infarction; cerebrovascular accident
Hypertrophic cardiomyopathy; Cardiac Magnetic resonance; Late gadolinium enhancement; myocardial fibrosis
Use of anti-arrhythmic drugs is limited by the high incidence of serious adverse events including QT prolongation and torsades de pointes. Recent studies have demonstrated a role for NOS1AP gene variants in modulating QT interval in healthy subjects and modification of the severity of presentation and the risk of arrhythmias in LQTS.
We carried out an association study using 167 SNPs spanning the NOS1AP gene in 58 Caucasian patients experiencing dLQTS and 87 Caucasian controls from the DARE Study.
Association analysis identified one polymorphism significantly associated with dLQTS (rs10800397: p=3.7×10−4; OR=3.3, 99.95% CI=1.0–10.8). The associations were more pronounced in the subgroup of amiodarone users, in which three SNPs including rs10800397 were significantly associated (most significant SNP rs10919035: p=3.0×10−4; OR=5.5, 99.95% CI=1.1–27.9). We genotyped rs10919035 in an independent replication cohort of 28 amiodarone-dLQTS cases versus 173 controls (meta-analysis of both studies: OR=2.81; p=2.4×10−4; 95% CI=1.62–4.89). Analysis of QTc among 74 controls from our dataset showed a similar pattern of significance over the gene region as the case-control analysis. This pattern was confirmed in 1,480 controls from the BRIGHT cohort (top SNP DARE rs12734991 in meta-analysis: mean [SD] increase in QTc interval per C allele=9.1 [3.2]ms; p=1.7×10−4).
Our results provide the first demonstration that common variations in the NOS1AP gene are associated with a significant increase in the risk of dLQTS. We suggest that common variation in the NOS1AP gene may have relevance for future pharmacogenomic applications in clinical practice permitting safer prescription of drugs for vulnerable patients.
cardiac arrhythmias; NOS1AP; drug; single nucleotide polymorphisms; genetics; risk stratification
To determine the relevance of S100A12 expression to human thoracic aortic aneurysms (TAA) and type A dissection (TAAD) and to study mechanisms of S100A12 mediated dysfunction of aortic smooth muscle cells.
Transgenic expression of pro-inflammatory S100A12 protein in murine aortic smooth muscle causes thoracic aneurysm in genetically modified mice.
Immunohistochemistry of aortic tissue (n=50) for S100A12, myeloperoxidase and caspase 3 was examined, and S100A12 mediated pathways were studied in cultured primary aortic smooth muscle cells.
We found S100A12 protein expressed in all cases of acute TAAD, and in approximately 25% of clinically stable TAA cases. S100A12 tissue expression was associated with increased length of stay in patients undergoing elective surgical repair for TAA despite similar preoperative risk as determined by EuroSCORE. Reduction of S100A12 expression in human aortic smooth muscle cells using shRNA attenuates gene and protein expression of many inflammatory and apoptosis regulating factors. Moreover, genetic ablation of the receptor for S100A12, RAGE, in murine aortic smooth muscle cells abolished cytokine- augmented activation of caspase 3 and smooth muscle cell apoptosis in S100A12-expressing cells.
S100A12 is enriched in human thoracic aortic aneurysms and dissections. Reduction of S100A12 or genetic ablation of its cell surface receptor RAGE in aortic smooth muscle resulted in decreased activation of caspase 3 and in reduced apoptosis. By establishing a link between S100A12 expression and apoptosis of aortic smooth muscle cells, this study identifies novel S100A12 signaling pathways and indicates that S100A12 may be a useful molecular marker and possible target for treatment for human aortic diseases.
Thoracic aortic aneurysm and dissection; S100 proteins; RAGE; aortic smooth muscle cells; cell death
The aim of this study was to assess acute ablation injuries seen on late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) immediately post-ablation (IPA) and the association with permanent scar 3 months post-ablation (3moPA).
Success rates for atrial fibrillation catheter ablation vary significantly, in part because of limited information about the location, extent, and permanence of ablation injury at the time of procedure. Although the amount of scar on LGE MRI months after ablation correlates with procedure outcomes, early imaging predictors of scar remain elusive.
Thirty-seven patients presenting for atrial fibrillation ablation underwent high-resolution MRI with a 3-dimensional LGE sequence before ablation, IPA, and 3moPA using a 3-T scanner. The acute left atrial wall injuries on IPA scans were categorized as hyperenhancing (HE) or nonenhancing (NE) and compared with scar 3moPA.
Heterogeneous injuries with HE and NE regions were identified in all patients. Dark NE regions in the left atrial wall on LGE MRI demonstrate findings similar to the “no-reflow” phenomenon. Although the left atrial wall showed similar amounts of HE, NE, and normal tissue IPA (37.7 ± 13%, 34.3 ± 14%, and 28.0 ± 11%, respectively; p = NS), registration of IPA injuries with 3moPA scarring demonstrated that 59.0 ± 19% of scar resulted from NE tissue, 30.6 ± 15% from HE tissue, and 10.4 ± 5% from tissue identified as normal. Paired t-test comparisons were all statistically significant among NE, HE, and normal tissue types (p < 0.001). Arrhythmia recurrence at 1-year follow-up correlated with the degree of wall enhancement 3moPA (p = 0.02).
Radiofrequency ablation results in heterogeneous injury on LGE MRI with both HE and NE wall lesions. The NE lesions demonstrate no-reflow characteristics and reveal a better predictor of final scar at 3 months. Scar correlates with procedure outcomes, further highlighting the importance of early scar prediction.
ablation; atrium; fibrosis; magnetic resonance imaging
Comparative effectiveness research (CER) aims to provide decision-makers the evidence needed to evaluate the benefits and harms of alternative clinical management strategies. CER has become a national priority, with considerable new research funding allocated. Cardiovascular disease is a priority area for CER. This workshop report provides an overview of CER methods, with an emphasis on practical clinical trials and observational treatment comparisons. The report also details recommendations to the National Heart Lung and Blood Institute for a new framework for evidence development to foster cardiovascular CER, and specific studies to address eight clinical issues identified by the Institute of Medicine as high priorities for cardiovascular CER.
comparative effectiveness; research methods; clinical trials
We sought to determine the range and prevalence of practices being implemented by hospitals to reduce 30-day readmissions of patients with heart failure or acute myocardial infarction (AMI).
Readmissions of patients with heart failure or AMI are both common and costly; however evidence on strategies adopted by hospitals to reduce readmission rates is limited.
We used a web-based survey to conduct a cross-sectional study of hospitals’ reported use of specific practices to reduce readmissions for patients with heart failure or AMI. We contacted all hospitals enrolled in the Hospital to Home (H2H) quality improvement initiative as of July 2010. Of 594 hospitals, 537 completed the survey (response rate of 90.4%). We used standard frequency analysis to describe the prevalence of key hospital practices in the areas of 1) quality improvement resources and performance monitoring, 2) medication management efforts, and 3) discharge and follow-up processes.
Nearly 90% of hospitals agreed or strongly agreed that they had a written objective of reducing preventable readmission for patients with heart failure or AMI. More hospitals reported having quality improvement teams to reduce preventable readmissions for patients with heart failure (87%) than for patients with AMI (54%). On average, hospitals used 4.8 of 10 key practices; fewer than 3% of hospitals utilized all 10 practices.
Although most hospitals have a written objective of reducing preventable readmissions of patients with heart failure or AMI, the implementation of recommended practices varied widely. More evidence establishing the effectiveness of various practices is needed.
Heart failure; AMI; readmissions; quality improvement; medication reconciliation; discharge
We investigated the effect of reducing mitochondrial oxidative stress by the mitochondrial-targeted antioxidant peptide SS-31 in hypertensive cardiomyopathy.
Oxidative stress has been implicated in hypertensive cardiovascular diseases. Mitochondria and NADPH oxidase have been proposed as primary sites of reactive oxygen species (ROS) generation.
The mitochondrial targeted antioxidant peptide SS-31 was used to determine the role of mitochondrial oxidative stress in Angiotensin II (Ang)-induced cardiomyopathy, as well as in Gαq overexpressing mice with heart failure.
Angiotensin II induces mitochondrial ROS in neonatal cardiomyocytes, which is prevented by SS-31, but not the non-targeted antioxidant N-acetyl cysteine (NAC). Continuous administration of Ang for 4 weeks in mice significantly increased both systolic and diastolic blood pressure, and this was not affected by SS-31 treatment. Ang was associated with upregulation of NADPH oxidase 4 (NOX4) expression, increased cardiac mitochondrial protein oxidative damage and induced the signaling for mitochondrial biogenesis. Reducing mitochondrial ROS by SS-31 substantially attenuated Ang-induced NOX4 upregulation, mitochondrial oxidative damage, upregulation of mitochondrial biogenesis, phosphorylation of p38 MAP kinase, and prevented apoptosis, concomitant with amelioration of Ang induced cardiac hypertrophy, diastolic dysfunction, and fibrosis, despite the absence of blood pressure lowering effect. NAC did not show any beneficial effect. SS-31 administration for 4 weeks also partially rescued the heart failure phenotype of Gαq overexpressing mice.
Mitochondrial targeted peptide SS-31 ameliorates cardiomyopathy resulting from prolonged Ang stimulation as well as Gαq overexpression, suggesting its potential clinical application for target organ protection in hypertensive cardiovascular diseases.
mitochondria; hypertension; cardiomyopathy
ST-elevation myocardial infarction; quality improvement
We tested the hypothesis whether selective blunting of platelet-derived growth factor (PDGF)–dependent vascular smooth muscle cell (VSMC) proliferation and migration is sufficient to prevent neointima formation after vascular injury.
To prevent neointima formation and stent thrombosis after coronary interventions, it is essential to inhibit VSMC proliferation and migration without harming endothelial cell function. The role of PDGF—a potent mitogen and chemoattractant for VSMC that does not affect endothelial cells—for neointima formation remains controversial.
To decipher the signaling pathways that control PDGF beta receptor (βPDGFR)–driven VSMC proliferation and migration, we characterized 2 panels of chimeric CSF1R/βPDGFR mutants in which the binding sites for βPDGFR-associated signaling molecules (Src, phosphatidylinositol 3-kinase [PI3K], GTPase activating protein of ras, SHP-2, phospholipase Cγ 1 [PLCγ]) were individually mutated. Based on in vitro results, the importance of PDGF-initiated signals for neointima formation was investigated in genetically modified mice.
Our results indicate that the chemotactic response to PDGF requires the activation of Src, PI3K, and PLCγ, whereas PDGF-dependent cell cycle progression is exclusively mediated by PI3K and PLCγ. These 2 signaling molecules contribute to signal relay of the βPDGFR by differentially regulating cyclin D1 and p27kip1. Blunting of βPDGFR-induced PI3K and PLCγ signaling by a combination mutant (F3) completely abolished the mitogenic and chemotactic response to PDGF. Disruption of PDGF-dependent PI3K and PLCγ signaling in mice expressing the F3 receptor led to a profound reduction of neointima formation after balloon injury.
Signaling by the activated βPDGFR, particularly through PI3K and PLCγ, is crucial for neointima formation after vascular injury. Disruption of these specific signaling pathways is sufficient to attenuate pathogenic processes such as vascular remodeling in vivo.
PI-3 kinase; PLCγ; platelet-derived growth factor; proliferation; restenosis
This study sought to test the hypothesis that “virtual” electrophysiologic studies (EPS) on an anatomic platform generated by 3D MRI reconstruction of the left ventricle (LV) can reproduce the reentrant circuits of induced ventricular tachycardia (VT) in a porcine model of myocardial infarction (MI).
Delayed-enhancement MRI has been used to characterize MI and “gray zones”, which are thought to reflect heterogeneous regions of viable and non-viable myocytes.
MI by coronary artery occlusion was induced in eight pigs. After a recovery period, 3D cardiac MRIs were obtained from each pig in-vivo. Normal areas, gray zones, and infarct cores were classified based on voxel intensity. In the computer model, gray zones were assigned slower conduction and longer action potential durations than those for normal myocardium. Virtual EPS was performed and was compared to results of actual in vivo programmed stimulation and non-contact mapping.
The LV volumes ranged from 97.8 to 166.2 cm3 with 4.9 to 17.5% of voxels classified as infarct zones. Six of the seven pigs that developed VT during actual EPS were also inducible with virtual EPS. Four of the six pigs that had simulated VT had reentrant circuits that approximated the circuits seen with non-contact mapping, while the remaining two had similar circuits but propagating in opposite directions.
This initial study demonstrates the feasibility of applying a mathematical model to MRI reconstructions of the LV to predict VT circuits. Virtual EPS may be helpful to plan catheter ablation strategies or to identify patients who are at risk for future episodes of VT.
Ventricular tachycardia; computer-based model; myocardial infarction; magnetic resonance imaging