PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes.

Pluripotent stem-cell-derived cardiomyocytes (PSC-CMs) provide an unprecedented opportunity to study human heart development and disease, but they are functionally and structurally immature. Here, we induce efficient human PSC-CM (hPSC-CM) maturation through metabolic-pathway modulations. Specifically, we find that peroxisome-proliferator-associated receptor (PPAR) signaling regulates glycolysis and fatty acid oxidation (FAO) in an isoform-specific manner. While PPARalpha (PPARa) is the most active isoform in hPSC-CMs, PPARdelta (PPARd) activation efficiently upregulates the gene regulatory networks underlying FAO, increases mitochondrial and peroxisome content, enhances mitochondrial cristae formation, and augments FAO flux. PPARd activation further increases binucleation, enhances myofibril organization, and improves contractility. Transient lactate exposure, which is frequently used for hPSC-CM purification, induces an independent cardiac maturation program but, when combined with PPARd activation, still enhances oxidative metabolism. In summary, we investigate multiple metabolic modifications in hPSC-CMs and identify a role for PPARd signaling in inducing the metabolic switch from glycolysis to FAO in hPSC-CMs.

Hereditary Palpebro-Gingival Fibrosis Syndrome.

This is a case report involving 3 siblings, ages 22, 21, and 3 years old, of consanguineous parents and Syrian descent with a particularly unique clinical phenotype and eyelid/gingival findings that have not been previously characterized. Full-thickness eyelid biopsies for 2 of the siblings were evaluated by ophthalmic pathology showed generalized fibrosis without any active destructive process or amyloid. Three of the 9 siblings were affected by this order with no familial history. Ophthalmic plastic surgeons should be aware of this new entity as genetic localization and further identification may help families affected by this disorder.

Three-Year Efficacy and Safety of the Misago Peripheral Stent for Superficial Femoral Artery Disease: Final Results from the OSPREY Trial.

PURPOSE: This study evaluated the long-term outcomes of the Misago peripheral stent trial (Terumo) for atherosclerotic lesions in the superficial femoral artery (SFA) in patients with claudication. MATERIALS AND METHODS: This was a prospective multicenter, single-arm, clinical trial of primary stent placement for de novo cases of SFA disease conducted in the United States and Asia. The primary endpoint was freedom from clinically driven target lesion revascularization (CD-TLR) at 36 months. Secondary outcomes were ankle-brachial index (ABI), Rutherford score, Walking Impairment Questionnaire (WIQ), a quality of life survey, and rate of device fracture. RESULTS: A total of 276 patients (64.4% male; mean age, 69.3 ± 10.1 years) were enrolled. Freedom from CD-TLR was 78.5% (95% confidence interval [CI], 73.0%-83.0%) at 24 months and 75.4% (95% CI, 69.6%-80.2%) at 36 months. Baseline ABI was 0.7 ± 0.1 and 0.98 ± 0.20 (P < .001) at 30 days after the procedure. Baseline Rutherford score was 3.6 ± 0.6 and 1.6 ± 1.0 30 at 30 days after the procedure (P < .001). Mean (and changed) ABI and Rutherford score at 36 months compared to day 30 after the procedure were, respectively, 0.91 (-0.1 ± 0.2) and 1.5 (-0.2 ± 1.1). WIQ score at baseline was 21.49 ± 26.30 and 50.51 ± 38.49 at 30 days after the procedure ( P < .001). The mean WIQ score at 2 years was 46.65 ± 37.31 (P = .12). Stent fracture rate at 36 months was 2.0% (4 of 202 patients). CONCLUSIONS: OSPREY (Occlusive-Stenotic Peripheral Artery Revascularization Study) 36-month data demonstrated persistent freedom from CD-TLR and sustained improvement in ABI and Rutherford score with primary stent placement for SFA lesions.

Epidemiology of sudden cardiac death in rural South India - insights from the andhra pradesh rural health initiative.

BACKGROUND: Sudden cardiac death (SCD) is a common initial presentation of coronary artery disease (CAD). Despite the growing epidemic of CAD in India, the epidemiology of SCD is largely unknown. OBJECTIVE: The objective of the study was to define the prevalence and determinants of sudden cardiac deaths in rural South India. METHODS: Prospective mortality surveillance was conducted in 45 villages (180,162 subjects) in rural South India between January 2006 and October 2007. Trained multipurpose health workers sought to do verbal autopsies within 4 weeks of any death. Detailed questionnaires including comorbidities and circumstances surrounding death were recorded. SCD was adjudicated using the modified Hinkle-Thaler classification. RESULTS: A total of 1916 deaths occurred in the study population over the 22 month time period and verbal autopsy was obtained in 1827 (95%) subjects. Overall mean age of the deceased was 62 ± 20 years and 1007 (55%) were men. Cardiovascular and cerebrovascular diseases together accounted for 559 deaths (31%), followed by infectious disease (163 deaths, 9%), cancer (126 deaths, 7%) and suicide (93 deaths, 5%). Of the 1827 deaths, after excluding accidental deaths (89 deaths), 309 deaths (17%) met criteria for SCD. Cardiovascular disease was the underlying causes in the majority of the SCD events (231/309 (75%)). On multivariate analyses, previous MI/CAD (p < 0.001, OR 14.25), hypertension (p < 0.001, OR 1.84), and age groups between 40-60 yrs (p=0.029) were significantly associated with SCD. CONCLUSION: Sudden cardiac death accounted for up to half of the cardiovascular deaths in rural Southern India. Traditional cardiovascular risk factors were strongly associated with SCD.

Cutaneous Sporothrix schenckii of the human eyelid.

An 87-year-old patient presented with a 6-week history of an isolated progressive destructive nodular eyelid mass, secondary nodular and ulcerative lesions, and regional painful lymphadenopathy. After 4 weeks, fungal cultures demonstrated Sporothrix schenckii. S. schenckii is a rare dimorphic fungus that can occasionally involve the periocular skin. The authors' case demonstrates typical clinical features, emphasizes the delay in diagnosis, and shows effective treatment with oral itraconazole.

Percutaneous coronary intervention for ST-elevation myocardial infarction: drug-eluting stents or bare metal stents?

The treatment paradigm for patients with an ST-elevation myocardial infarction (STEMI) has shifted greatly in the last 20 years. The use of fibrinolytic agents vastly altered the landscape in treating this entity and was further advanced by the introduction of percutaneous catheter-based methods of therapy. Percutaneous coronary intervention (PCI) has become the preferred method of treatment for patients with this condition when compared with thrombolytic agents as evidenced by a number of positive clinical trials. However, PCI in itself has had several adaptations over the last decade, namely in the shift from a balloon-only approach to the widespread usage of balloon-expandable metallic stents. The use of bare metal stents has proven to be more efficacious in regard to rates of repeat procedures when compared with the balloon-only approach and has become a standard in PCI for STEMI. The composition of the stents themselves had also undergone transformation as evidenced by the introduction of drug-eluting stents (DES). Although there have been encouraging data to support the use of DES in the elective setting, the use of these devices in primary PCI has been controversial. The pathologic milieu that is present in the STEMI setting is distinctly different than that seen in the elective, stable atherosclerotic setting and the use of DES has raised concerns over safety issues with their implementation. There have been a host of recent studies dedicated to elucidating the risk of using DES versus bare metal stents in the setting of STEMI and although the results have been generally favorable for the use of DES, this subject remains one that is under significant scrutiny.

Impact of thienopyridine administration prior to primary stenting in acute myocardial infarction.

The impact of thienopyridine administration prior to primary stenting in acute myocardial infarction (AMI) has not been well studied. We therefore examined the database from the prospective, multicenter, controlled CADILLAC trial in which 1,036 patients were randomized to bare metal stenting with or without abciximab to determine whether patients who received a thienopyridine prior to bare metal stenting in AMI had superior clinical outcomes. Per operator discretion, 659 patients (63.6%; Th+) received either a 500 mg ticlopidine loading dose (n = 623) or a 300 mg clopidogrel loading dose (n = 40), while 377 patients (36.4%; Th-) received no thienopyridine prior to stent implantation. Baseline and procedural characteristics of the two groups, including abciximab use (52.5% vs 52.8%, P = 0.93) were well matched. Th+ compared to Th- patients had lower rates of core lab assessed TIMI 0/1 flow postprocedure (0.8% vs 2.7%, P = 0.01). Th+ compared to Th- patients also had significantly reduced in-hospital and 30-day rates of ischemic target vessel revascularization (TVR) (1.1% vs 3.2%, P = 0.01 and 1.5% vs 3.8%, P = 0.02, respectively) and major adverse cardiovascular events (MACE) (2.7% vs 5.8%, P = 0.01 and 4.0% vs 6.9%, P = 0.03, respectively), results that remained significant after covariate adjustment. In conclusion, in this large prospective, controlled trial, patients receiving a thienopyridine prior to primary stenting in AMI were less likely to have TIMI 0/1 flow postprocedure and experienced reduced in-hospital and 30-day rates of ischemic TVR and MACE compared to those not administered a thienopyridine prior to stent implantation.

Safety and efficacy of drug-eluting and bare metal stents: comprehensive meta-analysis of randomized trials and observational studies.

BACKGROUND: The safety and efficacy of drug-eluting stents (DES) among more generalized "real-world" patients than those enrolled in pivotal randomized controlled trials (RCTs) are controversial. We sought to perform a meta-analysis of DES studies to estimate the relative impact of DES versus bare metal stents (BMS) on safety and efficacy end points, particularly for non-Food and Drug Administration-labeled indications. METHODS AND RESULTS: Comparative DES versus BMS studies published or presented through February 2008 with > or =100 total patients and reporting mortality data with cumulative follow-up of > or =1 year were identified. Data were abstracted from studies comparing DES with BMS; original source data were used when available. Data from 9470 patients in 22 RCTs and from 182 901 patients in 34 observational studies were included. RCT and observational data were analyzed separately. In RCTs, DES (compared with BMS) were associated with no detectable differences in overall mortality (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.81 to 1.15; P=0.72) or myocardial infarction (HR, 0.95; 95% CI, 0.79 to 1.13; P=0.54), with a significant 55% reduction in target vessel revascularization (HR, 0.45; 95% CI, 0.37 to 0.54; P<0.0001); point estimates were slightly lower in off-label compared with on-label analyses. In observational studies, DES were associated with significant reductions in mortality (HR, 0.78; 95% CI, 0.71 to 0.86), myocardial infarction (HR, 0.87; 95% CI, 0.78 to 0.97), and target vessel revascularization (HR, 0.54; 95% CI, 0.48 to 0.61) compared with BMS. CONCLUSIONS: In RCTs, no significant differences were observed in the long-term rates of death or myocardial infarction after DES or BMS use for either off-label or on-label indications. In real-world nonrandomized observational studies with greater numbers of patients but the admitted potential for selection bias and residual confounding, DES use was associated with reduced death and myocardial infarction. Both RCTs and observational studies demonstrated marked and comparable reductions in target vessel revascularization with DES compared with BMS. These data in aggregate suggest that DES are safe and efficacious in both on-label and off-label use but highlight differences between RCT and observational data comparing DES and BMS.

Novel applications of noncardiac vascular devices for the treatment of coronary artery pathology.

Transcatheter percutaneous therapy for the treatment of vascular disease has markedly expanded over the last 20 years. This growth of endovascular technology has encouraged application of these modalities to vascular pathology in numerous territories that are not optimally suited for open-surgical techniques. Though the initial development and use of these devices was directed towards specific vascular beds (i.e., coronary, peripheral, cerebrovascular), it is becoming increasingly apparent that these devices can be effectively used in alternate situations when clinically indicated. We describe two cases of nontraditional uses of noncoronary devices (specifically biliary self-expanding stents and neurovascular coils) in patients with coronary artery pathology.

Use of magnetic guidewire navigation in the treatment of lower extremity peripheral vascular disease: report of the first human clinical experience.

The use of a magnetic navigation system (MNS) to facilitate catheter placement in electrophysiologic procedures has been increasingly documented over the past decade. Recently, the utilization of MNS to aid guidewire directionality in complex coronary lesions has also been described. Given the multifaceted ability of MNS to be applied to varying vascular beds, we describe the successful employment of this modality to facilitate treatment of lower extremity peripheral arterial disease in a symptomatic male with gangrenous toe ulceration.

Beyond platelet inhibition: potential pleiotropic effects of ADP-receptor antagonists.

The adenosine diphosphate (ADP) receptor antagonists, specifically the class of thienopyridines, have emerged as potent tools in the clinician's arsenal for the treatment of athero-thrombotic disease over the last two decades. Though these medications have been clearly demonstrated to have significant platelet-inhibiting effects, their potential positive impact on other systemic processes has been less well elucidated. Recent evidence points to a number of potential pleiotropic effects of these agents, most notably in the attenuation of several pro-inflammatory pathways, which may be independent of their anti-platelet-aggregating effect. Additionally, several new ADP receptor antagonists are under investigation; it remains to be seen if these agents possess any additional beneficial pleiotropic properties as well.

Neutral endopeptidase inhibitors and endothelin antagonists.

The current treatment paradigm for heart failure revolves around the central theory of neurohormonal antagonism. With the success of angiotensin-converting-enzyme inhibition, beta-blockade, and aldosterone antagonism in heart failure, alternative areas of the hormonal cascade have been targeted for potential benefits. Two such agents, neutral endopeptidase inhibitors and endothelin antagonists, have demonstrated promising initial results in animal models and small, human-based studies but have fallen short when examined in larger clinical trials. The reasons for these shortcomings are varied and require analysis of the design of the studies as well as the intrinsic functions of these agents.

Diagnosis of Factor XI deficiency following congenital cataract extraction.

Factor XI deficiency is a rare coagulopathy that requires a specific approach to preoperative planning. Herein we report a case where ophthalmic surgery led to this diagnosis in a 4-month old boy and review the warranted prophylactic measures prior to operative intervention.

Greater adverse effects of cholesterol and diabetes on carotid intima-media thickness in South Asian Indians: comparison of risk factor-IMT associations in two population-based surveys.

Asian Indians appear particularly susceptible to coronary heart disease compared with other ethnic groups. We compared the effects of vascular risk factors on carotid intima-media thickness (IMT) in a population of South Asians from Andhra Pradesh, India with a population of Caucasians from Perth, Australia. Cardiovascular risk factors and ultrasound-assessed carotid IMT were measured in randomly selected adults from two villages in rural India (n=303) and compared to those for randomly sampled adults from Australia (n=1111). Regression models with interaction terms were used to compare the strengths of associations between risk factors and carotid IMT, in these two populations. There were stronger associations of cholesterol (p for interaction=0.009) and diabetes (p=0.04) with carotid IMT in the Indian compared to the Australian population. Also, while increasing HDL-cholesterol was associated with decreasing carotid IMT in the Australian population the reverse was true for the Indian population (p<0.001). The associations with IMT of blood pressure, triglycerides, age, HDL to total cholesterol ratio, glucose, BMI, waist, waist to hip ratio and smoking were not different between the populations. Greater adverse effects of total cholesterol and diabetes on atherosclerosis and no protective effect of HDL-cholesterol amongst Asian Indians provide a novel possible explanation for observed excess rates of cardiovascular disease amongst these populations.

Effect of cardiac resynchronization therapy on myocardial gene expression in patients with nonischemic dilated cardiomyopathy.

BACKGROUND: Cardiac resynchronization therapy (CRT) improves echocardiographic measures of ventricular structure and function in the failing heart. To determine whether or not these changes are representative of true biologic reverse ventricular remodeling or simply an artifact of an improved contraction pattern, we evaluated changes in myocardial gene expression typical of reverse remodeling before and after chronic CRT. METHODS AND RESULTS: Optimally medically treated patients with nonischemic heart failure meeting standard clinical criteria for CRT were enrolled. Before implantation of a CRT device, baseline echocardiogram and endomyocardial biopsies were obtained. These studies were repeated after 6 months of CRT. Using quantitative reverse-transcriptase polymerase chain reaction, the amount of messenger RNA for selected genes regulating contractile function (sarcoplasmic reticulum Ca2+ ATPase, alpha- and beta-myosin heavy chain [MHC] isoforms, phospholamban [PLB]), and pathologic hypertrophy (beta-MHC and atrial natriuretic peptide [ANP]) was determined from biopsy samples. Changes in gene expression (baseline to 6 months) were determined and correlated to changes in echocardiographic remodeling parameters. Ten patients were enrolled in the study, with 7 completing both baseline and follow-up biopsies and echocardiograms. On average, a significant increase was observed in alpha-MHC and PLB gene expression from baseline to 6 months (P = .016 for both). Beta-MHC levels tended to decrease with CRT (P = .078). Increased alpha-MHC levels correlated best with decreases in left ventricular end-diastolic dimension (P = .073, r = -0.71) and reductions in mitral regurgitation. No significant correlation between ejection fraction and gene expression was found. CONCLUSIONS: These changes in myocardial gene expression support the occurrence of reverse remodeling during chronic CRT. The changes are similar to those reported previously with beta-blockade, but were seen on top of standard drug therapies for heart failure.