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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Chronic diseases now a leading cause of death in rural India--mortality data from the Andhra Pradesh Rural Health Initiative.

INTRODUCTION: India is undergoing rapid epidemiological transition as a consequence of economic and social change. The pattern of mortality is a key indicator of the consequent health effects but up-to-date, precise, and reliable statistics are few, particularly in rural areas. METHODS: Deaths occurring in 45 villages (population 180 162) were documented during a 12-month period in 2003-04 by multipurpose primary healthcare workers trained in the use of a verbal autopsy tool. Algorithms were used to define causes of death according to a limited list derived from the international classification of disease version 10. Causes were assigned by two independent physicians with disagreements resolved by a third. RESULTS: A total of 1354 deaths were recorded with verbal autopsies completed for 98%. A specific underlying cause of death was assigned for 82% of all verbal autopsies done. The crude death rate was 7.5/1000 (95% confidence interval, 7.1-7.9). Diseases of the circulatory system were the leading causes of mortality (32%), with similar proportions of deaths attributable to ischaemic heart disease and stroke. Second was injury and external causes of mortality (13%) with one-third of these deaths attributable to deliberate self harm. Third were infectious and parasitic diseases (12%). Tuberculosis and intestinal conditions each caused one-third of deaths within this category. HIV was assigned as the cause for 2% of all deaths. The fourth and fifth leading causes of death were neoplasms (7%) and diseases of the respiratory system (5%). CONCLUSION: Non-communicable and chronic diseases are the leading causes of death in this part of rural India. The observed pattern of death is unlikely to be unique to these villages and provides new insight into the rapid progression of epidemiological transition in rural India.

Brain natriuretic peptide levels and left ventricular functional recovery in a chronic heart failure population.

Due to the poor correlation between symptoms and left ventricular (LV) ejection fraction in a chronic heart failure (HF) population, the ability to identify patients who demonstrate LV functional recovery poses a dilemma for the clinician. Serial echocardiograms are not practical in a large outpatient HF population. Plasma brain natriuretic peptide (BNP) levels have a high predictive value for excluding patients with ventricular dysfunction and therefore could serve as a marker for identifying patients who demonstrate improved LV function. To evaluate this point, the researchers obtained baseline BNP levels in 380 chronic systolic HF patients seen in an outpatient HF clinic. Each patient already had a baseline echocardiogram performed before or on entry into the clinic. Fifty patients were identified in this group as having normal BNP levels (< or = 100 pg/mL). Echocardiograms were then repeated in this group and compared with initial echocardiographic data obtained from a retrospective chart review. The results showed that the mean LV ejection fraction for the group was increased (p < 0.001), mean LV internal dimension was decreased (p < 0.001), and the number of patients with an ejection fraction > 50% increased from zero to 20 (p < 0.001). Thus, normal BNP levels can correlate with LV recovery and could potentially offer a cost-effective method of assessing changes in LV function in patients with chronic HF.

Difficult cases in heart failure: polycystic ovary syndrome and heart failure.

This is a case of a 21-year-old female with a history of polycystic ovary syndrome who was subsequently diagnosed with heart failure. The patient did not have a family history of heart failure, nor did the patient herself have evidence of ischemic or valvular heart disease or prior viral infection. The patient was found, upon further evaluation, to have significant obstructive sleep apnea, a condition that has been linked to the development and/or worsening of heart failure. Interestingly enough, recent evidence has revealed that patients with polycystic ovary syndrome have been found to have a predilection for developing obstructive sleep apnea, irrespective of body weight or habitus.

Anemia in chronic heart failure: can EPO reduce deaths?

Many patients with chronic heart failure also have anemia, an association that has been increasingly recognized in recent years. Whether treating anemia will improve outcomes in patients with heart failure has yet to be determined, however. The decision to use an agent to treat anemia in heart failure should be made on a case-by-case basis.

Practical considerations for switching beta-blockers in heart failure patients.

The use of beta-blocker therapy has proven extremely useful in a variety of clinical settings, including the management of hypertension, acute- and post-myocardial infarction, and in congestive heart failure (HF). However, there are noticeable differences among individual beta-blockers in regard to efficacy of treatment and clinical outcomes in many of these conditions. These differences are particularly apparent in the treatment of HF, where effects on reverse remodeling and interactions on the periphery are potential factors that can differentiate between the efficacy of one drug versus another. In fact, beta-blockers are not a singular, homogeneous group, but rather a class made up of a number of agents with individual differences in pharmacology, receptor biology, hemodynamic effects, and tolerability. In the event of ongoing disease progression, the onus of choosing the most appropriate beta-blocker falls on the clinician's shoulders. Given the baseline differences among medications of this class, the rationale and manner for transitioning to a different beta-blocker should take into account the specific receptor-blockade subtype of any given agent, as well as any other intrinsic effects attributed to a specific drug. This article includes 2 protocols for switching between carvedilol, a third generation non-selective agent with vasodilatory properties through a1-blockade, and a beta1-selective agent (e.g., metoprolol, atenolol). The aim is to simplify and maximize the safety and tolerability of performing this exchange. With the increasing amount of clinical evidence supporting the use of one beta-blocker over another in the treatment of HF, it behooves physicians treating this patient population to utilize the adrenergic blocking agent that provides optimal therapy with minimal side effects and intolerability.

Tumor necrosis factor alpha polymorphism in heart failure/cardiomyopathy.

Tumor necrosis factor a (TNF-alpha) is a proinflammatory cytokine that is produced by activated macrophages. It has been shown to stimulate the release of endothelial cytokines and NO, increase vascular permeability, decrease contractility, and induce a prothrombotic state. The most studied TNF-a gene mutation in heart disease is a gamma to alpha substitution, which occurs when 308 nucleotides move upstream from the transcription initiation site in the TNF promoter and has been associated with elevated levels of TNF-alpha. The TNF1 allele (wild type) contains gamma at this site, while the TNF2 allele has an alpha substitution at the site. The TNF2 allele is a more powerful transcriptional activator, therefore leading to higher TNF-alpha levels. Most of the studies to date have failed to conclusively show any link between the polymorphism and heart disease, both coronary artery disease and cardiomyopathy/heart failure.

Nesiritide for the treatment of congestive heart failure.

Nesiritide (Natrecor) is a recombinant form of the human B-type natriuretic peptide (BNP) that has been shown, through several studies, to have beneficial natriuretic, diuretic and vasodilatory effects in the treatment of congestive heart failure (CHF). Nesiritide mimics the actions of endogenous BNP by binding to and stimulating receptors in the heart, kidney and vasculature. Nesiritide functions as both a potent venous and arterial vasodilator and has been shown to improve cardiac haemodynamics more rapidly and to a greater extent than intravenous nitroglycerin, as well as having fewer side effects. When compared in an open-label trial, nesiritide has also been shown to be less proarrhythmic than dobutamine. The major adverse effect of nesiritide, as with other vasodilators, is symptomatic hypotension, which occurred infrequently in clinical trials. Overall, nesiritide represents an effective and safe therapeutic option for the treatment of decompensated CHF.