Randomized placebo controlled trial evaluating the safety and efficacy of single low-dose intracoronary insulin-like growth factor following percutaneous coronary intervention in acute myocardial infarction (RESUS-AMI).

BACKGROUND: Residual and significant postinfarction left ventricular (LV) dysfunction, despite technically successful percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI), remains an important clinical issue. In preclinical models, low-dose insulin-like growth factor 1 (IGF1) has potent cytoprotective and positive cardiac remodeling effects. We studied the safety and efficacy of immediate post-PCI low-dose intracoronary IGF1 infusion in STEMI patients. METHODS: Using a double-blind, placebo-controlled, multidose study design, we randomized 47 STEMI patients with significantly reduced (≤40%) LV ejection fraction (LVEF) after successful PCI to single intracoronary infusion of placebo (n = 15), 1.5 ng IGF1 (n = 16), or 15 ng IGF1 (n = 16). All received optimal medical therapy. Safety end points were freedom from hypoglycemia, hypotension, or significant arrhythmias within 1 hour of therapy. The primary efficacy end point was LVEF, and secondary end points were LV volumes, mass, stroke volume, and infarct size at 2-month follow-up, all assessed by magnetic resonance imaging. Treatment effects were estimated by analysis of covariance adjusted for baseline (24 hours) outcome. RESULTS: No significant differences in safety end points occurred between treatment groups out to 30 days (χ2 test, P value = .77). There were no statistically significant differences in baseline (24 hours post STEMI) clinical characteristics or LVEF among groups. LVEF at 2 months, compared to baseline, increased in all groups, with no statistically significant differences related to treatment assignment. However, compared with placebo or 1.5 ng IGF1, treatment with 15 ng IGF1 was associated with a significant improvement in indexed LV end-diastolic volume (P = .018), LV mass (P = .004), and stroke volume (P = .016). Late gadolinium enhancement (±SD) at 2 months was lower in 15 ng IGF1 (34.5 ± 29.6 g) compared to placebo (49.1 ± 19.3 g) or 1.5 ng IGF1 (47.4 ± 22.4 g) treated patients, although the result was not statistically significant (P = .095). CONCLUSIONS: In this pilot trial, low-dose IGF1, given after optimal mechanical reperfusion in STEMI, is safe but does not improve LVEF. However, there is a signal for a dose-dependent benefit on post-MI remodeling that may warrant further study.

The PHARMS (Patient Held Active Record of Medication Status) feasibility study: a research proposal.

OBJECTIVE: Medication errors are a major source of preventable morbidity, mortality and cost and many occur at the times of hospital admission and discharge. Novel interventions (such as new methods of recording medication information and conducting medication reconciliation) are required to facilitate accurate transfer of medication information. With existing evidence supporting the use of information technology and the patient representing the one constant in the care process, an electronic patient held medication record may provide a solution. This study will assess the feasibility of introducing a patient held electronic medication record in primary and secondary care using the Consolidated Framework for Implementation Research (CFIR).This feasibility study is a mixed method study of community dwelling older adult patients admitted to an urban secondary care facility comprising a non-randomised intervention and qualitative interviews with key stakeholders. Outcomes of interest include clinical outcomes and process evaluation.This study will yield insights pertaining to feasibility, acceptability and participation for a more definitive evaluation of the intervention. The study also has the potential to contribute to knowledge of implementation of technology in a healthcare context and to the broader area of implementation science.

The role of trimetazidine in cardiovascular disease: beyond an anti-anginal agent.

With evidence for efficacy in such diverse clinical settings such as stable coronary artery disease, reperfusion injury, and contrast-induced nephropathy, trimetazidine (TMZ) is novel among cardiovascular agents. In spite of this and almost half a century of clinical experience with the drug, it remains licensed only as an adjunct in the management of angina pectoris in patients who are inadequately controlled by or intolerant to first-line therapies. Although no single pharmacological mechanism has been hitherto universally accepted, TMZ is known to target deranged cellular energetics particularly in ischaemic myocardial tissue. Mechanistically, this separates the drug from conventional anti-anginal therapies, namely beta-adrenergic antagonists, calcium channel blockers, and nitrates. Moreover, a haemodynamically neutral side-effect profile should make TMZ a much more attractive therapeutic agent in this setting. Such ostensibly beneficial pharmacodynamics notwithstanding, the drug has a limited role in angina pectoris treatment algorithms. Concerns regarding a potential for new onset movement disorder further complicate its use and have led to a licensing revocation in some jurisdictions for the treatment of vestibular disorders. In this review article, we examine the pertinent literature and assess the evidence base for TMZ as a viable treatment option in a number of clinical settings.

Exercise and associated dietary extremes impact on gut microbial diversity.

OBJECTIVE: The commensal microbiota, host immunity and metabolism participate in a signalling network, with diet influencing each component of this triad. In addition to diet, many elements of a modern lifestyle influence the gut microbiota but the degree to which exercise affects this population is unclear. Therefore, we explored exercise and diet for their impact on the gut microbiota. DESIGN: Since extremes of exercise often accompany extremes of diet, we addressed the issue by studying professional athletes from an international rugby union squad. Two groups were included to control for physical size, age and gender. Compositional analysis of the microbiota was explored by 16S rRNA amplicon sequencing. Each participant completed a detailed food frequency questionnaire. RESULTS: As expected, athletes and controls differed significantly with respect to plasma creatine kinase (a marker of extreme exercise), and inflammatory and metabolic markers. More importantly, athletes had a higher diversity of gut micro-organisms, representing 22 distinct phyla, which in turn positively correlated with protein consumption and creatine kinase. CONCLUSIONS: The results provide evidence for a beneficial impact of exercise on gut microbiota diversity but also indicate that the relationship is complex and is related to accompanying dietary extremes.

Effects of centrally acting angiotensin converting enzyme inhibitors on functional decline in patients with Alzheimer's disease.

BACKGROUND: Centrally acting angiotensin converting enzyme inhibitors (CACE-Is) are associated with reduced rates of cognitive decline in patients with dementia. CACE-Is may also improve exercise tolerance in functionally impaired older adults with normal cognition, suggesting that CACE-Is may positively influence activities of daily living (ADL) in dementia. OBJECTIVE: To compare rates of decline in patients with mild to moderate Alzheimer's disease (AD) receiving CACE-Is to those not currently treated with CACE-Is (NoCACE-I), included in the Doxycycline and Rifampicin for Alzheimer's Disease study (n = 406). METHODS: Patients were included if baseline and end-point (twelve months apart) scores were available for measures including the Standardized Alzheimer's Disease Assessment Scale - Cognitive Subscale; Quick Mild Cognitive Impairment screen; Clinical Dementia Rating Scale (CDR-SB), and Lawton-Brody ADL Scale. RESULTS: There was a significant, 25% difference (median one-point) in the 12-month rate of decline in ADL scores in patients taking CACE-Is (n = 91), compared to the NoCACE-I group (n = 274), p = 0.024. This remained significant after adjusting for age, gender, education, and blood pressure, p = 0.034. When individual CACE-Is were compared to the NoCACE-I group, a significant reduction in the rate of decline in ADLs (median one versus four points), were only observed for perindopril, p = 0.01. The CDR-SB was also reduced (median one-point) for the perindopril compared to the NoCACE-I group, p = 0.04. CONCLUSION: This observational study suggests that CACE-Is, and potentially perindopril in particular, are associated with a reduced rate of functional decline in patients with AD, without an association with mood or behavior. This suggests that CACE-Is may slow disease progression in AD.

Effects of centrally acting ACE inhibitors on the rate of cognitive decline in dementia.

OBJECTIVES: There is growing evidence that antihypertensive agents, particularly centrally acting ACE inhibitors (CACE-Is), which cross the blood-brain barrier, are associated with a reduced rate of cognitive decline. Given this, we compared the rates of cognitive decline in clinic patients with dementia receiving CACE-Is (CACE-I) with those not currently treated with CACE-Is (NoCACE-I), and with those who started CACE-Is, during their first 6 months of treatment (NewCACE-I). DESIGN: Observational case-control study. SETTING: 2 university hospital memory clinics. PARTICIPANTS: 817 patients diagnosed with Alzheimer's disease, vascular or mixed dementia. Of these, 361 with valid cognitive scores were included for analysis, 85 CACE-I and 276 NoCACE-I. MEASUREMENTS: Patients were included if the baseline and end-point (standardised at 6 months apart) Standardised Mini-Mental State Examination (SMMSE) or Quick Mild Cognitive Impairment (Qmci) scores were available. Patients with comorbid depression or other dementia subtypes were excluded. The average 6-month rates of change in scores were compared between CACE-I, NoCACE-I and NewCACE-I patients. RESULTS: When the rate of decline was compared between groups, there was a significant difference in the median, 6-month rate of decline in Qmci scores between CACE-I (1.8 points) and NoCACE-I (2.1 points) patients (p=0.049), with similar, non-significant changes in SMMSE. Median SMMSE scores improved by 1.2 points in the first 6 months of CACE treatment (NewCACE-I), compared to a 0.8 point decline for the CACE-I (p=0.003) group and a 1 point decline for the NoCACE-I (p=0.001) group over the same period. Multivariate analysis, controlling for baseline characteristics, showed significant differences in the rates of decline, in SMMSE, between the three groups, p=0.002. CONCLUSIONS: Cognitive scores may improve in the first 6 months after CACE-I treatment and use of CACE-Is is associated with a reduced rate of cognitive decline in patients with dementia.

In vivo impact of prodrug isosorbide-5-nicotinate-2-aspirinate on lipids and prostaglandin D2: is this a new immediate-release therapeutic option for niacin?

OBJECTIVES: To evaluate the pharmacokinetics and effects of the first immediate-release (IR) niacin-aspirin prodrug (ST0702) on lipid, prostaglandin and thromboxane levels in non-human primates (NHPs). METHODS: We compared 28 mg/kg crystalline IR niacin, equimolar doses of crystalline IR ST0702 and control on low density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) and triglycerides (Tg) in NHPs (6 per group) over 48 h (daily oral gavage). In addition, we compared IR niacin and ST0702 effects on prostaglandin (PG)D(2), ex vivo thromboxane B(2) (TXB(2)) levels and plasma pharmacokinetics. RESULTS: ST0702 is metabolised in vivo to aspirin, niacin and salicylic acid with T(max) values of 30, 45 and 95 min respectively using a non-compartmental model. ST0702 resulted in 38% and 40% reductions in LDL-C and ApoB levels compared to control over the 48 h period (p = 0.027 and p = 0.012 respectively). Corresponding values were 32% and 25% for niacin (both p = NS vs control). ST0702, but not niacin, decreased Tg levels (p = 0.017 for between group difference). Post prandial glycaemia was attenuated vs baseline in the ST0702 group only. Ex vivo serum TXB(2) generation was suppressed at 15 min and complete suppression of TXB(2) was sustained at 24h (p<0.01 vs niacin). ST0702 suppressed PGD(2) exposure eightfold (p = 0.012) compared to niacin over the first 24h. CONCLUSIONS: This two-dose study in NHPs suggests that ST0702 is more effective than IR niacin on lipid profiles, while suppressing TXB(2) and PGD(2) increases and prevents post-prandial glycaemia. ST0702 shows promise as a new IR therapeutic option for niacin.

Isolated Rheumatic Tricuspid Stenosis with Reverse Lutembacher's Physiology.

Tricuspid valve dysfunction occurs frequently in patients with rheumatic heart disease and is usually manifested as functional or organic tricuspid regurgitation. Rheumatic tricuspid stenosis is less common and occurs characteristically in the presence of concomitant mitral valve disease. In this report, we describe the clinical and echocardiographic findings in a patient with isolated rheumatic tricuspid stenosis and a right-to-left shunt across the interatrial septum, likely as a result of a patent foramen ovale, resulting in central cyanosis. This case illustrates an interesting association of tricuspid stenosis and an interatrial right-to-left shunt suggestive of a reverse Lutembacher's physiology.