The APEX Trial:Effects of Allopurinol on Exercise Capacity, Coronary and Peripheral Endothelial Function and Natriuretic Peptides in Patients with Cardiac Syndrome X

The role of endothelial dysfunction and oxidative stress in the pathogenesis of cardiac syndrome X has recently been recognized. Allopurinol has previously been shown to improve endothelial dysfunction, reduce oxidative stress burden, and improve myocardial efficiency. In this “proof of concept” study, we investigated the effect of allopurinol on exercise capacity, coronary and peripheral endothelial function, and serum B-type natriuretic peptide (BNP: a marker of cardiac function and myocardial ischemia) in patients with cardiac syndrome X. Methods and Results: This study was a randomized, double-blind, placebo-control crossover trial. Nineteen patients (mean age 59 ± 10 years, 11 women and 8 men) with cardiac syndrome X were randomized to a 6-week treatment with either allopurinol (600 mg/day) or placebo. After 4 weeks of washout period, they were crossed over to the other arm. Outcomes measured at baseline and after treatment were maximum exercise time (ET) derived from Bruce protocol exercise treadmill test, serum BNP measurement, coronary flow reserve (CFR) as assessed by measuring the response of flow velocity in the left anterior descending artery to adenosine, and flow-mediated vasodilatation of the brachial artery (FMD). Allopurinol significantly reduced serum uric acid levels when compared with placebo (−48 ± 24% vs 1.9 ± 11%, P &lt;.001). There was no significant difference in maximum ET, CFR, and FMD between allopurinol and placebo. However, there was a trend that allopurinol reduced serum BNP when compared to placebo (−8% [interquartile range −22% to 65%] vs 44% [interquartile range −18% to 140%]; P =.07). Conclusion: In patients with cardiac syndrome X, high-dose allopurinol did not improve exercise capacity, and coronary or peripheral endothelial function.</p

Ischaemic heart disease in women: are there sex differences in pathophysiology and risk factors?: Position Paper from the Working Group on Coronary Pathophysiology and Microcirculation of the European Society of Cardiology

Cardiovascular disease (CVD) is the leading cause of death in women, and knowledge of the clinical consequences of atherosclerosis and CVD in women has grown tremendously over the past 20 years. Research efforts have increased and many reports on various aspects of ischaemic heart disease (IHD) in women have been published highlighting sex differences in pathophysiology, presentation, and treatment of IHD. Data, however, remain limited. A description of the state of the science, with recognition of the shortcomings of current data, is necessary to guide future research and move the field forward. In this report, we identify gaps in existing literature and make recommendations for future research. Women largely share similar cardiovascular risk factors for IHD with men; however, women with suspected or confirmed IHD have less coronary atherosclerosis than men, even though they are older and have more cardiovascular risk factors than men. Coronary endothelial dysfunction and microvascular disease have been proposed as important determinants in the aetiology and prognosis of IHD in women, but research is limited on whether sex differences in these mechanisms truly exist. Differences in the epidemiology of IHD between women and men remain largely unexplained, as we are still unable to explain why women are protected towards IHD until older age compared with men. Eventually, a better understanding of these processes and mechanisms may improve the prevention and the clinical management of IHD in wome

Overexpression of CUGBP1 in skeletal muscle from adult classic myotonic dystrophy type 1 but not from myotonic dystrophy type 2

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are progressive multisystemic disorders caused by similar mutations at two different genetic loci. The common key feature of DM pathogenesis is nuclear accumulation of mutant RNA which causes aberrant alternative splicing of specific pre-mRNAs by altering the functions of two RNA binding proteins, MBNL1 and CUGBP1. However, DM1 and DM2 show disease-specific features that make them clearly separate diseases suggesting that other cellular and molecular pathways may be involved. In this study we have analysed the histopathological, and biomolecular features of skeletal muscle biopsies from DM1 and DM2 patients in relation to presenting phenotypes to better define the molecular pathogenesis. Particularly, the expression of CUGBP1 protein has been examined to clarify if this factor may act as modifier of disease-specific manifestations in DM. The results indicate that the splicing and muscle pathological alterations observed are related to the clinical phenotype both in DM1 and in DM2 and that CUGBP1 seems to play a role in classic DM1 but not in DM2. In conclusion, our results indicate that multisystemic disease spectrum of DM pathologies may not be explained only by spliceopathy thus confirming that the molecular pathomechanism of DM is more complex than that actually suggested

A review of methods for assessment of coronary microvascular disease in both clinical and experimental settings

Obstructive disease of the large coronary arteries is the prominent cause for angina pectoris. However, angina may also occur in the absence of significant coronary atherosclerosis or coronary artery spasm, especially in women. Myocardial ischaemia in these patients is often associated with abnormalities of the coronary microcirculation and may thus represent a manifestation of coronary microvascular disease (CMD). Elucidation of the role of the microvasculature in the genesis of myocardial ischaemia and cardiac damage—in the presence or absence of obstructive coronary atherosclerosis—will certainly result in more rational diagnostic and therapeutic interventions for patients with ischaemic heart disease. Specifically targeted research based on improved assessment modalities is needed to improve the diagnosis of CMD and to translate current molecular, cellular, and physiological knowledge into new therapeutic option

Utility of Whole Blood Thiamine Pyrophosphate Evaluation in TPK1-Related Diseases

TPK1 mutations are a rare, but potentially treatable, cause of thiamine deficiency. Diagnosis is challenging given the phenotypic overlap that exists with other metabolic and neurological disorders. We report a case of TPK1-related disease presenting with Leigh-like syndrome and review the diagnostic utility of thiamine pyrophosphate (TPP) blood measurement. The proband, a 35-year-old male, presented at four months of age with recurrent episodes of post-infectious encephalopathy. He subsequently developed epilepsy, learning difficulties, sensorineural hearing loss, spasticity, and dysphagia. There was a positive family history for Leigh syndrome in an older brother. Plasma lactate was elevated (3.51 mmol/L) and brain MRI showed bilateral basal ganglia hyperintensities, indicative of Leigh syndrome. Histochemical and spectrophotometric analysis of mitochondrial respiratory chain complexes I, II+III, and IV was normal. Genetic analysis of muscle mitochondrial DNA was negative. Whole exome sequencing of the proband confirmed compound heterozygous variants in TPK1: c. 426G>C (p. Leu142Phe) and c. 258+1G>A (p.?). Blood TPP levels were reduced, providing functional evidence for the deleterious effects of the variants. We highlight the clinical and bioinformatics challenges to diagnosing rare genetic disorders and the continued utility of biochemical analyses, despite major advances in DNA sequencing technology, when investigating novel, potentially disease-causing, genetic variants. Blood TPP measurement represents a fast and cost-effective diagnostic tool in TPK1-related diseases

Takayasu’s arteritis: A case report and a brief review of the literature

Takayasu’s arteritis primarily affects young women. The current case report focuses on a Caucasian middle-aged woman who complained of weakness, malaise, and fatigue for as many as 19 years. Delayed diagnosis and lack of specific treatment could explain the extent and the clinical severity of the disease at time of hospital admission. Angiography showed focal narrowings of the abdominal and thoracic aorta and occlusion of both the subclavian arteries, of the right coronary artery and severe stenosis of the first marginal obtuse. Takayasu’s arteritis is not limited to women of Japanese origin but is present worldwide. Early diagnosis and treatment is warranted. Outcome appears to be favorable when the disease is quiescent

Sex and age differences and outcomes in acute coronary syndromes

Background: There is conflicting information about sex differences in presentation, treatment, and outcome after acute coronary syndromes (ACS) in the era of reperfusion therapy and percutaneous coronary intervention. The aim of this study was to examine presentation, acute therapy, and outcomes of men and women with ACS with special emphasis on their relationship with younger age ( lt = 65 years). Methods: From January 2010 to June 2015, we enrolled 5140 patients from 3 primary PCI capable hospitals. Patients were registered according to the International Survey of Acute Coronary Syndrome in Transitional Countries (ISACS-TC) registry protocol (ClinicalTrials.gov: NCT01218776). The primary outcome was the incidence of in-hospital mortality. Results: The study population was constituted by 2876 patients younger than 65 years and 2294 patients older. Women were older than men in both the young (56.2 +/- 6.6 vs. 54.1 +/- 7.4) and old (74.9 +/- 6.4 vs. 73.6 +/- 6.0) age groups. There were 3421 (66.2%) patients with ST elevation ACS (STE-ACS) and 1719 (33.8%) patients without ST elevation ACS (NSTE-ACS). In STE-ACS, the percentage of patients who failed to receive reperfusion was higher in women than in men either in the young (21.7% vs. 15.8%) than in the elderly (35.2% vs. 29.6%). There was a significant higher mortality in women in the younger age group (age-adjusted OR 1.52, 95% CI: 1.01-2.29), but there was no sex difference in the older group (age-adjusted OR 1.10, 95% CI: 0.87-1.41). Significantly sex differences in mortality were not seen in NSTE-ACS patients. Conclusions: In-hospital mortality from ACS is not different between older men and women. A higher short-term mortality can be seen only in women with STEMI and age of 65 or less