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Articles by H Watkins
Total Records ( 2 ) for H Watkins
  K Abozguia , P Elliott , W McKenna , T. T Phan , G Nallur Shivu , I Ahmed , A. R Maher , K Kaur , J Taylor , A Henning , H Ashrafian , H Watkins and M. Frenneaux
  Background—

Hypertrophic cardiomyopathy patients exhibit myocardial energetic impairment, but a causative role for this energy deficiency in the pathophysiology of hypertrophic cardiomyopathy remains unproven. We hypothesized that the metabolic modulator perhexiline would ameliorate myocardial energy deficiency and thereby improve diastolic function and exercise capacity.

Methods and Results—

Forty-six consecutive patients with symptomatic exercise limitation (peak Vo2 <75% of predicted) caused by nonobstructive hypertrophic cardiomyopathy (mean age, 55±0.26 years) were randomized to perhexiline 100 mg (n=24) or placebo (n=22). Myocardial ratio of phosphocreatine to adenosine triphosphate, an established marker of cardiac energetic status, as measured by 31P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak Vo2, symptoms, quality of life, and serum metabolites were assessed at baseline and study end (4.6±1.8 months). Perhexiline improved myocardial ratios of phosphocreatine to adenosine triphosphate (from 1.27±0.02 to 1.73±0.02 versus 1.29±0.01 to 1.23±0.01; P=0.003) and normalized the abnormal prolongation of heart rate normalized time to peak filling between rest and exercise (0.11±0.008 to –0.01±0.005 versus 0.15±0.007 to 0.11±0.008 second; P=0.03). These changes were accompanied by an improvement in primary end point (peak Vo2) (22.2±0.2 to 24.3±0.2 versus 23.6±0.3 to 22.3±0.2 mL · kg–1 · min–1; P=0.003) and New York Heart Association class (P<0.001) (all P values ANCOVA, perhexiline versus placebo).

Conclusions—

In symptomatic hypertrophic cardiomyopathy, perhexiline, a modulator of substrate metabolism, ameliorates cardiac energetic impairment, corrects diastolic dysfunction, and increases exercise capacity. This study supports the hypothesis that energy deficiency contributes to the pathophysiology and provides a rationale for further consideration of metabolic therapies in hypertrophic cardiomyopathy.

Clinical Trial Registration—

URL: http://www.clinicaltrials.gov. Unique identifier: NCT00500552.

  G Pare , D. I Chasman , A. N Parker , R. R.Y Zee , A Malarstig , U Seedorf , R Collins , H Watkins , A Hamsten , J. P Miletich and P. M Ridker
 

Background— Homocysteine is a sulfur amino acid whose plasma concentration has been associated with the risk of cardiovascular diseases, neural tube defects, and loss of cognitive function in epidemiological studies. Although genetic variants of MTHFR and CBS are known to influence homocysteine concentration, common genetic determinants of homocysteine remain largely unknown.

Methods and Results— To address this issue comprehensively, we performed a genome-wide association analysis, testing 336 469 single-nucleotide polymorphisms in 13 974 healthy white women. Although we confirm association with MTHFR (1p36.22; rs1801133; P=8.1x10–35) and CBS (21q22.3; rs6586282; P=3.2x10–10), we found novel associations with CPS1 (2q34; rs7422339; P=1.9x10–11), MUT (6p12.3; rs4267943; P=2.0x10–9), NOX4 (11q14.3; rs11018628; P=9.6x10–12), and DPEP1 (16q24.3; rs1126464; P=1.2x10–12). The associations at MTHFR, DPEP1, and CBS were replicated in an independent sample from the PROCARDIS study, whereas the association at CPS1 was only replicated among the women.

Conclusions— These associations offer new insight into the biochemical pathways involved in homocysteine metabolism and provide opportunities to better delineate the role of homocysteine in health and disease.

 
 
 
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