Blood pressure in treated hypertensive individuals with the MTHFR 677TT genotype is responsive to intervention with riboflavin: findings of a targeted randomized trial.

Intervention with riboflavin was recently shown to produce genotype-specific lowering of blood pressure (BP) in patients with premature cardiovascular disease homozygous for the 677C→T polymorphism (TT genotype) in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR). Whether this effect is confined to patients with high-risk cardiovascular disease is unknown. The aim of this randomized trial, therefore, was to investigate the responsiveness of BP to riboflavin supplementation in hypertensive individuals with the TT genotype but without overt cardiovascular disease. From an available sample of 1427 patients with hypertension, we identified 157 with the MTHFR 677TT genotype, 91 of whom agreed to participate in the trial. Participants were stratified by systolic BP and randomized to receive placebo or riboflavin (1.6 mg/d) for 16 weeks. At baseline, despite being prescribed multiple classes of antihypertensive drugs, >60% of participants with this genotype had failed to reach goal BP (≤140/90 mm Hg). A significant improvement in the biomarker status of riboflavin was observed in response to intervention (P<0.001). Correspondingly, an overall treatment effect of 5.6±2.6 mm Hg (P=0.033) in systolic BP was observed, with pre- and postintervention values of 141.8±2.9 and 137.1±3.0 mm Hg (treatment group) and 143.5±3.0 and 144.3±3.1 mm Hg (placebo group), whereas the treatment effect in diastolic BP was not significant (P=0.291). In conclusion, these results show that riboflavin supplementation targeted at hypertensive individuals with the MTHFR 677TT genotype can decrease BP more effectively than treatment with current antihypertensive drugs only and indicate the potential for a personalized approach to the management of hypertension in this genetically at-risk group. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: ISRCTN23620802.

Riboflavin offers a targeted strategy for managing hypertension in patients with the MTHFR 677TT genotype: a 4-y follow-up.

BACKGROUND: We recently reported that the elevated blood pressure (BP) observed in patients with cardiovascular disease who are homozygous for the 677C→T polymorphism (TT genotype) in the gene encoding methylenetetrahydrofolate reductase (MTHFR) was responsive to supplementation with riboflavin-the cofactor for MTHFR. OBJECTIVE: The objective was to investigate the effect of riboflavin on BP targeted at patients with the TT genotype 4 y after initial investigation, during which time major changes in the clinical guidelines for antihypertensive therapy were introduced. DESIGN: A total of 83 patients (representing all 3 genotypes) who participated in a placebo-controlled riboflavin intervention for 16 wk in 2004 agreed to take part. Nested within this follow-up, those with the TT genotype (n = 31) proceeded to intervention with riboflavin (1.6 mg/d for 16 wk) or placebo, conducted in a crossover style whereby the 2004 treatment groups were reversed. RESULTS: At follow-up in 2008, as in 2004, patients with the TT genotype had higher systolic BP (P < 0.01), with a nonsignificant trend noted for higher diastolic BP (P = 0.051). Despite the marked changes in antihypertensive therapy that had occurred, BP remained unchanged in patients with the TT genotype at the time of follow-up. Riboflavin supplementation (administered in 2004 and 2008) produced an overall decrease in systolic (-9.2 ± 12.8 mm Hg; P = 0.001) and diastolic (-6.0 ± 9.9 mm Hg; P = 0.003) BP. CONCLUSIONS: Optimizing riboflavin status offers a low-cost targeted strategy for managing elevated BP in this genetically at-risk group. These findings, if confirmed in the general population, could have important implications for the prevention of hypertension.

A pilot study of a low-tilt biphasic waveform for transvenous cardioversion of atrial fibrillation: improved efficacy compared with conventional capacitor-based waveforms in patients.

BACKGROUND: The optimal waveform tilt for defibrillation is not known. Most modern defibrillators used for the cardioversion of atrial fibrillation (AF) employ high-tilt, capacitor-based biphasic waveforms. METHODS: We have developed a low-tilt biphasic waveform for defibrillation. This low-tilt waveform was compared with a conventional waveform of equivalent duration and voltage in patients with AF. Patients with persistent AF or AF induced during a routine electrophysiology study (EPS) were randomized to receive either the low-tilt waveform or a conventional waveform. Defibrillation electrodes were positioned in the right atrial appendage and distal coronary sinus. Phase 1 peak voltage was increased in a stepwise progression from 50 V to 300V. Shock success was defined as return of sinus rhythm for >/=30 seconds. RESULTS: The low-tilt waveform produced successful termination of persistent AF at a mean voltage of 223 V (8.2 J) versus 270 V (6.7 J) with the conventional waveform (P = 0.002 for voltage, P = ns for energy). In patients with induced AF the mean voltage for the low-tilt waveform was 91V (1.6 J) and for the conventional waveform was 158 V (2.0 J) (P = 0.005 for voltage, P = ns for energy). The waveform was much more successful at very low voltages (less than or equal to 100 V) compared with the conventional waveform (Novel: 82% vs Conventional 22%, P = 0.008). CONCLUSION: The low-tilt biphasic waveform was more successful for the internal cardioversion of both persistent and induced AF in patients (in terms of leading edge voltage).

Impedance compensated biphasic waveforms for transthoracic cardioversion of atrial fibrillation: a multi-centre comparison of antero-apical and antero-posterior pad positions.

AIMS: To compare the success rate for transthoracic direct current cardioversion (DCC) of atrial fibrillation (AF) with antero-posterior (AP) and antero-apical (AA) electrode positions using an impedance compensated biphasic (ICB) waveform. METHODS AND RESULTS: Three-hundred and seven patients [mean age 66 (SD+/-13), 195 male] with AF were recruited in three centres. Patients were randomized to an AA (n=150) or AP (n=144) pad position. Thirteen patients with implanted pacemakers were defaulted to the AP pad position. Cardioversion was performed using an ICB waveform with a 70, 100, 150, and 200 J energy selection protocol. If the fourth shock was unsuccessful, the pads were crossed over to the alternative position for a final 200 J shock. Shock 1 was successful in 54/150 (36%) AA and 45/144 (31%) AP patients, whereas success was achieved by shock 2 in 99/150 (66%) AA and 74/144 (51%) AP, by shock 3 in 123/150 (82%) AA and 109/144 (76%) AP, and by shock 4 in 143/150 (95%) AA and 127/144 (88%) AP and after cross-over in 144/150 (96%) AA and 135/144 (94%) AP. Overall success rate was higher than expected at 95%. Pad position was not associated significantly with success. There was a trend towards an improved outcome with the AA configuration (P=0.05). CONCLUSION: The influence of pad position for DCC of AF may be less pertinent with ICB waveforms than with monophasic waveforms.