Sushma Rekhraj

High-Dose Allopurinol Reduces Left Ventricular Mass in Patients With Ischemic Heart Disease

OBJECTIVES This study sought to ascertain if high-dose allopurinol regresses left ventricular mass (LVM) in patients with ischemic heart disease (IHD). BACKGROUND LV hypertrophy (LVH) is common in patients with IHD including normotensive patients. Allopurinol, a xanthine oxidase inhibitor, has been shown to reduce LV afterload in IHD and may therefore also regress LVH. METHODS A randomized, double-blind, placebo-controlled, parallel group study was conducted in 66 patients with IHD and LVH, comparing 600 mg/day allopurinol versus placebo therapy for 9 months. The primary outcome measure was change in LVM, assessed by cardiac magnetic resonance imaging (CMR). Secondary outcome measures were changes in LV volumes by CMR, changes in endothelial function by flow-mediated dilation (FMD), and arterial stiffness by applanation tonometry. RESULTS Compared to placebo, allopurinol significantly reduced LVM (allopurinol -5.2 ± 5.8 g vs. placebo -1.3 ± 4.48 g; p = 0.007) and LVM index (LVMI) (allopurinol -2.2 ± 2.78 g/m(2) vs. placebo -0.53 ± 2.5 g/m(2); p = 0.023). The absolute mean difference between groups for change in LVM and LVMI was -3.89 g (95% confidence interval: -1.1 to -6.7) and -1.67 g/m(2) (95% confidence interval: -0.23 to -3.1), respectively. Allopurinol also reduced LV end-systolic volume (allopurinol -2.81 ± 7.8 mls vs. placebo +1.3 ± 7.22 mls; p = 0.047), improved FMD (allopurinol +0.82 ± 1.8% vs. placebo -0.69 ± 2.8%; p = 0.017) and augmentation index (allopurinol -2.8 ± 5.1% vs. placebo +0.9 ± 7%; p = 0.02). CONCLUSIONS High-dose allopurinol regresses LVH, reduces LV end-systolic volume, and improves endothelial function in patients with IHD and LVH. This raises the possibility that allopurinol might reduce future cardiovascular events and mortality in these patients. (Does a Drug Allopurinol Reduce Heart Muscle Mass and Improve Blood Vessel Function in Patients With Normal Blood Pressure and Stable Angina?; ISRCTN73579730).

Improving the Primary Prevention of Cardiovascular Events by Using Biomarkers to Identify Individuals With Silent Heart Disease

OBJECTIVES The aim of this study was to examine whether biomarkers can identify silent cardiac target organ damage (cTOD) in a primary prevention population. BACKGROUND One possible way to improve primary prevention of cardiovascular events is to identify those patients who already harbor silent cTOD (i.e., myocardial ischemia, left ventricular hypertrophy, systolic dysfunction, diastolic dysfunction, or left atrial enlargement). This might be possible by screening with a biomarker (e.g. high sensitivity cardiac troponin T [hs-cTnT] or B-type natriuretic peptide [BNP]). METHODS We prospectively recruited 300 asymptomatic individuals already receiving primary prevention therapy. Transthoracic echocardiography, stress echocardiography, and/or myocardial perfusion imaging were performed to identify silent cTOD. RESULTS One hundred two (34%) patients had evidence of cTOD. Left ventricular hypertrophy was the most prevalent (29.7%) form of cTOD, followed by diastolic dysfunction (21.3%), left atrial enlargement (15.3%), systolic dysfunction (6.3%), and ischemia (6.3%). The area under the curve (AUC) for BNP to identify any form of silent cTOD was 0.78 overall and 0.82 in men. The equivalent figures for hs-cTnT were 0.70 and 0.75 in women. The AUC for BNP and hs-cTnT together was 0.81 and 0.82 in men. However, the discrimination power of other markers was poor, with AUCs of 0.61 for microalbuminuria, 0.49 for uric acid, and 0.58 for eGFR. CONCLUSIONS In asymptomatic treated primary prevention patients, BNP screening is able to identify existing silent cTOD. The performance of hs-cTnT was not as good as that of BNP. B-type natriuretic peptide plus hs-cTnT together performed best. Prescreening with BNP ± cTnT followed by targeted phenotyping is worth exploring further as a possible way to improve primary prevention.

Are Either or Both Hyperuricemia and Xanthine Oxidase Directly Toxic to the Vasculature? A critical appraisal

Basic research and clinical studies have implicated a role for hyperuricemia and for xanthine oxidoreductase (XOR), the enzyme that generates uric acid (UA), in not only gout but also vascular diseases. At present, asymptomatic hyperuricemia (i.e., in the absence of gout, urate nephrolithiasis, or tumor lysis syndrome) is not an indication for therapy. With the rise over the past several decades in prevalence of both gout and hyperuricemia, clarifying the potential adverse effects of hyperuricemia (in patients with and without gout) is of public health importance. UA is not simply an inert end-product of purine metabolism in humans, but rather has potential antioxidant, pro-oxidant, and pro-inflammatory effects. However controversy remains as to which, if any, of these effects are of clinical relevance in development and complications of human vascular diseases in gout and asymptomatic hyperuricemia. Clearly, not all individuals with hyperuricemia develop gout, and studies to date have also been unable to clarify in which subjects hyperuricemia may have detrimental effects on the vasculature. Further, studies of urate-lowering therapy with XOR inhibition or uricosuric agents have not been able to definitively identify whether any such effects may be mediated by UA versus XO. Adequately sized, prospective randomized clinical trials of sufficient duration, and employing appropriate biomarkers, now appear critical to resolve the putative toxic roles of UA and XO in the human arterial circulation.

The Impact of Renin-Angiotensin-Aldosterone System Blockade on Heart Failure Outcomes and Mortality in Patients Identified to Have Aortic Regurgitation : A Large Population Cohort Study

OBJECTIVES The aim of this study was to investigate the effect of renin-angiotensin system blockade on outcomes in patients with aortic regurgitation (AR). BACKGROUND Angiotensin-converting enzyme (ACE) inhibitors have the potential to reduce afterload, blunt left ventricular wall stress, and limit left ventricular dilation and hypertrophy. However, long-term studies have yielded inconsistent results, and very few have assessed clinical outcomes. METHODS The Health Informatics Centre dispensed prescription and morbidity and mortality database for the population of Tayside, Scotland, was linked through a unique patient identifier to the Tayside echocardiography database. Patients diagnosed with at least moderate AR from 1993 to 2008 were identified. Cox regression analysis was used to assess differences in all-cause mortality and cardiovascular (CV) and AR events (heart failure hospitalizations, heart failure deaths, or aortic valve replacement) between those treated with and without ACE inhibitors or angiotensin receptor blockers (ARBs). RESULTS A total of 2,266 subjects with AR (median age 74 years; interquartile range: 64 to 81 years) were studied, with a mean follow-up period of 4.4 ± 3.7 years. Seven hundred and five patients (31%) received ACE inhibitor or ARB therapy. There were 582 all-cause deaths (25.7%). Patients treated with ACE inhibitors or ARBs had significantly lower all-cause mortality and fewer CV and AR events, with adjusted hazard ratios of 0.56 (95% confidence interval [CI]: 0.64 to 0.89; p < 0.01) for all-cause mortality, 0.77 (95% CI: 0.67 to 0.89; p < 0.01) for CV events, and 0.68 (95% CI: 0.54 to 0.87; p < 0.01) for AR events. CONCLUSIONS This large retrospective study shows that the prescription of ACE inhibitors or ARBs in patients with moderate to severe AR was associated with significantly reduced all-cause mortality and CV and AR events. These data need to be confirmed by a prospective randomized controlled outcome trial.

Left ventricular hypertrophy in COPD without hypoxemia: the elephant in the room?

BACKGROUND COPD is associated with significant cardiovascular mortality. Left ventricular hypertrophy (LVH) is a pivotal cardiovascular risk factor. The prevalence of LVH in COPD is currently unknown. METHODS We performed a pilot study of 93 normoxemic patients with COPD and 34 control subjects. Patients underwent echocardiography to measure left ventricular (LV) dimensions, ECG, measurement of serum B-type natriuretic peptide (BNP) levels, and 24-h BP recording. Spirometry and oxygen saturations were also recorded. RESULTS The oxygen saturations of patients with COPD were normal, at 96.5% (95% CI, 96.1%-97.0%), with a mean FEV(1) of 70.0% predicted (95% CI, 65.2%-74.8%). A total of 30.1% of patients with COPD met the echocardiographic criteria for LVH based on LV mass index, with more LVH in female patients than in male patients (43.2% vs 21.4%, P = .02). The LV mass index in patients with COPD was 96.2 g/m(2) (95% CI, 90.1-102.7 g/m(2)) vs 82.9 g/m(2) (95% CI, 75.8-90.6 g/m(2)) in control subjects ( P = .017). The LV mass index remained high in patients with COPD in the absence of a hypertension history (94.5 g/m(2) vs 79.9 g/m(2), P = .015) and with 24-h systolic BP <135 mm Hg (96.7 g/m(2) vs 82.5 g/m(2), P = .024). The LV ejection fraction (mean = 63.4%) and BNP (mean = 28.7 pg/mL) were normal in patients with COPD. The mean 24-h BP was normal in patients with COPD, at 125/72 mm Hg. ECG was less sensitive for detecting LVH than was echocardiography. CONCLUSION LVH with normal LV ejection fraction and BNP levels was present in a significant proportion of normotensive, normoxemic patients with COPD, especially female patients. Clinical trials are, therefore, indicated to evaluate treatments to regress LVH in patients with COPD.

Renin-angiotensin system blockers are associated with reduced mortality and heart failure hospitalization in patients paced for complete atrioventricular block.

BACKGROUND Right ventricular apical pacing can cause dyssynchronous activation of the ventricles, increase sympathetic activation, cause abnormalities in myocardial perfusion, worsen cardiac output and endothelial function, and may be associated with adverse cardiovascular effects. The use of rennin-angiotensin system blockers (RASBs) may be beneficial in counteracting these potentially harmful effects of right ventricular pacing. OBJECTIVE To explore the impact of RASB use on the outcome in patients with right ventricular pacemakers implanted for complete atrioventricular (AV) block. METHODS Patients implanted with right ventricular pacemakers for complete AV block between 1994 and 2009 were identified from the Tayside Pacing Registry. Cox proportional hazards model was used to assess differences in all-cause mortality and congestive heart failure hospitalizations for those receiving RASB during follow-up, adjusted for confounding variables. We also performed 2 sensitivity analyses--a propensity score-matched analysis and time-dependent analyses--to minimize bias. RESULTS Eight hundred twenty patients (57% men; median age 73 years; range 22-103 years) received pacemakers for complete AV block between 1994 and 2008 (54% dual-chamber pacemaker and 46% ventricular demand pacemaker). Two hundred seventy-eight (34%) patients had received RASBs. Mean follow-up was 4.9 ± 4.6 years, with 540 (65%) deaths. RASB use was independently associated with significantly reduced mortality (adjusted hazard ratio 0.67; 95% confidence interval 0.47-0.94; P = .017) and reduced heart failure hospitalization (adjusted hazard ratio 0.42; 95% confidence interval 0.17-0.92; P <.001). CONCLUSIONS This study suggests that RASBs may confer outcome benefits in patients with right ventricular pacemakers implanted for complete AV block.

MRI of the left atrium at 3T: evaluation of measurement reproducibility in healthy volunteers and patients with cardiovascular disease

Background Left ventricular (LV) function has traditionally been the focus for cardiac magnetic resonance imaging (MRI) investigations, but similar methods can also be applied to the left atrium (LA). Previous studies elsewhere have almost entirely involved the use of 1.5T systems, but 3T MRI can provide faster data acquisition with thinner image slices, and may be more suitable for quantifying the structure and function of the LA. Purpose To evaluate 3T-MRI for LA volume assessments in: (i) healthy volunteers (HV); (ii) patients with LV-hypertrophy and ischemia (LVHI); and (iii) patients with LV-hypertrophy and diabetes (LVHD). Material and Methods Participants were imaged using a balanced steady-state free precession sequence. Healthy volunteers were scanned twice and patients were scanned on one occasion. Volumes were segmented by two observers, and coefficients of repeatability (CoR) were derived. Results For LA volumes (indexed to body surface area), CoRs were in the range of 1.3–4.6 mL/m2. The LVHI patients had enlarged LA volumes (diastolic, 46.4 mL/m2; systolic, 25.9 mL/m2) and reduced ejection fraction (EF) (44.9%) relative to the HV (diastolic, 39.0 mL/m2; systolic, 17.8 mL/m2; EF, 54.5%) and LVHD groups (diastolic, 41.4 mL/m2; systolic, 20.2 mL/m2; EF, 50.7%). LA volumes were moderately correlated with LV mass in the HV group (R2 = 0.59 for LA end-systolic volume), but became weaker (R2 ≤ 0.17) for patient groups. Conclusion 3T-MRI derived LA volume measurements are simple and repeatable, and can elicit clear differences between LVHI patients and HVs. These MRI endpoints provide scope for improved radiological interpretation of LA structure and function, and the high degree of repeatability validates their use for longitudinal investigations where precision work is essential.

136 HIGH DOSE ALLOPURINOL IMPROVES ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH ISCHAEMIC HEART DISEASE AND LEFT VENTRICULAR HYPERTROPHY BUT DOES NOT MATCH AGE AND GENDER MATCHED CONTROLS

Background Endothelial dysfunction is a poor prognostic marker in patients with ischaemic heart disease (IHD). Superoxide free radicals, which are generated by xanthine oxidase, contribute to oxidative stress and leads to the development of endothelial dysfunction. Aim of this sub-study was to investigate if high dose allopurinol, a xanthine oxidase inhibitor, could improve endothelial function in patients with IHD and left ventricular hypertrophy (LVH) to the same level of age and gender matched healthy volunteers. Methods 66 patients with IHD and LVH were recruited into a randomised, double blind, placebo controlled parallel study. They received 600 mg/day allopurinol or placebo therapy over a 9 month follow up period. Endothelial function tests were performed at baseline, 6 months and 9 months visit. In addition, thirty age and gender matched healthy volunteers (HV) attended a single study visit for endothelial function tests. Endothelial function was assessed using flow-mediated dilatation (FMD) of the brachial artery and arterial stiffness measured using pulse wave analysis. Results 60 patients completed the main study (31 active, 29 placebo). At baseline, the HV had a significantly greater FMD and lower AIx compared to the allopurinol group. Allopurinol significantly improved brachial artery FMD (ΔFMD: +0.82%±1.8% allopurinol vs—0.69%±2.8% placebo; p=0.017) and central augmentation index (Δ AIx: −2.8%±5.1% allopurinol vs +0.9%±7% placebo; p=0.02). However, after 9 months of allopurinol therapy, their absolute endothelial function did not match that of age and gender matched healthy volunteers (FMD: 4.94±2.2% allopurinol vs 6.3±3.74% HV, p=0.092; AIx: 17.4±8.6% vs 12.8±11% HV, p=0.071). Conclusions In conclusion, high dose allopurinol improves endothelial dysfunction in patients with ischaemic heart disease and left ventricular hypertrophy but their absolute endothelial function does not match age and gender matched healthy volunteers.

Update on heart failure

Heart failure is common in patients with diabetes and about half of all patients with the syndrome of heart failure have preserved ejection fraction. The combination of heart failure and diabetes is an ominous sign and requires aggressive treatment. Heart failure treatments have improved the morbidity and mortality associated with heart failure dramatically over the past 20—30 years. We now review the basis for current medical therapies looking back over the important landmark trials which have led to the routine use of angiotensin converting enzyme inhibitors, β-blockers, aldosterone antagonists and others, concentrating particularly on the best therapies for patients with diabetes. Device therapy is also becoming more widespread and the recommendations are reviewed also. There are newer treatments emerging, such as fish oils and ivabradine, which may alter heart failure management in the future.

53 B-type natriuretic peptide performs better than current cardiovascular risk scores in identifying silent “pancardiac” target organ damage in already treated primary prevention patients

Background Primary prevention needs to be improved because up to 70% of cardiovascular (CV) events occur outwith those classified as high risk by CV risk scores currently used in clinical practice (eg, Framingham). One possible way to improve primary prevention of CV disease is to identify those patients who may already harbour silent pancardiac target organ damage in the form of left ventricular hypertrophy (LVH), systolic dysfunction (LVSD), diastolic dysfunction (LVDD), left atrial enlargement (LAE) or silent myocardial ischaemia. This could be achieved by reapplying traditional CV risk scores to primary prevention patients after they have been treated or by screening with a simple biomarker like B-type natriuretic peptide (BNP). Methods We prospectively recruited 300 asymptomatic individuals without known cardiovascular disease already on primary prevention therapy. Patients with valvular heart disease, atrial fibrillation and renal impairment were excluded. We measured BNP and calculated 10-year global CV risk scores (based on Framingham, QRISK and ASSIGN) in each participant. Transthoracic echocardiography was used to assess LV mass, LV systolic and diastolic function, and left atrial volume while the presence of inducible ischaemia was assessed by dobutamine stress echocardiography or dipyridamole myocardial perfusion imaging. Patients were divided into low, intermediate and high risk groups based on 10-year global CV risk. The prevalence of various cardiac TOD in each group was compared and ROC curves were constructed for BNP and for 10-year global CV risk scores to assess their ability to detect presence of silent cardiac TOD. Results One hundred and two (34%) patients (Mean age 64±6.0 years, 58% males) had evidence of silent cardiac TOD (29.7% LVH, 18% LAE, 17.3% LVDD, 7.3% LVSD and 6.3% Ischaemia). The prevalence of cardiac TOD ranged from 19 to 28% in the low risk, 26%–33% in the intermediate risk and 36%–41% in the high risk groups based on three commonly used CV risk equations. BNP levels were significantly higher (median (IQR); 21.6 (13.6–40.0) vs 11.4 (6.3–20.0) pg/ml, p<0.0001) in those with cardiac TOD compared to those without. The AUC for BNP to identify any form of cardiac TOD was 0.77 (p<0.0001) overall and 0.83 (p<0.0001) in males. However, discrimination power of CV risk scores was poor with area under curve of only 0.58 (p=0.02) for QRISK, 0.62 (p=0.001) for Framingham and 0.62 (p=0.001) for ASSIGN to detect presence of any form of TOD. Conclusion Silent cardiac TOD is highly prevalent (34%) in already treated primary prevention population but current CV risk estimation alone performs poorly in the detection of these silent cardiac abnormalities. However, a raised BNP is able to identify existing silent cardiac TOD of various subtypes particularly in males. Using BNP to identify silent cardiac TOD could, in the future, become a new way to improve the primary prevention of CV events.