Impact of Left Ventricular Hypertrophy on Survival in Chronic Obstructive Pulmonary Disease.

PURPOSE: Left ventricular hypertrophy (LVH) is a significant cardiac risk factor, associated with increased mortality. The impact of LVH on mortality in chronic obstructive pulmonary disease (COPD) is unknown. We evaluated the impact of LVH on mortality in COPD patients by measurement of left ventricular dimensions by echocardiography. METHODS: Retrospective cohort study utilizing a NHS database of COPD patients (TARDIS), in Tayside, Scotland (2001-2010), linked with databases regarding echocardiograms, pharmacy prescription, and the General Register Office for Scotland death registry. Cox proportional hazard regression was used to determine hazard ratios for mortality and hospital admissions based upon left ventricular mass index (LVMI) and left ventricular internal diastolic diameter after correction for all available influential covariates. Increased LVIDd was defined as >5.3 cm (female) and >5.9 cm (male). LVH was defined as an LVMI of >95 g/m(2) (female) and >115 g/m(2) (male). RESULTS: 617 patients were included for analysis. Mean (SD) age at diagnosis, 70 (9); mean FEV1 % (SD), 60.6 (19.3); mean resting SaO2 % (SD), 92.7 (10). Mean follow-up 4.5 years. Increased LVIDd was not associated with increased mortality, χ (2)= 0.767, p = 0.381. Increased LVMI was associated with a significant increased risk of mortality, χ (2) = 5.447, p = 0.02 with an adjusted HR (95 % CI) of 1.542 (1.068-2.228), p = 0.021. CONCLUSIONS: The presence of LVH, demonstrated by elevated left ventricular mass index is associated with a significantly increased risk of mortality in COPD patients. Therapeutic interventions are required to address this important modifiable risk factor in COPD patients.

Right ventricular pacing impairs endothelial function in man.

AIMS: Clinical trial data show that right ventricular pacing worsens cardiovascular outcomes. The underlying pathophysiology of this is undetermined. We studied the effects of right ventricular pacing on cardiac measures of vascular health (endothelial function), ventricular wall stress (B-type natriuretic peptide), and cardiac reserve (cardiac output response to exercise) in subjects with pacemakers. METHODS AND RESULTS: Twenty-two subjects [mean age 68.4 ± 8.8 (SD) years] with dual-chamber pacemakers implanted for sino-atrial disease were studied in a randomized crossover study comparing minimal right ventricular pacing [RVP-min; pacing with long atrioventricular delay (AVD)] to maximal right ventricular pacing (RVP-max; pacing with short AVD). Endothelial function was measured with reactive hyperaemia peripheral arterial tonometry. Cardiac output at rest and during exercise was determined using an inert gas rebreathing method. Right ventricular pacing was significantly higher in RVP-max when compared with RVP-min (90 ± 16 vs. 15 ± 20%, P < 0.001). Reactive hyperaemia peripheral arterial tonometry index was significantly lower after RVP-max vs. RVP-min (1.73 ± 0.33 vs. 1.96 ± 0.37, P < 0.05). B-type natriuretic peptide was not significantly different between pacing modes (113 ± 80 vs. 104 ± 108 pg/mL, P = NS). Cardiac output at peak exercise was significantly lower during RVP-max (7.65 ± 3.15 vs. 7.05 ± 2.61 L/min, P < 0.05). CONCLUSION: Right ventricular pacing is associated with worsened endothelial function and cardiac reserve.

Mean HbA1c and mortality in diabetic individuals with heart failure: a population cohort study.

AIMS: Controversy exists regarding the importance of glycaemic control in patients with type 2 diabetes mellitus (T2DM) and chronic heart failure (CHF) based on conflicting reports using single baseline glycosyated haemoglobin (HbA1c ). Using the time-weighted mean of serial HbA1c measurements has been found to be a better predictor of diabetic complications as it reflects the glycaemic burden for that individual over time. We therefore sought to confirm this in a large cohort of patients with T2DM and incident CHF. METHODS AND RESULTS: A time-weighted mean HbA1c was calculated using all HbA1c measurements following CHF diagnosis. Patients were grouped into five categories of HbA1c (≤6.0%, 6.1-7.0%, 7.1-8.0%, 8.1-9.0%, and >9.0%). The relationship between time-weighted mean HbA1c and all-cause death after CHF diagnosis was assessed. A total of 1447 patients with T2DM met the study criteria. During a median follow-up of 2.8 years, there were 826 (57.1%) deaths, with a crude death rate of 155 deaths per 1000 person-years [95% confidence interval (CI) 144-166]. A Cox regression model, adjusted for all significant predictors, with the middle HbA1c category (7.1-8.0%) as the reference, showed a U-shaped relationship between HbA1c and outcome [HbA1c <6.0%, hazard ratio (HR) 2.5, 95% CI 1.8-3.4; HbA1c 6.1-7.0%, HR 1.4, 95% 1.1-1.7; HbA1c 8.1-9.0%, HR 1.3, 95% CI 1.0-1.6; and HbA1c >9.0%, HR 1.8, 95% CI 1.4-2.3]. Further analysis revealed a protective effect of insulin sensitizers (i.e. metformin) (HR 0.7, 95% CI 0.61-0.93) but not other drug classes. CONCLUSIONS: In patients with T2DM and CHF, our study shows a U-shaped relationship between HbA1c and mortality, with the lowest risk in patients with modest glycaemic control (HbA1c 7.1-8.0%) and those treated with insulin sensitizers.

Both high and low HbA1c predict incident heart failure in type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus is an independent risk factor for heart failure development, but the relationship between incident heart failure and antecedent glycemia has not been evaluated. METHODS AND RESULTS: The Genetics of Diabetes Audit and Research in Tayside Study study holds data for 8683 individuals with type 2 diabetes mellitus. Dispensed prescribing, hospital admission data, and echocardiography reports were linked to extract incident heart failure cases from December 1998 to August 2011. All available HbA1c measures until heart failure development or end of study were used to model HbA1c time-dependently. Individuals were observed from study enrolment until heart failure development or end of study. Proportional hazard regression calculated heart failure development risk associated with specific HbA1c ranges accounting for comorbidities associated with heart failure, including blood pressure, body mass index, and coronary artery disease. Seven hundred and one individuals with type 2 diabetes mellitus (8%) developed heart failure during follow up (mean 5.5 years, ±2.8 years). Time-updated analysis with longitudinal HbA1c showed that both HbA1c <6% (hazard ratio =1.60; 95% confidence interval, 1.38-1.86; P value <0.0001) and HbA1c >10% (hazard ratio =1.80; 95% confidence interval, 1.60-2.16; P value <0.0001) were independently associated with the risk of heart failure. CONCLUSIONS: Both high and low HbA1c predicted heart failure development in our cohort, forming a U-shaped relationship.

High-potency statin and ezetimibe use and mortality in survivors of an acute myocardial infarction: a population-based study.

OBJECTIVE: To determine all-cause mortality in patients with a first myocardial infarct who were treated with simvastatin compared with high-potency statin and simvastatin/ezetimibe combination. BACKGROUND: Despite statin use, residual cardiovascular risk remains. Therapeutic options include more potent statins or addition of ezetimibe. There is no clinical outcome data on the use of ezetimibe in such patients. METHODS: Retrospective longitudinal study using the United Kingdom General Practice Research Database. Patients who had survived 30 days after their first acute myocardial infarct (AMI), had not received prior statin or ezetimibe therapy and were started on a statin within 30 days of AMI were included. Three groups were identified according to their follow-up: (i) simvastatin monotherapy; (ii) high-potency statin group (patients who started on simvastatin and switched to atorvastatin or rosuvastatin); and (iii) ezetimibe/statin combination group (patients who received ezetimibe in addition to statin). RESULTS: 9597 patients (57% male, mean age of 65 ± 13 years) matched study criteria: simvastatin (n=6990 (72.8%)); high-potency statin (n=1883, (19.6%)); and ezetimibe/statin combination (n=724 (7.5%)). During a mean follow-up of 3.2 years, there were 1134 (12%) deaths. In the multivariate proportional hazards model, the adjusted HR for high-potency statin and ezetimibe group were 0.72 (95% CI 0.59 to 0.88, p<0.001) and 0.96 (95% CI 0.64 to 1.43, p=0.85), respectively. A similar result was also obtained in the propensity score analysis that took into account covariates that predicted drug treatment groups. CONCLUSIONS: Patients switched to a high-potency statin had a significantly reduced mortality compared with simvastatin monotherapy. There was no observed mortality benefit in the ezetimibe group.

Aortic valvular heart disease: Is there a place for angiotensin-converting-enzyme inhibitors?

Aortic valve disease (AVD) is the most common form of valvular heart disease in the western world. The only proven therapy for severe AVD is open aortic valve replacement, with trans-catheter aortic valve implantation emerging as a promising modality to treat severe aortic stenosis in a selected group of patients. AVD has a long asymptomatic phase with symptoms occurring late in the disease and once symptoms develop, prognosis is poor. There is a growing appreciation that aortic valvular heart disease incorporates a disease process that extends beyond the valve itself leading to an aortic valvular 'heart' disease. The renin-angiotensin system is known to modulate adverse left ventricular remodeling and myocardial fibrosis, which could be caused by increased load caused by the AVD. In this review, the authors explore evidence that suggest that drugs that target the renin-angiotensin system may have a potential therapeutic role in AVD.

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.

The impact of tiotropium on mortality and exacerbations when added to inhaled corticosteroids and long-acting ß-agonist therapy in COPD.

BACKGROUND: Tiotropium has been shown to improve lung function, quality of life, and exacerbations and reduce mortality when compared with placebo in COPD. It remains unclear whether benefits are seen when tiotropium is used in conjunction with inhaled corticosteroids (ICSs) plus long-acting ß-agonists (LABAs). METHODS: We performed a retrospective cohort study using a National Health Service database of patients with COPD in Tayside, Scotland, between 2001 and 2010 that is linked with databases regarding hospital admissions, pharmacy prescriptions, and death registries. The impact of the addition of tiotropium (Tio) to ICS + LABA therapy on all-cause mortality, hospital admissions for respiratory disease, and emergency oral corticosteroid bursts was evaluated. Adjusted hazard ratios (HRs) were calculated by Cox regression after inclusion of the following covariates: cardiovascular and respiratory disease, diabetes, smoking, age, sex, and deprivation index. RESULTS: A total of 1,857 patients were given ICS + LABA + Tio, and 996 were given ICS + LABA. Mean follow-up was 4.65 years. The adjusted HR for all-cause mortality for ICS + LABA + Tio vs ICS + LABA was 0.65 (95% CI, 0.57-0.75; P < .001). Adjusted HRs for hospital admissions and oral corticosteroid bursts were 0.85 (95% CI, 0.73-0.99; P = .04) and 0.71 (95% CI, 0.63-0.80; P < .001), respectively. CONCLUSIONS: The study suggests that the addition of tiotropium to ICSs and LABA therapy may confer benefits in reducing all-cause mortality, hospital admissions, and oral corticosteroid bursts in patients with COPD. Triple therapy is widely used in the real-life management of COPD, with only limited scientific support. The study supports the use of triple therapy in COPD and provides a platform for randomized controlled trials specifically addressing this topic.

Pulmonary hypertension predicts all-cause mortality in patients with heart failure: a retrospective cohort study.

AIMS: The presence of pulmonary hypertension (PH) in left ventricular systolic dysfunction (LVSD) and symptomatic heart failure is an ominous sign. There are insufficient data regarding the risk conferred by increasing severity of PH in patients with heart failure. METHODS AND RESULTS: We performed a record linkage study in Tayside, Scotland (population ∼400,000) utilizing the Tayside echocardiogram database (>50,000 echocardiograms) maintained by the Health Informatics Centre (HIC). Data sets from the HIC include mortality data, cardiovascular medications, and other healthcare activities linked anonymously by the community health index (CHI) number. Patients were included in the analysis if they had LVSD, had a valid right ventricular systolic pressure (RVSP) measurement, and had a loop diuretic prescription (provided not more than 1 year prior to echocardiogram). A Cox proportional hazard model was used to examine the effects of RVSP on all-cause mortality. A total of 1612 patients [mean age, 75.2 ± 10.9 (SD) years; 57.4% male] met the entry criteria. Mean RVSP for the cohort was 44.9 ± 13.1 mmHg and mean follow-up was 2.8 ± 2.5 years. For each 5 mmHg stepwise increase in RVSP, after adjustment for confounding factors including the degree of LVSD and the presence of chronic obstructive pulmonary disease, the hazard ratio (HR) for all-cause mortality was 1.06 (1.03-1.08, P < 0.001). CONCLUSIONS: Pulmonary hypertension predicted all-cause mortality in a heterogeneous group of patients with heart failure. Each 5 mmHg rise in RVSP was associated with a 6% increased risk of death.

Pacing-induced heart disease: understanding the pathophysiology and improving outcomes.

Pacemaker implantation remains the only therapeutic option that improves morbidity and mortality for patients with symptomatic bradycardia. However, pacing from the right ventricular apex can induce 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 outcomes. This article reviews the current knowledge on the pathophysiology of pacing-induced cardiovascular disease and current strategies to avoid and mitigate the adverse effects of right ventricular pacing.

Effect of beta blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study.

OBJECTIVE: To examine the effect of ß blockers in the management of chronic obstructive pulmonary disease (COPD), assessing their effect on mortality, hospital admissions, and exacerbations of COPD when added to established treatment for COPD. DESIGN: Retrospective cohort study using a disease specific database of COPD patients (TARDIS) linked to the Scottish morbidity records of acute hospital admissions, the Tayside community pharmacy prescription records, and the General Register Office for Scotland death registry. SETTING: Tayside, Scotland (2001-2010) Population 5977 patients aged >50 years with a diagnosis of COPD. MAIN OUTCOME MEASURES: Hazard ratios for all cause mortality, emergency oral corticosteroid use, and respiratory related hospital admissions calculated through Cox proportional hazard regression after correction for influential covariates. RESULTS: Mean follow-up was 4.35 years, mean age at diagnosis was 69.1 years, and 88% of ß blockers used were cardioselective. There was a 22% overall reduction in all cause mortality with ß blocker use. Furthermore, there were additive benefits of ß blockers on all cause mortality at all treatment steps for COPD. Compared with controls (given only inhaled therapy with either short acting ß agonists or short acting antimuscarinics), the adjusted hazard ratio for all cause mortality was 0.28 (95% CI 0.21 to 0.39) for treatment with inhaled corticosteroid, long acting ß agonist, and long acting antimuscarinic plus ß blocker versus 0.43 (0.38 to 0.48) without ß blocker. There were similar trends showing additive benefits of ß blockers in reducing oral corticosteroid use and hospital admissions due to respiratory disease. ß blockers had no deleterious impact on lung function at all treatment steps when given in conjunction with either a long acting ß agonist or antimuscarinic agent CONCLUSIONS: ß blockers may reduce mortality and COPD exacerbations when added to established inhaled stepwise therapy for COPD, independently of overt cardiovascular disease and cardiac drugs, and without adverse effects on pulmonary function. NCT Number: NCT01221480

Impact of renin-angiotensin system blockade therapy on outcome in aortic stenosis.

OBJECTIVES: The purpose of this study was to investigate the impact of renin-angiotensin system blockade therapy on outcomes in aortic stenosis (AS). BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are perceived to be relatively contraindicated in AS. However, inhibitors of the renin-angiotensin system may be beneficial in AS through their cardioprotective and beneficial effects on left ventricular remodeling. METHODS: The Health Informatics dispensed prescribing, morbidity, and mortality database for the population of Tayside, Scotland, was linked through a unique patient identifier to the Tayside echocardiography database (>110,000 scans). Patients with a diagnosis of AS from 1993 to 2008 were identified. Cox regression model (adjusted for confounding variables) and propensity score analysis were used to assess the impact of ACEIs or ARBs on all-cause mortality and cardiovascular (CV) events (CV death or hospitalizations). RESULTS: A total of 2,117 patients with AS (mean age 73 ± 12 years, 46% men) were identified and 699 (33%) were on ACEI or ARB therapy. Over a mean follow-up of 4.2 years, there were 1,087 (51%) all-cause deaths and 1,018 (48%) CV events. Those treated with ACEIs or ARBs had a significantly lower all-cause mortality with an adjusted hazard ratio of 0.76 (95% confidence interval: 0.62 to 0.92, p < 0.0001) and fewer CV events with an adjusted hazard ratio of 0.77 (95% confidence interval: 0.65 to 0.92, p < 0.0001). The outcome benefits of ACEIs/ARBs were further supported by propensity score analysis. CONCLUSIONS: This large observational study suggests that ACEI/ARB therapy is associated with an improved survival and a lower risk of CV events in patients with AS.

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.