Weight loss enhances cardiac energy metabolism and function in heart failure associated with obesity.

AIMS: Obesity is associated with high rates of cardiac fatty acid oxidation, low rates of glucose oxidation, cardiac hypertrophy and heart failure. Whether weight loss can lessen the severity of heart failure associated with obesity is not known. We therefore determined the effect of weight loss on cardiac energy metabolism and the severity of heart failure in obese mice with heart failure. MATERIALS AND METHODS: Obesity and heart failure were induced by feeding mice a high-fat (HF) diet and subjecting them to transverse aortic constriction (TAC). Obese mice with heart failure were then switched for 8 weeks to either a low-fat (LF) diet (HF TAC LF) or caloric restriction (CR) (40% caloric intake reduction, HF TAC CR) to induce weight loss. RESULTS: Weight loss improved cardiac function (%EF was 38 ± 6% and 36 ± 6% in HF TAC LF and HF TAC CR mice vs 25 ± 3% in HF TAC mice, P < 0.05) and it decreased cardiac hypertrophy post TAC (left ventricle mass was 168 ± 7 and 171 ± 10 mg in HF TAC LF and HF TAC CR mice, respectively, vs 210 ± 8 mg in HF TAC mice, P < 0.05). Weight loss enhanced cardiac insulin signalling, insulin-stimulated glucose oxidation rates (1.5 ± 0.1 and 1.5 ± 0.1 µmol/g dry wt/min in HF TAC LF and HF TAC CR mice, respectively, vs 0.2 ± 0.1 µmol/g dry wt/min in HF TAC mice, P < 0.05) and it decreased pyruvate dehydrogenase phosphorylation. Cardiac fatty acid oxidation rates, AMPKTyr172 /ACCSer79 signalling and the acetylation of ß-oxidation enzymes, were attenuated following weight loss. CONCLUSIONS: Weight loss is an effective intervention to improve cardiac function and energy metabolism in heart failure associated with obesity.

Canadian Cardiovascular Society Quality Indicators for Heart Failure.

A working group was convened by the Canadian Cardiovascular Society (CCS) in 2010 to identify quality indicators (QIs) for heart failure (HF). Using the CCS "Best Practices for Developing Cardiovascular Quality Indicators" methodology, a total of 49 "long-list" QIs was identified and rated. Subsequent ranking and discussion led to the selection of an initial "short-list" of 6 QIs to evaluate quality care, including daily assessment of blood chemistry indicators, chest radiography, patient education, in-hospital use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, assessment of left ventricular function, and 30-day hospital readmission. The short-list QIs were selected as being important for quality assurance and because the patient information, for the most part, can be captured during the inpatient setting, which would allow these QIs to be adopted more easily. These 6 QIs were subjected to a feasibility test that found that even within the inpatient setting, there is a significant gap between the existing knowledge infrastructure and the necessary information-tracking processes to measure QIs. Only 1 QI (30-day hospital readmission) can currently be measured comparatively across Canada, although the other 5 of 6 short-list QIs can be measured using other data collected by jurisdictions. Standardization and enhancements to knowledge infrastructure are essential to provide the comprehensive patient data necessary to evaluate the quality of HF care across Canada.

Lowering body weight in obese mice with diastolic heart failure improves cardiac insulin sensitivity and function: implications for the obesity paradox.

Recent studies suggest improved outcomes and survival in obese heart failure patients (i.e., the obesity paradox), although obesity and heart failure unfavorably alter cardiac function and metabolism. We investigated the effects of weight loss on cardiac function and metabolism in obese heart failure mice. Obesity and heart failure were induced by feeding mice a high-fat (HF) diet (60% kcal from fat) for 4 weeks, following which an abdominal aortic constriction (AAC) was produced. Four weeks post-AAC, mice were switched to a low-fat (LF) diet (12% kcal from fat; HF AAC LF) or maintained on an HF (HF AAC HF) for a further 10 weeks. After 18 weeks, HF AAC LF mice weighed less than HF AAC HF mice. Diastolic function was improved in HF AAC LF mice, while cardiac hypertrophy was decreased and accompanied by decreased SIRT1 expression, increased FOXO1 acetylation, and increased atrogin-1 expression compared with HF AAC HF mice. Insulin-stimulated glucose oxidation was increased in hearts from HF AAC LF mice, compared with HF AAC HF mice. Thus lowering body weight by switching to LF diet in obese mice with heart failure is associated with decreased cardiac hypertrophy and improvements in both cardiac insulin sensitivity and diastolic function, suggesting that weight loss does not negatively impact heart function in the setting of obesity.

Obesity-induced lysine acetylation increases cardiac fatty acid oxidation and impairs insulin signalling.

AIMS: Lysine acetylation is a novel post-translational pathway that regulates the activities of enzymes involved in both fatty acid and glucose metabolism. We examined whether lysine acetylation controls heart glucose and fatty acid oxidation in high-fat diet (HFD) obese and SIRT3 knockout (KO) mice. METHODS AND RESULTS: C57BL/6 mice were placed on either a HFD (60% fat) or a low-fat diet (LFD; 4% fat) for 16 or 18 weeks. Cardiac fatty acid oxidation rates were significantly increased in HFD vs. LFD mice (845 ± 76 vs. 551 ± 87 nmol/g dry wt min, P < 0.05). Activities of the fatty acid oxidation enzymes, long-chain acyl-CoA dehydrogenase (LCAD), and ß-hydroxyacyl-CoA dehydrogenase (ß-HAD) were increased in hearts from HFD vs. LFD mice, and were associated with LCAD and ß-HAD hyperacetylation. Cardiac protein hyperacetylation in HFD-fed mice was associated with a decrease in SIRT3 expression, while expression of the mitochondrial acetylase, general control of amino acid synthesis 5 (GCN5)-like 1 (GCN5L1), did not change. Interestingly, SIRT3 deletion in mice also led to an increase in cardiac fatty acid oxidation compared with wild-type (WT) mice (422 ± 29 vs. 291 ± 17 nmol/g dry wt min, P < 0.05). Cardiac lysine acetylation was increased in SIRT3 KO mice compared with WT mice, including increased acetylation and activity of LCAD and ß-HAD. Although the HFD and SIRT3 deletion decreased glucose oxidation, pyruvate dehydrogenase acetylation was unaltered. However, the HFD did increase Akt acetylation, while decreasing its phosphorylation and activity. CONCLUSION: We conclude that increased cardiac fatty acid oxidation in response to high-fat feeding is controlled, in part, via the down-regulation of SIRT3 and concomitant increased acetylation of mitochondrial ß-oxidation enzymes.

Pan-Canadian cardiovascular data definitions and quality indicators: a status update.

After the 2009 publication of Building a Heart Healthy Canada, the Canadian Cardiovascular Society was commissioned to address a long-standing information gap related to the compatibility and comparability of data on the quality of cardiovascular care in Canada. Through collaboration between the Canadian Institute for Health Information, the Institute for Clinical Evaluative Sciences, the Public Health Agency of Canada, and 5 regional cardiovascular registries, 2 committees were tasked with developing standardized cardiovascular data definitions and quality indicators. The work culminated in national consensus on the definitions of 55 patient, disease, and therapeutic variables (core and optional) to facilitate cardiovascular care comparisons within and across Canada. Supplemental data definition chapters were then developed on acute coronary syndrome and coronary angiography/revascularization, with chapters on heart failure and atrial fibrillation electrophysiology to follow. This foundational work led to a critical appraisal of cardiac quality indicator development initiatives via the Appraisal of Guidelines for Research and Evaluation II (AGREE II) Quality Indicator tool, followed by the development of quality indicator catalogues on heart failure and atrial fibrillation. These indicators will be embedded within the clinical practice guidelines of the Canadian Cardiovascular Society, facilitating national comparisons across Canada on cardiovascular disease incidence, prevalence, patterns and quality of care, and clinical outcomes. This methodology-achieving national stakeholder consensus on a standardized process for the development and selection of cardiovascular quality indicators-illustrates the capacity to reach agreement by drawing on expertise and research across diverse organizational mandates and agendas, potentially contributing to improved cardiovascular care and outcomes for patients.

Heart failure clinics are associated with clinical benefit in both tertiary and community care settings: data from the Improving Cardiovascular Outcomes in Nova Scotia (ICONS) registry.

BACKGROUND: Heart failure (HF) clinics are known to improve outcomes of patients with HF. Studies have been limited to single, usually tertiary centres whose experience may not apply to the general HF population. OBJECTIVES: To determine the effectiveness of HF clinics in reducing death or all-cause rehospitalization in a real-world population. METHODS: A retrospective analysis of the Improving Cardiovascular Outcomes in Nova Scotia (ICONS) disease registry was performed. All 8731 patients with a diagnosis of HF (844 managed in HF clinics) who were discharged from the hospital between October 15, 1997, and July 1, 2000, were identified. Patients enrolled in any one of four HF clinics (two community-based and two academic-based) were compared with those who were not. The primary outcome was the one-year combined hospitalization and mortality. RESULTS: Patients followed in HF clinics were younger (68 versus 75 years), more likely to be men (63% versus 48%), and had a lower ejection fraction (35% versus 44%), lower systolic blood pressure (137 mmHg verus 146 mmHg) and lower serum creatinine (121 micromol/L versus 130 micromol/L). There was no difference in the prevalence of hypertension (56%), diabetes (35%) or stroke/transient ischemic attack (16%). The one-year mortality rate was 23%, while 31% of patients were rehospitalized; the combined end point was 51%. Enrollment in an HF clinic was independently associated with reduced risk of total mortality (hazard ratio [HR] 0.69 [95% CI 0.51 to 0.90], P=0.008; number needed to treat for one year to prevent the occurrence of one event [NNT]=16), all-cause hospital readmission (HR 0.27 [95% CI 0.21 to 0.36], P<0.0001; NNT=4), and combined mortality or hospital readmission (HR 0.73 [95% CI 0.60 to 0.89], P<0.0015; NNT=5). DISCUSSION: HF clinics are associated with reductions in rehospitalization and mortality in an unselected HF population, independent of whether they are academic- or community-based. Such clinics should be made widely available to the HF population.

The effect of spironolactone use on heart failure mortality: a population-based study.

BACKGROUND: Spironolactone use for heart failure (HF) has increased dramatically after the publication of the Randomized Aldactone Evaluation Study trial; yet, few studies have examined its real-world impact. We aimed to determine the population effect of spironolactone use on mortality in HF patients discharged from hospital. METHODS AND RESULTS: All patients discharged alive between October 1997 and December 2001 in Nova Scotia, Canada, with a primary diagnosis of HF were enrolled in the Improving Cardiovascular Outcomes Study. Two year, all-cause mortality was the primary end point. A total of 7816 patients were identified, of whom 644 (8%) were discharged home on spironolactone. After adjusting for differences in clinical covariates, spironolactone use did not emerge as an independent predictor of long-term survival (OR 0.97, P = .80). When only the subgroup of patients enrolled in a HF clinic were included (n = 990), spironolactone use was associated with reduced rates of all-cause mortality at 2 years (OR 0.52, P = .003). CONCLUSIONS: Although spironolactone use was not associated with improved long-term survival in the general HF population, it was associated with improved long-term survival in patients enrolled in HF clinics. These data highlight the challenges of knowledge translation from a clinical trial into practice.

Trends in event rate and case fatality of patients hospitalized with myocardial infarction between 1984 and 2001.

Between 1984 and 1993, prevalence and case fatality of hospitalized acute myocardial infarction (AMI) had declined in the population of Halifax County. We aimed to determine whether these trends continued into the 21st century by investigating patient characteristics, treatment methods, and fatality for hospital admissions of residents of Halifax County, aged 25-74, during 1984-1989 (period 1), 1990-1993 (period 2), and 1998-2001 (period 3) and diagnosed as AMI that were extracted from databases for the Halifax County MONICA and ICONS (Improving Cardiovascular Outcomes in Nova Scotia) Studies. Trends in patient characteristics and treatment methods were assessed by chi2 statistics. Their association with 28-day fatality was determined by logistic regression. Event rate declined during 1984-1993 but not into 1998-2001 (p = 0.206). Compared with 1990-1993, fewer AMI patients during 1998-2001 were > or = 55 years (73.3% vs. 69.9%), cigarette smokers (49.8% vs. 42.9%), had a history of myocardial infarction (28.9% vs. 24.9%), and had an admission heart rate >100 (34.8% vs. 17.4%). Additionally, more patients had a history of diabetes (22.5% vs. 28.1%). Case fatality declined progressively over the 3 study time periods (16.6%, 13.1%, and 9.4%, respectively). Changes also occurred in prevalence of Killip class 4 status during admission (20.2%, 10.3%, and 13.3%, respectively), use of thrombolysis (9.0%, 30.9, and 32.6%, respectively), and percutaneous coronary intervention (PCI) (4.3%, 11.2%, and 22.4%, respectively) in the different periods. Significant associations were found between case fatality and patient history of diabetes, history of MI, age, elevated admission heart rate, Killip class 4 impairment, thrombolysis, and PCI. The ICONS registry of hospitalized acute myocardial infarctions was used to compare case fatality during 1998-2001 with that reported by the Halifax County MONICA Project for 1984-1993. Whereas the population rate of myocardial infarctions had declined between 1984-1993 but not subsequently, case fatality declined significantly throughout the study period. The continued decline in case fatality is likely explained by changes in patient profile on presentation and medical therapies, including the increased use of thrombolysis and PCI.

Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management.

Heart failure remains a common diagnosis, especially in older individuals. It continues to be associated with significant morbidity and mortality, but major advances in both diagnosis and management have occurred and will continue to improve symptoms and other outcomes in patients. The Canadian Cardiovascular Society published its first consensus conference recommendations on the diagnosis and management of heart failure in 1994, followed by two brief updates, and reconvened this consensus conference to provide a comprehensive review of current knowledge and management strategies. New clinical trial evidence and meta-analyses were critically reviewed by a multidisciplinary primary panel who developed both recommendations and practical tips, which were reviewed by a secondary panel. The resulting document is intended to provide practical advice for specialists, family physicians, nurses, pharmacists and others who are involved in the care of heart failure patients. Management of heart failure begins with an accurate diagnosis, and requires rational combination drug therapy, individualization of care for each patient (based on their symptoms, clinical presentation and disease severity), appropriate mechanical interventions including revascularization and devices, collaborative efforts among health care professionals, and education and cooperation of the patient and their immediate caregivers. The goal is to translate best evidence-based therapies into clinical practice with a measureable impact on the health of heart failure patients in Canada.

Improved prediction of early-onset coronary artery disease using APOE epsilon4, BChE-K, PPARgamma2 Pro12 and ENOS T-786C in a polygenic model.

OBJECTIVES: Coronary artery disease (CAD) is often polygenic due to multiple mutations that contribute small effects to susceptibility. Since most prior studies only evaluated the contribution of single candidate genes, we therefore looked at a combination of genes in predicting early-onset CAD [apolipoprotein E (APOE) epsilon4, butyrylcholinesterase (BChE) K, peroxisome proliferator-activated receptor gamma2 (PPARgamma2) Pro12Ala and endothelial nitric oxide synthase (ENOS) T-786C]. DESIGN AND METHODS: We examined the frequencies, individually and in combination, of all four alleles among patients with early-onset CAD (n = 150; <50 years), late-onset CAD (n = 150; >65 years) and healthy controls (n = 150, age range 47-93 years). Differences in the proportion of subjects in each group with the given gene combination were assessed and likelihood ratios (LR) were calculated using logistic regression to combine the results of multiple genes. RESULTS: Early-onset CAD patients had increased, but non-significant, frequencies of PPARgamma2 Pro12/Pro12 (P = 0.39) and ENOS T-786C (P = 0.72), while BChE-K was only significantly higher in early-onset CAD patients compared to controls (P = 0.03). There were significantly more APOE epsilon4 alleles alone (P = 0.02) or in combination with BChE-K (P = 0.02) among early-onset CAD patients compared to late-onset CAD ones or controls. When combined, there was a higher prevalence of all four alleles in early-onset CAD (early-onset CAD patients: 10.7%, late-onset CAD patients: 3.3% and controls: 2.7%, P = 0.01). LR for early-onset CAD for a single allele was relatively small (1.08 for PPARgamma2 to 1.70 for APOE epsilon4). This increased to 2.78 (1.44-5.37) when combining all four alleles, therefore increasing the pre-test probability of CAD from 5% to a post-test probability of 12.7%. CONCLUSIONS: While any single mutation causes only a mildly increased LR (none > 1.7), in combination, the likelihood of early-onset CAD increased to 2.78 with four mutations. The genetics of early-onset CAD appear to be multifactorial, requiring polygenic models to elucidate risk.

Use of complementary and alternative medical therapies in patients with cardiovascular disease.

BACKGROUND: Complementary and alternative medical (CAM) therapies are becoming increasingly popular, yet little information is available about the prevalence and patterns of CAM therapy use by patients with cardiovascular disease (CVD). METHODS: Interviewers administered telephone questionnaires to 107 patients randomly selected from a stratified cohort of 2487 eligible patients participating in a registry of patients with CVD. RESULTS: The current use of CAM therapies was reported by 64% of the patients surveyed. Nutritional supplements (40%) and megadose vitamins (35%) were the most frequently used preparations. Most CAM therapy users (65%) cited their underlying cardiac condition as the reason for taking such therapy. The most common sources of information about CAM were a friend or relative (43%) or the respondent's usual physician. However, although 80% of respondents claimed that they had discussed their use of CAM therapies with their physician, 58% of respondents taking a potentially toxic cardiovascular medication (digoxin, warfarin, sotalol, or amiodarone) were simultaneously taking an oral supplement. CONCLUSION: The use of CAM therapies was high in the cohort of patients surveyed. Physicians caring for patients with CVD need to inquire about CAM therapy use. Further scientific study should be performed to evaluate the potential benefits and risks of CAM therapies in this patient population.

Physician specialty and quality of care for CHF: different patients or different patterns of practice?

BACKGROUND: Previous reports have suggested that internists employ evidence-based care for congestive heart failure (CHF) less frequently than cardiologists. Reasons for this possible difference are unclear. METHODS: A retrospective review of 185 consecutive patients admitted to a Canadian tertiary care facility between April 1998 and March 1999 with a primary diagnosis of CHF and who were treated by internists (IM group) or cardiologists (CARD group) was conducted. RESULTS: The CARD group (n=65) was younger (70 versus 76 years, P<0.001) and had larger left ventricular end-diastolic diameter by echocardiography (57 versus 51 mm, P=0.006) than the IM group (n=120). The CARD group documented ejection fraction in 90% of cases versus 54% in the IM group (P<0.05). There was no difference in angiotensin-converting enzyme (ACE) inhibitor usage (68% versus 63%, P=0.48) or optimal ACE dosage (CARD 50% versus IM 42%, P=0.44). Multivariate predictors of ACE inhibitor usage were serum creatinine, male sex, peripheral edema and increasing serum glucose. The CARD group had higher usage of beta-blockers (69% versus 49%, P<0.009), lipid lowering medication (35% versus 17%, P<0.004) and warfarin therapy for atrial fibrillation (74% versus 28%, P<0.005). CONCLUSION: The data suggest that Canadian cardiologists and internists use ACE inhibitors equally and care for a relatively similar group of CHF patients. However, beta-blockade, warfarin, lipid lowering therapy and documentation of critical data occurred more frequently under cardiologist care. The possibility that there may be a gradation of adoption of newer guidelines for CHF care according to physician specialty is raised.

Identifying opportunities to address the congestive heart failure burden: the Improving Cardiovascular Outcomes in Nova Scotia (ICONS) study.

BACKGROUND: Medical, social and economic costs of congestive heart failure (CHF) continue to rise. There exists a 'care gap' between what the optimal care populations with CHF should receive and actually do receive. Central to the goal to develop effective strategies against the 'care gap' is accurate measurement of the CHF burden. Administrative data are limited in detail and accuracy and clinical databases suffer from limited size. Improving Cardiovascular Outcomes in Nova Scotia (ICONS) is a province-wide population-based disease management study with access to all patient health data including outcomes. METHODS: Medical records of all patients admitted to any Nova Scotia health care institution with a cardiovascular disorder were prospectively examined by trained abstractors. Patients were followed up and health outcomes measured through assignment of unique identifier numbers and linkage with Vital Statistics Nova Scotia. This report summarizes baseline data for the population admitted to hospital with a diagnosis of CHF between October 15, 1997 and October 14, 1998. RESULTS: There were 2637 unique patients enrolled with 3547 hospitalizations. The median length of stay was eight days, with in-hospital mortality of 18.2%; 10.8% were discharged to long term care. The mortality rate was 38.7% at 12 months and the rehospitalization rate was 39.9%. Average age was 75 +/- 10 years (median 76) and 52% were female. There were 4.5 comorbidities per patient. Left ventricular ejection fraction (LVEF) was measured in fewer than 40%; of these, fewer than 39% had a documented ejection fraction less than 40%. At discharge, 61.3% of survivors were prescribed angiotensin-converting enzyme (ACE) inhibitors, 6.0% angiotensin blockers, 42.1% beta-blockers, 75.6% diuretics, 26.1% calcium channel blockers and 19.3% warfarin. Females were older and had lower rate of LVEF testing and ACE and warfarin usage. CONCLUSION: The burden of disease for CHF in Nova Scotia is large and affects an elderly population with multiple comorbidities. Adverse outcomes such as death, rehospitalization and admission to a chronic care facility are common. Measurement of the 'care gap' requires consideration of these factors and of elderly and female patients regardless of left ventricular function. Successful strategies will likely be multidisciplinary in scope with a focus toward improving access to care.

Undocumented patient information: an impediment to quality of care.

PURPOSE: Poor documentation in medical records might reduce the quality of care and undermine analyses based on retrospective chart reviews. We assessed the documentation of cardiac risk factors and cardiac history in the records of patients hospitalized with myocardial infarction or heart failure. METHODS: We performed a retrospective cohort study involving direct chart audit of all consecutive hospitalizations for myocardial infarction (n = 2,109) or heart failure (n = 3,392) in Nova Scotia, Canada, from October 15, 1997, to October 14, 1998. The main outcome measures were the documentation rates for prespecified clinical items, including cardiac risk factors and history of myocardial infarction or heart failure, which were recognized as indicators of the quality of care for the conditions under study. RESULTS: Information was not documented in a high proportion of cases, ranging from 9% (smoking) to 58% (previous history of heart failure) in charts from patients hospitalized for myocardial infarction, and from 19% (smoking) to 69% (hyperlipidemia) in charts from heart failure hospitalizations. Lack of documentation was more common in women and the elderly. CONCLUSION: Documentation of important clinical information is poor even in the hospital charts of patients with severe conditions. This quality-of-care issue has implications for health services and outcomes research, including the development of report cards.

Relation between butyrylcholinesterase K variant, paraoxonase 1 (PON1) Q and R and apolipoprotein E epsilon 4 genes in early-onset coronary artery disease.

OBJECTIVES: The common K variant of butyrylcholinesterase (BChE-K), an enzyme which metabolizes acetylcholine and organophosphates, has been associated with Alzheimer's disease, especially in the presence of the apolipoprotein E epsilon 4 allele (APOE-epsilon 4). Although APOE-epsilon 4 has been associated with the development of coronary artery disease (CAD), an association between the BChE-K variant and CAD has not been explored. Paraoxonase 1 (PON1), located within HDL, is an enzyme which also metabolizes organophosphates and may be antiatherogenic. The R192 variant of PON1 (PON1-R) has been associated with CAD. DESIGN AND METHODS: To determine whether BChE-K is also associated with premature CAD, we examined the frequency of BChE-K among patients with early-onset CAD (n = 150; < 50 yr) vs. late-onset CAD (n = 150; > 65 yr) by molecular analysis. We also examined the frequency of the PON1-R allele in both groups, and explored whether there was synergism between BChE-K and APOE-epsilon 4, BChE-K and PON1-R or PON1-R and APOE-epsilon 4. RESULTS: The frequency of the BChE-K allele tended to be greater among early-onset CAD patients compared to late-onset CAD patients (41.3% vs. 31.3%; p = 0.07), but without any significant difference between males and females. There was no difference in the prevalence of the PON1-R allele between those with early- or late-onset CAD (46.0% vs. 52.7%; p = 0.25). Twenty-two patients with early-onset CAD had both the BChE-K plus APOE-epsilon 4 alleles (14.7%) compared to 11 late-onset CAD patients (7.3%) (p = 0.04). There was no such association between BChE-K and PON1-R, nor PON1-R and APOE-epsilon 4. CONCLUSIONS: Our study suggests that there is a minor association between BChE-K and early-onset CAD, especially in the presence of the APOE-epsilon 4 allele.