Comprehensive treatment of microvascular angina in overweight women - a randomized controlled pilot trial.

AIMS: Coronary microvascular dysfunction (CMD) carries a poor cardiovascular prognosis and may explain angina in women without obstructive coronary artery disease (CAD). Currently, no evidence-based treatment for CMD exists. We investigated whether reducing cardiovascular risk factors improves symptoms and microvascular function in women with non-endothelial dependent CMD and no obstructive CAD. METHODS: We randomized 62 women aged 40-75, with body mass index (BMI) >25 kg/m2, angina ≥monthly, and coronary flow velocity reserve (CFVR) ≤2.5 to a 24-week intervention comprising low energy diet, exercise training, and optimized treatment of hypertension, dyslipidemia and diabetes or to control. Patients were assessed before randomization and after 24 weeks. Primary outcomes were CFVR assessed by transthoracic Doppler stress-echocardiography and angina burden by Seattle Angina Questionnaire (SAQ). Secondary outcomes were exercise capacity, body composition, glycemic control, myocardial function, and anxiety and depression symptoms. RESULTS: Fifty-six participants (90%) completed the study. Median (IQR) age was 65.2 (57.1;70.7) years, BMI was 30.1 (28.4;32.7) kg/m2. The intervention resulted in relevant improvement in angina symptoms (9-21-point increase on SAQ-scales (all p<0.01)) but had no effect on CFVR (p = 0.468). Mean (CI) weight loss was 9.6 (7.80;11.48) kg, (p<0.0001). There was a significant mean (CI) decrease in depression symptoms = 1.16 (0.22;2.12), triglycerides = 0.52 (0.25;0.78) mmol/L, total cholesterol = 0.55 (0.12;0.98) mmol/L, and HbA1c in diabetics = 27.1 (1.60;52.6) mmol/mol but no effect on other secondary outcomes. CONCLUSION: A major weight loss and intensified risk factor control resulted in significantly improved angina burden but no improvement of coronary microvascular function among women with microvascular angina.

Effects of 1 year of exercise training versus combined exercise training and weight loss on body composition, low-grade inflammation and lipids in overweight patients with coronary artery disease: a randomized trial.

BACKGROUND: Dyslipidaemia and low-grade inflammation are central in atherogenesis and linked to overweight and physical inactivity. Lifestyle changes are important in secondary prevention of coronary artery disease (CAD). We compared the effects of combined weight loss and interval training with interval training alone on physical fitness, body composition, dyslipidaemia and low-grade inflammation in overweight, sedentary participants with CAD. METHODS: Seventy CAD patients, BMI 28-40 kg/m2 and age 45-75 years were randomised to (1) 12 weeks' aerobic interval training (AIT) at 90% of peak heart rate three times/week followed by 40 weeks' AIT twice weekly or (2) a low energy diet (LED) (800-1000 kcal/day) for 8-10 weeks followed by 40 weeks' weight maintenance including AIT twice weekly and a high-protein/low-glycaemic load diet. Effects of the intervention were evaluated by physical fitness, body weight and composition. Dyslipidaemia was described using both biochemical analysis of lipid concentrations and lipoprotein particle subclass distribution determined by density profiling. Low-grade inflammation was determined by C-reactive protein, soluble urokinase-type plasminogen activator receptor and tumour necrosis factor α. Effects on continuous outcomes were tested by mixed-models analysis. RESULTS: Twenty-six (74%) AIT and 29 (83%) LED + AIT participants completed the study. At baseline subject included 43 (78%) men; subjects averages were: age 63 years (6.2), body weight 95.9 kg (12.2) and VO2peak 20.7 mL O2/kg/min (4.9). Forty-six (84%) had pre-diabetes (i.e. impaired fasting glucose and/or impaired glucose tolerance). LED + AIT reduced body weight by 7.2 kg (- 8.4; - 6.1) and waist circumference by 6.6 cm (- 7.7; - 5.5) compared to 1.7 kg (- 0.7; - 2.6) and 3.3 cm (- 5.1; - 1.5) after AIT (within-group p < 0.001, between-group p < 0.001 and p = 0.018, respectively). Treatments caused similar changes in VO2peak and lowering of total cholesterol, triglycerides, non-HDL cholesterol and low-grade inflammation. A shift toward larger HDL particles was seen following LED + AIT while AIT elicited no change. CONCLUSIONS: Both interventions were feasible. Both groups obtained improvements in VO2peak, serum-lipids and inflammation with superior weight loss and greater central fat loss following LED + AIT. Combined LED induced weight loss and exercise can be recommended to CAD patients. Trial registration NCT01724567, November 12, 2012, retrospectively registered (enrolment ended in April 2013).

Liraglutide in combination with metformin may improve the atherogenic lipid profile and decrease C-reactive protein level in statin treated obese patients with coronary artery disease and newly diagnosed type 2 diabetes: A randomized trial.

BACKGROUND AND AIMS: Atherosclerosis in obesity and type 2 diabetes (T2DM) is associated with low-grade inflammation (LGI) and dyslipidemia, where especially small, dense lipoprotein particles are atherogenic. The glucagon-like peptide-1 receptor agonist, liraglutide, reduces cardiovascular events by poorly understood mechanisms. We investigated the effect of liraglutide combined with metformin on LGI and lipoprotein density profiles in patients with stable coronary artery disease (CAD) and newly diagnosed T2DM. METHODS: We conducted a randomized, double-blind, placebo-controlled, cross-over trial over a 12 + 12-week period, with ≥2-week wash-out. INTERVENTION: liraglutide/metformin vs. placebo/metformin. Lipoproteins were separated by continuous density gradient ultracentrifugation, and LDL divided into five subfractions between 226 and 270 Å, considering particle size ≤255 Šas the atherogenic pattern. Plasma C-reactive protein and tumor necrosis factor-α were assessed by the enzyme-linked immunosorbent-assay. RESULTS: 28 out of 41 randomized patients completed all visits. Intention-to-treat analysis was performed but one patient had statin dosage and was excluded from the analysis. 95% of the patients were on statin therapy. Overall, liraglutide did not affect lipid subfractions or markers of LGI compared to placebo. The combination of liraglutide and metformin reduced the total LDL subfractions, primarily by reducing the most atherogenic subfraction LDL5, and reduced CRP but not TNF-α. Explorative analyses suggested that the subfraction LDL5 during the wash-out period rebounded significantly at least in a per-protocol analysis of the sub-group of patients starting the liraglutide therapy. CONCLUSIONS: In patients with CAD and newly diagnosed T2DM on stable statin therapy, liraglutide combined with metformin may improve the atherogenic LDL lipid profile and CRP.

Liraglutide improves the beta-cell function without increasing insulin secretion during a mixed meal in patients, who exhibit well-controlled type 2 diabetes and coronary artery disease.

BACKGROUND: Hyperinsulinemia aggravates insulin resistance and cardio-vascular disease. How the insulinotropic glucagon-like peptide-1 receptor agonist liraglutide in a physiologic post-prandial setting may act on pancreatic alpha and beta-cell function in patients with coronary artery disease (CAD) and type 2 diabetes (T2DM) is less clear. METHODS: Insulin resistant patients with established CAD and newly diagnosed well-controlled T2DM were recruited to a placebo-controlled, cross-over trial with two treatment periods of 12 weeks and a 2 weeks wash-out period before and in-between. Treatment was liraglutide or placebo titrated from 0.6 mg q.d. to 1.8 mg q.d. within 4 weeks and metformin titrated from 500 mg b.i.d to 1000 mg b.i.d. within 4 weeks. Before and after intervention in both 12 weeks periods insulin, C-peptide, glucose, and glucagon were measured during a meal test. Beta-cell function derived from the oral glucose tolerance setting was calculated as changes in insulin secretion per unit changes in glucose concentration (Btotal) and whole-body insulin resistance using ISIcomposite. RESULTS: Liraglutide increased the disposition index [Btotal × ISIcomposite, by 40% (n = 24, p < 0.001)] compared to placebo. Post-prandial insulin and glucose was reduced by metformin in combination with liraglutide and differed, but not significantly different from placebo, moreover, glucagon concentration was unaffected. Additionally, insulin clearance tended to increase during liraglutide therapy (n = 26, p = 0.06). CONCLUSIONS: The insulinotropic drug liraglutide may without increasing the insulin concentration reduce postprandial glucose but not glucagon excursions and improve beta-cell function in newly diagnosed and well-controlled T2DM.Trial registration Clinicaltrials.gov ID: NCT01595789.

Coronary flow velocity reserve by echocardiography: feasibility, reproducibility and agreement with PET in overweight and obese patients with stable and revascularized coronary artery disease.

BACKGROUND: Coronary flow velocity reserve (CFVR) measured by transthoracic Doppler echocardiography of the LAD is used to assess microvascular function but validation studies in clinical settings are lacking. We aimed to assess feasibility, reproducibility and agreement with myocardial flow reserve (MFR) measured by PET in overweight and obese patients. METHODS: Participants with revascularized coronary artery disease were examined by CFVR. Subgroups were examined by repeated CFVR (reproducibility) or Rubidium-82-PET (agreement). To account for time variation, results were computed for scans performed within a week (1-week) and for all scans regardless of time gap (total) and to account for scar tissue for patients with and without previous myocardial infarction (MI). RESULTS: Eighty-six patients with median BMI 30.9 (IQR 29.4-32.9) kg × m(-2) and CFVR 2.29 (1.90-2.63) were included. CFVR was feasible in 83 (97 %) using a contrast agent in 14 %. For reproducibility overall (n = 21) limits of agreement (LOA) were (-0.75;0.71), within-subjects coefficient of variation (CV) 11 %, and reliability 0.84. For reproducibility within 1-week (n = 13) LOA were (-0.33;0.25), within-subjects CV 5 %, and reliability 0.97. Agreement with MFR of the LAD territory (n = 35) was without significant bias and overall LOA were (-1.40;1.46). Agreement was best for examinations performed within 1-week of participants without MI of the LAD-territory (n = 12); LOA = (-0.68;0.88). CONCLUSIONS: CFVR was highly feasible with a good reproducibility on par with other contemporary measures applied in cardiology. Agreement with MFR was acceptable, though discrepancy related to prior MI has to be considered. CFVR of LAD is a valid tool in overweight and obese patients.

Risk Factors for Myocardial Infarction in Women and Men: A Review of the Current Literature.

BACKGROUND: Cardiovascular disease has been the leading cause of death in both sexes in developed countries for decades. In general, men and women share the same cardiovascular risk factors. However, in recent trials including both men and women sexspecific analyses have raised awareness of sex differences in cardiovascular risk factors due to both biological and cultural differences. RESULTS: Women experience their first myocardial infarction (MI) 6-10 years later than men and a protective effect of their natural estrogen status prior to menopause has been suggested. Female sex hormones have been associated with a less atherogenic lipid profile and a more healthy fat distribution. These differences are attenuated following menopause. Regarding life style the prevalence of smoking is highest in men but female smokers have a relatively higher cardiovascular risk than male smokers. Men are more physically active than women while women have healthier dietary habits. Genetic factors also affect cardiovascular risk but no sex differences have been seen. Increased cardiovascular risk attributed to psychosocial distress is similar in men and women, but since women are more prone to psychosocial distress their burden of disease is greater. Compared with a healthy population the relative risk of MI in a diabetic population is higher in women than in men. No sex difference exists in the prevalence of hypertension but it has an earlier onset in men. CONCLUSION: Sex differences in cardiovascular risk are becoming more apparent and paying attention to this is pivotal when addressing risk factors in preventive efforts.

Weight loss is superior to exercise in improving the atherogenic lipid profile in a sedentary, overweight population with stable coronary artery disease: A randomized trial.

BACKGROUND: Dyslipidemia and low-grade inflammation are integral in the pathogenesis of atherosclerosis. We aim to compare the effects of a considerable weight loss and intensive exercise training on lipid atherogenicity and low-grade inflammation in a high-risk population with coronary artery disease (CAD). METHODS: Seventy non-diabetic participants with CAD, BMI 28-40 kg/m(2), age 45-75 years were randomized to 12 weeks' aerobic interval training (AIT) at 85-90% of peak heart rate three times/week or a low energy diet (LED, 800-1000 kcal/day) for 8-10 weeks followed by 2-4 weeks' weight maintenance diet. Lipid profile atherogenicity was described using lipoprotein particle size and density profiling. Low-grade inflammation was evaluated by tumor necrosis factor alpha (TNFα), C-reactive protein, interleukin 6 and soluble urokinase plasminogen activator receptor. RESULTS: Twenty-six (74%) AIT and 29 (83%) LED participants completed intervention per protocol. AIT and LED decreased total (AIT: -518 {-906;-129},P = 0.011, LED: -767 {-1128:-406},P < 0.001) and low-density lipoprotein (LDL, AIT: -186 {-306;-65},P = 0.004, LED: -277 {-433;-122},P < 0.001) assessed as the area under the density profile curve. LED was superior to AIT in decreasing atherogenicity reflected by increased LDL (between-group: 1.0 Å {0.4; 1.7},P = 0.003) and high-density lipoprotein (between-group: 1.2 Å {0.2; 2.4},P = 0.026) particle size and a decreased proportion of total lipoprotein constituted by the small, dense LDL5 subfraction (between-group: -5.0% {-8.4;-1.7},P = 0.004). LED decreased TNFα (9.5% {-15.8;-2.6},P = 0.009). No changes were seen following AIT. CONCLUSION: LED and AIT decreased total and LDL lipoprotein. LED was superior in decreasing atherogenicity assessed by a shift in density profile and increased particle size. Effect on low-grade inflammation was limited.

Coronary microvascular function, insulin sensitivity and body composition in predicting exercise capacity in overweight patients with coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) has a negative impact on exercise capacity. The aim of this study was to determine how coronary microvascular function, glucose metabolism and body composition contribute to exercise capacity in overweight patients with CAD and without diabetes. METHODS: Sixty-five non-diabetic, overweight patients with stable CAD, BMI 28-40 kg/m(2) and left ventricular ejection fraction (LVEF) above 35 % were recruited. A 3-hour oral glucose tolerance test was used to evaluate glucose metabolism. Peak aerobic exercise capacity (VO2peak) was assessed by a cardiopulmonary exercise test. Body composition was determined by whole body dual-energy X-ray absorptiometry scan and magnetic resonance imaging. Coronary flow reserve (CFR) assessed by transthoracic Doppler echocardiography was used as a measure of microvascular function. RESULTS: Median BMI was 31.3 and 72 % had impaired glucose tolerance or impaired fasting glucose. VO2peak adjusted for fat free mass was correlated with CFR (r = 0.41, p = 0.0007), LVEF (r = 0.33, p = 0.008) and left ventricular end-diastolic volume (EDV) (r = 0.32, p = 0.01) while it was only weakly linked to measures of glucose metabolism and body composition. CFR, EDV and LVEF remained independent predictors of VO2peak in multivariable regression analysis. CONCLUSION: The study established CFR, EDV and LVEF as independent predictors of VO2peak in overweight CAD patients with no or only mild functional symptoms and a LVEF > 35 %. Glucose metabolism and body composition had minor impact on VO2peak. The findings suggest that central hemodynamic factors are important in limiting exercise capacity in overweight non-diabetic CAD patients.

A randomized trial comparing the effect of weight loss and exercise training on insulin sensitivity and glucose metabolism in coronary artery disease.

AIM: The majority of patients with coronary artery disease (CAD) exhibit abnormal glucose metabolism, which is associated with mortality even at non-diabetic glucose levels. This trial aims to compare the effects of a considerable weight loss and exercise with limited weight loss on glucose metabolism in prediabetic, CAD patients. METHODS AND RESULTS: Seventy non-diabetic participants with CAD, BMI 28-40 kg/m(2), age 45-75 years were randomized to 12 weeks' aerobic interval training (AIT) at 90% peak heart rate three times weekly or a low energy diet (LED, 800-1,000 kcal/day) for 8-10 weeks followed by 2-4 weeks' weight maintenance diet. Glucose tolerance, insulin action, ß-cell function and suppression of lipolysis were assessed using a 3-h oral glucose tolerance test. ISI-composite and ISI-HOMA (=1/HOMA-IR) were calculated as surrogate measures of whole-body and hepatic insulin sensitivity, respectively. Magnetic resonance imaging estimated abdominal adipose tissue. Twenty-six (74%) AIT and 29 (83%) LED participants completed intervention per protocol. LED increased ISI-composite by 55% and ISI-HOMA by 70% (p<0.01) while AIT did not change insulin sensitivity (p>0.7) revealing a significant difference between the groups (p<0.05). No concurrent significant changes in lipolysis, ß-cell responsiveness or insulin clearance were seen. Changes in ISI-HOMA and ISI-composite were associated with reduced visceral abdominal fat, waist circumference and body weight. Intention-to-treat analyses (n=64) yielded similar results. CONCLUSION: LED is superior to AIT in improving insulin sensitivity in prediabetic CAD patients. Changes in insulin sensitivity are associated with decreased visceral abdominal fat, waist circumference and body weight.

A randomised trial comparing the effect of exercise training and weight loss on microvascular function in coronary artery disease.

BACKGROUND: Coronary microvascular function is associated with outcome and is reduced in coronary artery disease (CAD) and obesity. We compared the effect of aerobic interval training (AIT) and weight loss on coronary flow reserve (CFR) and peripheral vascular function in revascularised obese CAD patients. METHODS AND RESULTS: Seventy non-diabetic patients (BMI 28-40 kg × m(-2), age 45-75 years) were randomised to 12 weeks' AIT (three weekly sessions lasting 38 min with ≈ 16 min at 85-90% of VO2peak) or low energy diet (LED, 800-1000 kcal/day). Per protocol adherence was defined by training-attendance ≥ 60% and weight loss ≥ 5%, respectively. CFR was assessed by Doppler echocardiography of the LAD. Peripheral vascular function was assessed by arterial tonometry as reactive hyperaemia index (RHI) and augmentation index. Most participants had impaired CFR with a mean CFR of 2.38 (SD 0.59). Twenty-six AIT and 24 LED participants completed the study per protocol with valid CFR measurements. AIT resulted in a 10.4% improvement in VO2peak and LED in a 10.6% weight loss (between group differences both P<0.001). CFR increased by 0.26 (95%CI 0.04;0.48) after AIT and by 0.39 (95%CI 0.13;0.65) after LED without significant between-group difference (-0.13 (95%CI -0.45;0.20)). RHI and augmentation index remained unchanged after both interventions (P>0.50). Intention-to-treat analyses showed similar results. CONCLUSIONS: 12 weeks' AIT and LED increased CFR by comparable magnitude; thus both interventions might impact prognosis of CAD through improvement of coronary microvascular function. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01724567.

Copenhagen study of overweight patients with coronary artery disease undergoing low energy diet or interval training: the randomized CUT-IT trial protocol.

BACKGROUND: Coronary artery disease (CAD) is accountable for more than 7 million deaths each year according to the World Health Organization (WHO). In a European population 80% of patients diagnosed with CAD are overweight and 31% are obese. Physical inactivity and overweight are major risk factors in CAD, thus central strategies in secondary prevention are increased physical activity and weight loss. METHODS/DESIGN: In a randomized controlled trial 70 participants with stable CAD, age 45-75, body mass index 28-40 kg/m2 and no diabetes are randomized (1:1) to 12 weeks of intensive exercise or weight loss both succeeded by a 40-week follow-up. The exercise protocol consist of supervised aerobic interval training (AIT) at 85-90% of VO2peak 3 times weekly for 12 weeks followed by supervised AIT twice weekly for 40 weeks. In the weight loss arm dieticians instruct the participants in a low energy diet (800-1000 kcal/day) for 12 weeks, followed by 40 weeks of weight maintenance combined with supervised AIT twice weekly. The primary endpoint of the study is change in coronary flow reserve after the first 12 weeks' intervention. Secondary endpoints include cardiovascular, metabolic, inflammatory and anthropometric measures. DISCUSSION: The study will compare the short and long-term effects of a protocol consisting of AIT alone or a rapid weight loss followed by AIT. Additionally, it will provide new insight in mechanisms behind the benefits of exercise and weight loss. We wish to contribute to the creation of effective secondary prevention and sustainable rehabilitation strategies in the large population of overweight and obese patients diagnosed with CAD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01724567.

Insulin resistance and exercise tolerance in heart failure patients: linkage to coronary flow reserve and peripheral vascular function.

BACKGROUND: Insulin resistance has been linked to exercise intolerance in heart failure patients. The aim of this study was to assess the potential role of coronary flow reserve (CFR), endothelial function and arterial stiffness in explaining this linkage. METHODS: 39 patients with LVEF < 35% (median LV ejection fraction (LVEF) 31 (interquartile range (IQ) 26-34), 23/39 of ischemic origin) underwent echocardiography with measurement of CFR. Peak coronary flow velocity (CFV) was measured in the LAD and coronary flow reserve was calculated as the ratio between CFV at rest and during a 2 minutes adenosine infusion. All patients performed a maximal symptom limited exercise test with measurement of peak oxygen uptake (VO(2)peak), digital measurement of endothelial function and arterial stiffness (augmentation index), dual X-ray absorptiometry scan (DEXA) for body composition and insulin sensitivity by a 2 hr hyperinsulinemic (40 mU/min/m(2)) isoglycemic clamp. RESULTS: Fat free mass adjusted insulin sensitivity was significantly correlated to VO(2)peak (r = 0.43, p = 0.007). Median CFR was 1.77 (IQ 1.26-2.42) and was correlated to insulin sensitivity (r 0.43, p = 0.008). CFR (r = 0.48, p = 0.002), and arterial stiffness (r = -0.35, p = 0.04) were correlated to VO(2)peak whereas endothelial function and LVEF were not (all p > 0.15). In multivariable linear regression adjusting for age, CFR remained independently associated with VO2peak (standardized coefficient (SC) 1.98, p = 0.05) whereas insulin sensitivity (SC 1.75, p = 0.09) and arterial stiffness (SC -1.17, p = 0.29) were no longer associated with VO2peak. CONCLUSIONS: The study confirms that insulin resistance is associated with exercise intolerance in heart failure patients and suggests that this is partly through reduced CFR. This is the first study to our knowledge that shows an association between CFR and exercise capacity in heart failure patients and links the relationship between insulin resistance and exercise capacity to CFR.