High-Intensity Interval Training in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Small studies have suggested that high-intensity interval training (HIIT) is superior to moderate continuous training (MCT) in reversing cardiac remodeling and increasing aerobic capacity in patients with heart failure with reduced ejection fraction. The present multicenter trial compared 12 weeks of supervised interventions of HIIT, MCT, or a recommendation of regular exercise (RRE). METHODS: Two hundred sixty-one patients with left ventricular ejection fraction ≤35% and New York Heart Association class II to III were randomly assigned to HIIT at 90% to 95% of maximal heart rate, MCT at 60% to 70% of maximal heart rate, or RRE. Thereafter, patients were encouraged to continue exercising on their own. Clinical assessments were performed at baseline, after the intervention, and at follow-up after 52 weeks. Primary end point was a between-group comparison of change in left ventricular end-diastolic diameter from baseline to 12 weeks. RESULTS: Groups did not differ in age (median, 60 years), sex (19% women), ischemic pathogenesis (59%), or medication. Change in left ventricular end-diastolic diameter from baseline to 12 weeks was not different between HIIT and MCT (P=0.45); left ventricular end-diastolic diameter changes compared with RRE were -2.8 mm (-5.2 to -0.4 mm; P=0.02) in HIIT and -1.2 mm (-3.6 to 1.2 mm; P=0.34) in MCT. There was also no difference between HIIT and MCT in peak oxygen uptake (P=0.70), but both were superior to RRE. However, none of these changes was maintained at follow-up after 52 weeks. Serious adverse events were not statistically different during supervised intervention or at follow-up at 52 weeks (HIIT, 39%; MCT, 25%; RRE, 34%; P=0.16). Training records showed that 51% of patients exercised below prescribed target during supervised HIIT and 80% above target in MCT. CONCLUSIONS: HIIT was not superior to MCT in changing left ventricular remodeling or aerobic capacity, and its feasibility remains unresolved in patients with heart failure. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00917046.

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.

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.

Interval training does not modulate diastolic function in heart transplant recipients.

OBJECTIVES: This study investigates the effect of aerobic interval training on diastolic function at rest and during exercise in stable heart transplant (HTx) recipients. DESIGN: Twenty-three stable HTx recipients (74% males, mean age 50 ± 14.9 years) were recruited to a training programme. Intervention was 8 weeks intensive training or control in a randomized controlled design. RESULTS: At baseline, participants had normal or mild diastolic dysfunction at rest. During exercise, mean E/e' increased from 9.0 (± 2.8) to 12.8 (± 7.7) (p = 0.09), E/A increased from 2.1 (± 0.6) to 2.6 (± 0.7) (p = 0.02), and deceleration time decreased by over 50 ms, all markers of increased filling pressure. There were no correlations between diastolic function and VO 2 peak at baseline. After intervention VO 2 peak increased from 23.9 (± 4.5) to 28.3(± 6) ml/kg/min in the training group (difference between groups p = 0.0018). No consistent pattern of improvement in diastolic function at rest or during exercise was seen. CONCLUSION: The study does not support a role of diastolic dysfunction in the limited exercise capacity of HTx recipients and suggests that in these patients peripheral factors are of greater importance.

Coronary flow reserve predicts cardiopulmonary fitness in patients with coronary artery disease independently of systolic and diastolic function.

AIMS: Despite revascularization and optimal medical treatment, patients with coronary artery disease (CAD) have reduced exercise capacity. In the absence of coronary artery stenosis, coronary flow reserve (CFR) is a measure of coronary microvascular function, and a marker of future poor outcome in CAD patients. The aim of this study was to examine the relationship among CFR, systolic and diastolic function, peripheral vascular function, and cardiopulmonary fitness in CAD patients. METHODS AND RESULTS: Forty patients with median left ventricular ejection fraction (LVEF) 49 (interquartile 46-55) with documented CAD without significant left anterior descending artery (LAD) stenosis underwent cardiorespiratory exercise test with measurement of VO2 peak, digital measurement of endothelial function and arterial stiffness, and an echocardiography with measurement of LVEF using the biplane Simpson model, mitral early (E) and late (A) inflow velocities, and tissue Doppler diastolic (e') and systolic (s') velocities. Peak coronary flow velocity (CFV) was measured in the LAD using pulse-wave Doppler. CFR was calculated as the ratio between peak CFV at rest and during vasodilator stress. Median CFR was 2.22 (1.90-2.62) and VO2 peak was 21.8 (17.6-25.5). VO2 peak correlated significantly with CFR (r = 0.57, P < 0.001), E/e' (r = -0.35, P = 0.04), and s' (r = 0.41, P = 0.01) and with LVEF (r = 0.35, P = 0.03). CFR remained independently associated with VO2 peak after adjustment for systolic and diastolic function. CONCLUSIONS: Coronary flow reserve measured noninvasively predicts cardiopulmonary fitness independently of resting systolic and diastolic function in CAD patients, indicating that cardiac output during maximal exercise is dependent on the ability of the coronary circulation to adapt to the higher metabolic demands of the myocardium.

Transcription Factor Regulation of Gene Expression Network by ZNF385D and HAND2 in Carotid Atherosclerosis.

Carotid intima-media thickness (CIMT) is a surrogate indicator for atherosclerosis and has been shown to predict cardiovascular risk in multiple large studies. Identification of molecular markers for carotid atheroma plaque formation can be critical for early intervention and prevention of atherosclerosis. This study performed transcription factor (TF) network analysis of global gene expression data focusing on two TF genes, ZNF385D and HAND2, whose polymorphisms have been recently reported to show association with CIMT. Genome-wide gene expression data were measured from pieces of carotid endarterectomy collected from 34 hypertensive patients (atheroma plaque of stages IV and above according to the Stary classification) each paired with one sample of distant macroscopically intact tissue (stages I and II). Transcriptional regulation networks or the regulons were reconstructed for ZNF385D (5644 target genes) and HAND2 (781 target genes) using network inference. Their association with the progression of carotid atheroma was examined using gene-set enrichment analysis with extremely high statistical significance for regulons of both ZNF385D and HAND2 (p < 6.95 × 10-7) suggesting the involvement of expression quantitative loci (eQTL). Functional annotation of the regulon genes found heavy involvement in the immune system's response to inflammation and infection in the development of atherosclerosis. Detailed examination of the regulation and correlation patterns suggests that activities of the two TF genes could have high clinical and interventional impacts on impairing carotid atheroma plaque formation and preventing carotid atherosclerosis.

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.

Moderate continuous or high intensity interval exercise in heart failure with reduced ejection fraction: Differences between ischemic and non-ischemic etiology.

Background: Exercise for heart failure (HF) with reduced ejection fraction (HFrEF) is recommended by guidelines, but exercise mode and intensities are not differentiated between HF etiologies. We, therefore, investigated the effect of moderate or high intensity exercise on left ventricular end-diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF) and maximal exercise capacity (peak VO2) in patients with ischemic cardiomyopathy (ICM) and non-ischemic cardiomyopathy (NICM). Methods: The Study of Myocardial Recovery after Exercise Training in Heart Failure (SMARTEX-HF) consecutively enrolled 231 patients with HFrEF (LVEF ≤ 35 %, NYHA II-III) in a 12-weeks supervised exercise program. Patients were stratified for HFrEF etiology (ICM versus NICM) and randomly assigned (1:1:1) to supervised exercise thrice weekly: a) moderate continuous training (MCT) at 60-70 % of peak heart rate (HR), b) high intensity interval training (HIIIT) at 90-95 % peak HR, or c) recommendation of regular exercise (RRE) according to guidelines. LVEDD, LVEF and peak VO2 were assessed at baseline, after 12 and 52 weeks. Results: 215 patients completed the intervention. ICM (59 %; n = 126) compared to NICM patients (41 %; n = 89) had significantly lower peak VO2 values at baseline and after 12 weeks (difference in peak VO2 2.2 mL/(kg*min); p < 0.0005) without differences between time points (p = 0.11) or training groups (p = 0.15). Etiology did not influence changes of LVEDD or LVEF (p = 0.30; p = 0.12), even when adjusting for sex, age and smoking status (p = 0.54; p = 0.12). Similar findings were observed after 52 weeks. Conclusions: Etiology of HFrEF did not influence the effects of moderate or high intensity exercise on cardiac dimensions, systolic function or exercise capacity. Clinical Trial Registration­URL: http://www.clinicaltrials.gov. Unique identifier: NCT00917046.

Baseline and Exercise Predictors of V˙O2peak in Systolic Heart Failure Patients: Results from SMARTEX-HF.

PURPOSE: This study aimed to investigate baseline, exercise testing, and exercise training-mediated predictors of change in peak oxygen uptake (V˙O2peak) from baseline to 12-wk follow-up (ΔV˙O2peak) in a post hoc analysis from the SMARTEX Heart Failure trial. METHODS: We studied 215 patients with heart failure with left ventricular ejection fraction (LVEF) ≤35%, and New York Heart Association (NYHA) classes II-III who were randomized to either supervised high-intensity interval training with exercise target intensity of 90%-95% of peak heart rate (HRpeak) or supervised moderate continuous training (MCT) with target intensity of 60%-70% of HRpeak, or who received a recommendation of regular exercise on their own. Predictors of ΔV˙O2peak were assessed in two models: a logistic regression model comparing highest and lowest tertiles (baseline parameters) and a multivariate linear regression model (test/training/clinical parameters). RESULTS: The change in V˙O2peak in response to the interventions (ΔV˙O2peak) varied substantially, from -8.50 to +11.30 mL·kg·min. Baseline NYHA (class II gave higher odds vs III; odds ratio (OR), 7.1 (2.0-24.9); P = 0.002), LVEF (OR per percent, 1.1 (1.0-1.2); P = 0.005), and age (OR per 10 yr, 0.5 (0.3-0.8); P = 0.003) were associated with ΔV˙O2peak.In the multivariate linear regression, 34% of the variability in ΔV˙O2peak was explained by the increase in exercise training workload, ΔHRpeak between baseline and 12-wk posttesting, age, and ever having smoked. CONCLUSION: Exercise training response (ΔV˙O2peak) correlated negatively with age, LVEF, and NYHA class. The ability to increase workload during the training period and increased ΔHRpeak between baseline and the 12-wk test were associated with a positive outcome.

Cardiogenic Shock After Arterial Y-Graft Coronary Bypass Surgery Secondary to Critical Stenoses of the Left Subclavian and Left Main Coronary Arteries.

We present a case of a 62-year-old man who was in cardiogenic shock. He had a history of coronary artery bypass grafting 4 years previously, with left internal mammary radial artery Y-grafting to a left dominant coronary circulation. Critical stenoses of the left main coronary and left subclavian arteries were seen at angiography. An occluded abdominal aorta precluded the use of mechanical circulatory support. The patient underwent high-risk stenting of the left subclavian artery with a successful outcome. The case highlights the unresolved issue of screening for subclavian stenoses in patients being considered for revascularization with arterial Y-grafting.

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.

Coronary flow reserve as a link between diastolic and systolic function and exercise capacity in heart failure.

AIMS: In heart failure, a reduced exercise capacity is the prevailing symptom and an important prognostic marker of future outcome. The purpose of the study was to assess the relation of coronary flow reserve (CFR) to diastolic and systolic function in heart failure and to determine which are the limiting factors for exercise capacity. METHODS AND RESULTS: Forty-seven patients with left ventricular ejection fraction (LVEF) <35 [median LVEF 31 (inter-quartile range 26-34)] underwent cardiorespiratory exercise test with measurement of VO2 peak, a dual X-ray absorptiometry scan for body composition, and a full echocardiography with measurement of LVEF using the biplane Simpson model, mitral inflow velocities, and pulsed wave tissue Doppler. Peak coronary flow velocity (CFV) was measured in the LAD, using pulsed-wave Doppler. CFR was calculated as the ratio between peak CFV at rest and during 2 min of adenosine stress. Fat-free-mass-adjusted VO2 peak correlated significantly with CFR (r = 0.48, P = 0.002), E/e' (r = -0.35, P = 0.02), and s' (r = 0.45, P = 0.001) but not with LVEF (r = 0.23, P = 0.11). CFR correlated significantly with E/e' (r = -0.46, P = 0.003) and s' (r = 0.36, P = 0.02), but not with LVEF (r = 0.18, P = 0.26). When adjusting for CFR in a multivariable linear model, s' but not E/e' remained independently associated with VO2 peak. CONCLUSION: In this group of heart failure patients, VO2 peak was correlated with CFR, E/e', and s' but not with traditional measures of systolic function. CFR remained associated with VO2 peak independently of diastolic and systolic function and is likely to be a limiting factor in functional capacity of heart failure patients.