David J. Holland

Effect of If-channel inhibition on hemodynamic status and exercise tolerance in heart failure with preserved ejection fraction: a randomized trial.

OBJECTIVES The aim of this study was to test the effects of treatment with ivabradine on exercise capacity and left ventricular filling in patients with heart failure with preserved ejection fraction (HFpEF). BACKGROUND Because symptoms of HFpEF are typically exertional, optimization of diastolic filling time by controlling heart rate may delay the onset of symptoms. METHODS Sixty-one patients with HFpEF were randomly assigned to ivabradine 5 mg twice daily (n = 30) or placebo (n = 31) for 7 days in this double-blind trial. Cardiopulmonary exercise testing with echocardiographic assessment of myocardial function and left ventricular filling were undertaken at rest and after exercise. RESULTS The ivabradine group demonstrated significant improvement between baseline and follow-up exercise capacity (4.2 ± 1.8 METs vs. 5.7 ± 1.9 METs, p = 0.001) and peak oxygen uptake (14.0 ± 6.1 ml/min/kg vs. 17.0 ± 3.3 ml/min/kg, p = 0.001), with simultaneous reduction in exercise-induced increase in the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity (3.1 ± 2.7 vs. 1.3 ± 2.0, p = 0.004). Work load-corrected chronotropic response (the difference in heart rate at the same exercise time at the baseline and follow-up tests) showed a slower increase in heart rate during exercise than in the placebo-treated group. Therapy with ivabradine (β = 0.34, p = 0.04) and change with treatment in exertional increase in the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity (β = -0.30, p = 0.02) were independent correlates of increase in exercise capacity, and therapy with ivabradine (β = 0.32, p = 0.007) was independently correlated with increase in peak oxygen uptake. CONCLUSIONS In patients with HFpEF, short-term treatment with ivabradine increased exercise capacity, with a contribution from improved left ventricular filling pressure response to exercise as reflected by the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity. Because this patient population is symptomatic on exertion, therapeutic treatments targeting abnormal exercise hemodynamic status may prove useful. (Use of Exercise and Medical Therapies to Improve Cardiac Function Among Patients With Exertional Shortness of Breath Due to Lung Congestion; ACTRN12610001087044).

Effects of treatment on exercise tolerance, cardiac function, and mortality in heart failure with preserved ejection fraction: A meta-analysis

OBJECTIVES We sought to determine whether pharmacologic interventions changed exercise capacity, diastolic function, and mortality in a meta-analysis of trials in heart failure with preserved ejection fraction. BACKGROUND Treatment strategies for heart failure with preserved ejection fraction remain unproven despite several large-scale trials. METHODS Trials were included in the systematic review where clear comparisons between trial drug and diuretic or placebo were available. Exercise tolerance was assessed by treadmill time, and changes in diastolic function were quantified by transmitral flow (E/A ratio). The primary outcome was all-cause mortality. Weighted mean differences (MDs) and relative risks (RRs), along with their corresponding 95% confidence intervals (CIs), were computed using random-effects models for continuous and dichotomous variables, respectively. The impact of potential covariates was assessed by meta-regression. RESULTS Data from 53,878 patients enrolled in 30 published reports were collated, including 18 randomized controlled trials (n = 11,253) and 12 observational studies (n = 42,625). In the randomized controlled trials, exercise tolerance was improved by combined therapy (n = 183; weighted MD = 51.5; 95% CI: 27.3 to 75.7; p < 0.001), whereas E/A ratio was not (n = 472; weighted MD = -0.01, 95% CI: -0.02 to 0.02; p = 0.54) even after accounting for baseline E/A (p = 0.87). Over a mean follow-up of 18.6 months, all-cause mortality was not improved by therapy in randomized controlled trials (RR: 0.99, 95% CI: 0.92 to 1.06; p = 0.70), despite accounting for baseline ejection fraction (p = 0.72). In observational reports, there was a reduction in all-cause mortality with therapy in the unadjusted analyses (RR: 0.80, 95% CI: 0.66 to 0.97; p = 0.27), but not after adjustment for clinical and demographic data (RR: 0.93, 95% CI: 0.84 to 1.02; p = 0.10). CONCLUSIONS Pharmacotherapy of heart failure with preserved ejection fraction demonstrates a quantifiable improvement in exercise tolerance but not mortality.

Pulse Wave Analysis Is a Reproducible Technique for Measuring Central Blood Pressure During Hemodynamic Perturbations Induced by Exercise

BACKGROUND Central blood pressure (BP) and markers of wave reflection (augmentation index; AIx) measured by radial tonometry have prognostic value independent from brachial BP. The measurement of the central waveform is increasingly used during altered hemodynamics, including exercise, but reliability of the test has not been reported under changed loading conditions. This study aimed to test the techniques reproducibility during major hemodynamic perturbations induced by exercise. METHODS Radial waveforms were recorded (SphygmoCor) in 28 healthy subjects (aged 53 +/- 11 years) at rest, during submaximal exercise (cycling at 50, 60, and 70% of maximal age-predicted heart rate (HR)) and immediately after maximal treadmill exercise on two occasions separated by 9 +/- 5 days. Data were compared between testing days. Waveforms were calibrated with brachial BP measured using a mercury sphygmomanometer. Pulse pressure amplification (PPAmp) was defined as the ratio of brachial to central pulse pressure. RESULTS There was very good reproducibility between visits at all exercise intensities for all waveform measures, including AIx, central pulse pressure, and PPAmp (intraclass correlations at 50% exercise were 0.93, 0.89, and 0.89, respectively; P < 0.001). The mean difference between tests at this intensity was 0 +/- 4% for AIx, 4 +/- 6 mm Hg for central pulse pressure, and -0.02 +/- 0.09 for PPAmp. There were no significant differences between visits for HR, PPAmp, or AIx at rest or with exercise (P > 0.05 for all). CONCLUSIONS Radial tonometry is a reproducible technique for measurement of central waveform indices during perturbations induced by exercise. It should, therefore, be suitable for use in intervention studies in which hemodynamics are altered.

Prognostic Implications of Left Ventricular Filling Pressure With Exercise

Background—The estimation of left ventricular (LV) filling pressure from the ratio of transmitral and annular velocities (E/e′) after exercise echocardiography may identify diastolic dysfunction in patients who complain of exertional dyspnea. This study sought to determine the relative contributions of exercise E/e′ and ischemia to outcomes in patients referred for exercise echocardiography. Methods and Results—Rest and exercise E/e′ were obtained in 522 patients referred for exercise echocardiography, who were followed for cardiovascular death and hospitalization over a median of 13.2 months. Exercise E/e′ >2 SD from normal was used to denote raised LV filling pressure with stress (n=75), and ischemia (n=250) was identified by inducible wall motion abnormalities. There were 65 cardiovascular hospitalizations during the follow-up period. Survival analysis showed patients without ischemia and with normal exercise E/e′ to have a better prognosis than those with ischemia, with or without raised exercise E/e′ (P=0.003) and the outcomes of patients with isolated raised exercise E/e′ and isolated ischemia to be similar. Exercise E/e′ was most valuable in patients with normal resting E/e′; those with elevation with exercise had a worse outcome than those with normal exercise E/e′ (P=0.014). Exercise capacity (hazard ratio, 0.893; P=0.008), exercise wall motion score index (hazard ratio, 1.507; P<0.001), and exercise E/e′ >14.5 (hazard ratio, 2.988; P=0.002) were independent predictors of outcome. The addition of exercise E/e′ to exercise capacity and wall motion score index resulted in an increment in model power to predict adverse outcome (P=0.006). Conclusions—Exercise E/e′ is associated with cardiovascular hospitalization, independent of and incremental to inducible ischemia.

Severe hypoxemia due to shunting through a patent foramen ovale: A correctable complication of right ventricular infarction

A patient with recent inferior myocardial infarction with right ventricular involvement developed severe hypoxemia unresponsive to 100% oxygen. Contrast two-dimensional echocardiography revealed right to left shunting through an aneurysmal fossa ovalis with a patent foramen ovale. This was confirmed by cardiac catheterization. Surgical closure of the defect was probably life-saving. This case report illustrates that right to left shunting through a foramen ovale should be considered in the differential diagnosis of hypoxemia in patients presenting with inferior myocardial infarction.

Contribution of exercise echocardiography to the diagnosis of heart failure with preserved ejection fraction (HFpEF)

Objectives To examine the contribution of exercise echocardiography (ExE) to the diagnosis of heart failure with preserved ejection fraction (HFpEF). Design Cross-sectional study of patients undergoing ExE. Patients 436 patients with fatigue or dyspnoea presenting for ExE were studied. Methods Current criteria for the diagnosis of HFpEF (evidence of symptoms or signs of heart failure, EF>50%, abnormal transmitral flow and supplementary tissue Doppler measurements (E/e′) suggesting raised left ventricular filling pressure) were applied to this population. The impact of reclassification of clinical status based on exercise E/e′ >13 and ischaemia was evaluated. Results Of 436 patients, 37 had E/e′ >15 and 111 had E/e′ 8–15, with supplementary echocardiography criteria indicating HFpEF (n=148). Only 36 patients fulfilling the diagnosis of HFpEF had reduced exercise capacity. Fifteen of these patients had evidence of raised E/e′ with exercise, half (7) of whom had inducible myocardial ischaemia. Of 13 patients with raised filling pressure at rest or exercise, objective exercise intolerance and no ischaemia, five did not reach the current criteria for HFpEF. Conclusion The current classification for HFpEF may include patients with preserved functional status and many with ischaemia and normal exercise E/e′. Reduced exercise capacity, increase of E/e′ with exercise and ischaemia are three objective aspects of the HFpEF syndrome that might be considered for incorporation in the definition.

Subclinical LV dysfunction and 10-year outcomes in type 2 diabetes mellitus

Objective New imaging techniques have permitted the detection of subclinical LV dysfunction (LVD) in up to half of patients with type 2 diabetes mellitus (DM) with a normal EF. However, the connection between early LVD and prognosis is unclear. This study aimed to define the long-term outcome of LVD associated with type 2 DM. Methods In this prospective cohort study, 230 asymptomatic patients with type 2 DM underwent measurement of global longitudinal 2D strain (GLS) for detection of LVD and were followed for up to 10 years. All subjects had normal EF (≥50%) and no evidence of coronary artery disease at recruitment. Outcome data were obtained through centralised state-wide death and hospital admission registries. The primary endpoint was all-cause mortality and hospitalisation. Results On study entry, almost half (45%) of the cohort had evidence of LVD as detected by GLS. Over a median follow-up of 7.4±2.6 years (range 0.6–9.7 years), 68 patients (30%) met the primary endpoint (LVD: 37%; normal LV function: 24%). GLS was independently associated with the primary endpoint (HR=1.10; p=0.04), as was systolic blood pressure (HR=1.02; p<0.001) and levels of glycosylated haemoglobin (HR=1.28; p=0.011). Patients with LVD had significantly worse outcome than those without (χ2=4.73; p=0.030). Conclusions Subclinical LVD is common in asymptomatic patients with type 2 DM, is readily detectable by GLS imaging and is independently associated with adverse outcome. Trial registration number Australian and New Zealand Clinical Trials Registry (ACTRN12612001178831).

Exercise & Sports Science Australia Position Statement on exercise training and chronic heart failure

Chronic heart failure (CHF) is a complex syndrome characterised by progressive decline in left ventricular function, low exercise tolerance and raised mortality and morbidity. Regular exercise participation has been shown to be a safe and effective treatment modality in the majority of CHF patients, partially reversing some of the maladaptations evident in myocardial and skeletal muscle function, and resulting in improvements in physical fitness and quality of life, and perhaps reduced mortality. The volume and intensity of exercise that is recommended depends on the syndrome severity, however in most patients it should consist of a combination of low-to-moderate intensity aerobic (endurance) exercise on most days of the week and individually prescribed low-to-moderate intensity resistance (strength) training at least twice per week. Additionally, all patients should be closely monitored prior to and during exercise for contraindications by an appropriately trained health professional. The purpose of this statement is to inform and guide exercise practitioners and health professionals in the safe and effective prescription and supervision of exercise for patients with CHF.

Influence of Altered Blood Rheology on Ventricular-Vascular Response to Exercise

Blood (or plasma) rheology is related to cardiovascular risk. Mechanisms of this association are unclear but may be partially related to impaired left ventricular (LV) function and increased central blood pressure (BP) during light activity. This study aimed to test these hypotheses. Twenty patients (14 men; aged 61±12 years) with polycythemia rubra vera (n=16) or hemochromatosis (n=4) were studied at rest and during exercise at ≈50% of maximal heart rate before and after venesection (500 mL; volume replaced with saline) to elicit an acute decrease in plasma viscosity at stable BP. Controls (n=20) underwent the same protocol with 25-mL venesection. Central BP and augmentation index were determined by tonometry. Resting LV systolic (peak longitudinal systolic strain rate and strain) and diastolic functions were determined by tissue-Doppler echocardiography. Venesection with blood volume replacement decreased viscosity (1.46±0.10 to 1.41±0.11 centipoise), protein, and hemoglobin (P<0.05 for all) and increased strain rate and strain (P<0.001 for both) in patients but not in controls (P>0.10 for all). There was no change in LV diastolic function (P>0.12 for all). Exercise augmentation index in patients was reduced after venesection (24±12% to 17±9%; P=0.001) despite no significant change in other BP variables. Hemodynamics (resting or exercise) were not significantly changed in controls. Exercise central systolic BP correlated with triglycerides (r=0.59; P<0.001). However, neither exercise hemodynamic changes nor LV functional changes correlated with any biochemical changes after venesection (P>0.05). We conclude that an acute change in blood rheology improves ventricular-vascular interaction by enhanced LV systolic function and reduced light-exercise central BP.

Bucindolol: A pharmacogenomic perspective on Its Use in chronic Heart Failure

Bucindolol is a non-selective β-adrenergic receptor blocker with α-1 blocker properties and mild intrinsic sympatholytic activity. The Beta-Blocker Evaluation of Survival Trial (BEST), which is the largest clinical trial of bucindolol in patients with heart failure, was terminated prematurely and failed to show an overall mortality benefit. However, benefits on cardiac mortality and re-hospitalization rates were observed in the BEST trial. Bucindolol has not shown benefits in African Americans, those with significantly low ejection fraction and those in NYHA class IV heart failure. These observations could be due to the exaggerated sympatholytic response to bucindolol in these sub-groups that may be mediated by genetic polymorphisms or changes in gene regulation due to advanced heart failure. This paper provides a timely clinical update on the use of bucindolol in chronic heart failure.