Guido Claessen

Cardiac MRI A New Gold Standard for Ventricular Volume Quantification During High-Intensity Exercise

Background— Accurate measures are critical when attempting to distinguish normal from pathological changes in cardiac function during exercise, yet imaging modalities have seldom been assessed against invasive exercise standards. We sought to validate a novel method of biventricular volume quantification by cardiac MRI (CMR) during maximal exercise. Methods and Results— CMR was performed on 34 subjects during exercise and free-breathing with the use of an ungated real-time (RT-ungated) CMR sequence. ECG and respiratory movements were retrospectively synchronized, enabling compensation for cardiac cycle and respiratory phase. Feasibility of RT-ungated imaging was compared with standard exercise CMR imaging with ECG gating (gated); accuracy of RT-ungated CMR was assessed against an invasive standard (direct Fick); and reproducibility was determined after a second bout of maximal exercise. Ventricular volumes were analyzed more frequently during high-intensity exercise with RT-ungated compared with gated CMR (100% versus 47%; P<0.0001) and with better interobserver variability for RT-ungated (coefficient of variation=1.9% and 2.0% for left and right ventricular stroke volumes, respectively) than gated (coefficient of variation=15.2% and 13.6%; P<0.01). Cardiac output determined by RT-ungated CMR proved accurate against the direct Fick method with excellent agreement (intraclass correlation coefficient, R=0.96), which was highly reproducible during a second bout of maximal exercise (R=0.98). Conclusions— When RT-ungated CMR is combined with post hoc analysis incorporating compensation for respiratory motion, highly reproducible and accurate biventricular volumes can be measured during maximal exercise.Background— Accurate measures are critical when attempting to distinguish normal from pathological changes in cardiac function during exercise, yet imaging modalities have seldom been assessed against invasive exercise standards. We sought to validate a novel method of biventricular volume quantification by cardiac MRI (CMR) during maximal exercise. Methods and Results— CMR was performed on 34 subjects during exercise and free-breathing with the use of an ungated real-time (RT-ungated) CMR sequence. ECG and respiratory movements were retrospectively synchronized, enabling compensation for cardiac cycle and respiratory phase. Feasibility of RT-ungated imaging was compared with standard exercise CMR imaging with ECG gating (gated); accuracy of RT-ungated CMR was assessed against an invasive standard (direct Fick); and reproducibility was determined after a second bout of maximal exercise. Ventricular volumes were analyzed more frequently during high-intensity exercise with RT-ungated compared with gated CMR (100% versus 47%; P <0.0001) and with better interobserver variability for RT-ungated (coefficient of variation=1.9% and 2.0% for left and right ventricular stroke volumes, respectively) than gated (coefficient of variation=15.2% and 13.6%; P <0.01). Cardiac output determined by RT-ungated CMR proved accurate against the direct Fick method with excellent agreement (intraclass correlation coefficient, R =0.96), which was highly reproducible during a second bout of maximal exercise ( R =0.98). Conclusions— When RT-ungated CMR is combined with post hoc analysis incorporating compensation for respiratory motion, highly reproducible and accurate biventricular volumes can be measured during maximal exercise.

Sildenafil improves exercise hemodynamics in Fontan patients.

Background—Patients with Fontan circulation have reduced exercise capacity. The absence of a presystemic pump may limit flow through the pulmonary circulation, restricting ventricular filling and cardiac output. We evaluated exercise hemodynamics and the effect of sildenafil on exercise hemodynamics in Fontan patients. Methods and Results—Ten Fontan patients (6 men, 20±4 years) underwent cardiac magnetic resonance imaging at rest and during supine bicycle exercise before and after sildenafil. Systemic ventricular volumes were obtained at rest and during low- (34±15 W), moderate- (69±29 W), and high-intensity (97±36 W) exercise using an ungated, free-breathing cardiac magnetic resonance sequence and analyzed correcting for cardiac phase and respiratory translation. Radial and pulmonary artery pressures and cGMP were measured. Before sildenafil, cardiac index increased throughout exercise (4.0±0.9, 5.9±1.1, 7.0±1.6, 7.4±1.7 L/(min·m2); P<0.0001) with 106±49% increase in heart rate. Stroke volume index (P=0.015) and end-diastolic volume index (P=0.001) decreased during exercise. End-systolic volume index remained unchanged (P=0.8). Total pulmonary resistance index (P=0.005) increased, whereas systemic vascular resistance index decreased during exercise (P<0.0001). Sildenafil increased cardiac index (P<0.0001) and stroke volume index (P=0.003), especially at high-intensity exercise (interaction P=0.004 and P=0.003, respectively). Systemic vascular resistance index was reduced (P<0.0001–interaction P=0.1), whereas total pulmonary resistance index was reduced at rest and reduced further during exercise (P=0.008–interaction P=0.029). cGMP remained unchanged before sildenafil (P=0.9), whereas it increased significantly after sildenafil (P=0.019). Conclusions—In Fontan patients, sildenafil improved cardiac index during exercise with a decrease in total pulmonary resistance index and an increase in stroke volume index. This implies that pulmonary vasculature represents a physiological limitation, which can be attenuated by sildenafil, the clinical significance of which warrants further study.

Right Ventricular Fatigue Developing during Endurance Exercise: An Exercise Cardiac Magnetic Resonance Study.

INTRODUCTION Prolonged intense exercise has often been associated with the impairment of right ventricular (RV) function after activity, whereas this is rare for the left ventricle (LV). The effect of prolonged exercise on the heart has not been adequately measured during exercise itself. METHODS We performed real-time cardiac magnetic resonance imaging at rest and during incremental exercise in 14 male endurance athletes (mean ± SD; age = 36 ± 6 yr, BMI = 23.1 ± 1.94 kg·m) 1-3 wk before (baseline) and immediately after a 150-km cycling event (end-of-race) to measure LV and RV end-diastolic and end-systolic volumes (EDV and ESV), ejection fraction (EF), and ventricular-arterial coupling (stroke volume [SV]/ESV). RESULTS End-of-race RV EDV was unchanged from baseline at rest but was significantly increased during near-maximal exercise (235 ± 18 vs 217 ± 24 mL, P < 0.0001). Resting RV ESV was higher end-of-race (100 ± 16 vs 93 ± 15 mL, P = 0.009), which became more appreciable during near-maximal exercise (75 ± 15 vs 60 ± 14 mL, P < 0.0001). RV EF, although unchanged at rest, was significantly decreased during near-maximal exercise (68% ± 5% vs 73% ± 4%, P = 0.001). LV volume measures were similar at baseline and end-of-race. Therefore, the effect of endurance activity on the RV and LV was significantly different (P < 0.0001). Cardiac output increased to similar values at near-maximal exertion before and at the end of the race. However, whereas LV SV/ESV was unchanged, RV SV/ESV was attenuated end-of-race (P = 0.02 for interaction with race setting). CONCLUSIONS Intense endurance exercise does not affect LV volume or function but results in RV dilatation and reduced RV EF, which becomes even more significant during exercise. Alterations in RV ventricular-arterial coupling suggest that this may be an expression of exercise-induced RV contractile impairment rather than changes in autonomic or loading conditions.

Pulmonary Vascular and Right Ventricular Reserve in Patients With Normalized Resting Hemodynamics After Pulmonary Endarterectomy

Background Patients with normalized mean pulmonary artery pressure (mPAP) after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) do not always regain normal exercise capacity. We evaluated right ventricular function, its interaction with both pulsatile and resistive afterload, and the effect of sildenafil during exercise in these patients. Methods and Results Fourteen healthy controls, 15 CTEPH patients, and 7 patients with normalized resting mPAP (≤25 mm Hg) post‐PEA underwent cardiopulmonary exercise testing, followed by cardiac magnetic resonance imaging with simultaneous invasive mPAP measurement during incremental supine cycling exercise. Peak oxygen consumption and peak heart rate were significantly reduced in post‐PEA and CTEPH patients compared to controls. The mPAP–cardiac output slope was steeper in post‐PEA patients than in controls and similar to CTEPH. Relative to controls, resting right ventricular ejection fraction was reduced in CTEPH, but not in post‐PEA patients. In contrast, peak exercise right ventricular ejection fraction was reduced both in post‐PEA and CTEPH patients. Exercise led to reduction of pulmonary arterial compliance in all groups. Nevertheless, resting pulmonary arterial compliance values in CTEPH and post‐PEA patients were even lower than those in controls at peak exercise. In post‐PEA patients, sildenafil did not affect resting hemodynamics nor right ventricular function, but decreased the mPAP/cardiac output slope and increased peak exercise right ventricular ejection fraction. Conclusions Exercise intolerance in post‐PEA patients is explained by abnormal pulmonary vascular reserve and chronotropic incompetence. The mPAP/cardiac output slope and pulmonary arterial compliance are sensitive measures demonstrating abnormal resistive and pulsatile pulmonary vascular function in post‐PEA patients. These abnormalities are partially attenuated with sildenafil.

Subepicardial delayed gadolinium enhancement in asymptomatic athletes: let sleeping dogs lie?

Background Subepicardial delayed gadolinium enhancement (DGE) patches without underlying cardiomyopathy is poorly understood. It is often reported as the result of prior silent myocarditis. Its prognostic relevance in asymptomatic athletes is unknown; therefore, medical clearance for competitive sports participation is debated. This case series aims to relate this pattern of DGE in athletes to outcome. Methods We report on seven young asymptomatic athletes with isolated subepicardial DGE detected during workup of abnormalities on their regular screening examination, that is, pathological T-wave inversions on ECG (n=4) or ventricular arrhythmias on exercise test (n=3). All underwent a comprehensive initial investigation in order to assess left ventricular (LV) function at rest and exercise (exercise cardiac MRI and/or exercise echocardiography) and occurrence of arrhythmias (exercise test, 24 h-ECG Holter, electrophysiological study). All underwent a careful follow-up with biannual evaluation. Results All athletes had extensive subepicardial DGE (12.0±4.8% of LV mass), predominantly in the lateral wall. Three athletes had non-sustained ventricular arrhythmias, whereas two of them had LV ejection fraction <50% at rest with no contractile reserve at exercise. During a follow-up of 3.0±1.5 years in the four remaining athletes, two had symptomatic ventricular tachycardia and one demonstrated progressive LV dysfunction. Hence, six of seven athletes had to be excluded from competitive sports participation. Conclusions Isolated large areas of subepicardial DGE in an asymptomatic athlete are not benign and require a careful evaluation at exercise and a strict follow-up. These findings question whether extreme exercise during silent myocarditis may facilitate fibrosis generation and adverse remodelling.

Is Exercise Good for the Right Ventricle? Concepts for Health and Disease

There is substantial evidence supporting the prescription of exercise training in patients with left-sided heart disease, but data on the effects of exercise are far more limited for conditions that primarily affect the right ventricle. There is evolving evidence that right ventricular (RV) function is of critical importance to circulatory function during exercise. Even in healthy individuals with normal pulmonary vascular function, the hemodynamic load on the right ventricle increases relatively more during exercise than that of the left ventricle, and this disproportionate load is far greater in patients with pulmonary hypertension. Exercise-induced increases in pulmonary artery pressures can exceed RV contractile reserve (so-called arterioventricular uncoupling), resulting in attenuated cardiac output and exercise intolerance. In this review, we explore the spectrum of RV reserve-from transient RV dysfunction observed in athletes after extreme bouts of intense endurance exercise to RV failure with minimal exertion in patients with advanced pulmonary hypertension. Recent advances and novel approaches to echocardiographic and cardiac magnetic resonance imaging have provided more accurate means of assessing the right ventricle and pulmonary circulation during exercise such that quantification of exercise reserve may provide a valuable means of assessing prognosis and response to therapies. We discuss the potential benefits and risks of exercise training in both health and disease while recognizing the need for prospective studies that assess the long-term efficacy and safety of exercise interventions in patients with pulmonary vascular and RV pathologic conditions.

Exercise pathophysiology and sildenafil effects in chronic thromboembolic pulmonary hypertension

Objectives Symptoms in patients with chronic thromboembolic pulmonary hypertension (CTEPH) predominantly occur during exercise, while haemodynamic assessment is generally performed at rest. We hypothesised that exercise imaging of RV function would better explain exercise limitation and the acute effects of pulmonary vasodilator administration than resting measurements. Methods Fourteen patients with CTEPH and seven healthy control subjects underwent cardiopulmonary testing to determine peak exercise oxygen consumption (VO2peak) and ventilatory equivalent for carbon dioxide (VE/VCO2) at the anaerobic threshold. Subsequently, cardiac MRI was performed at rest and during supine bicycle exercise with simultaneous invasive measurement of mean pulmonary arterial pressure (mPAP) before and after sildenafil. Results During exercise, patients with CTEPH had a greater increase in the ratio of mPAP relative to cardiac output (CO) than controls (6.7 (5.1–8.7) vs 0.94 (0.86–1.8) mm Hg/L/min; p<0.001). Stroke volume index (SVi) and RVEF increased during exercise in controls, but not in patients with CTEPH (interaction p<0.001). Sildenafil decreased the mPAP/CO slope and increased SVi and RVEF in patients with CTEPH (p<0.05) but not in controls. In patients with CTEPH, RVEF reserve correlated moderately with VO2peak (r=0.60; p=0.030) and VE/VCO2 (r=−0.67; p=0.012). By contrast, neither VO2peak nor VE/VCO2 correlated with resting RVEF. Conclusions Exercise measures of RV function explain much of the variance in the exercise capacity of patients with CTEPH while resting measures do not. Sildenafil increases SVi during exercise in patients with CTEPH, but not in healthy subjects.

Cardiac Magnetic Resonance Imaging: A New Gold Standard for Ventricular Volume Quantification During High-Intensity Exercise

Background— Accurate measures are critical when attempting to distinguish normal from pathological changes in cardiac function during exercise, yet imaging modalities have seldom been assessed against invasive exercise standards. We sought to validate a novel method of biventricular volume quantification by cardiac MRI (CMR) during maximal exercise. Methods and Results— CMR was performed on 34 subjects during exercise and free-breathing with the use of an ungated real-time (RT-ungated) CMR sequence. ECG and respiratory movements were retrospectively synchronized, enabling compensation for cardiac cycle and respiratory phase. Feasibility of RT-ungated imaging was compared with standard exercise CMR imaging with ECG gating (gated); accuracy of RT-ungated CMR was assessed against an invasive standard (direct Fick); and reproducibility was determined after a second bout of maximal exercise. Ventricular volumes were analyzed more frequently during high-intensity exercise with RT-ungated compared with gated CMR (100% versus 47%; P<0.0001) and with better interobserver variability for RT-ungated (coefficient of variation=1.9% and 2.0% for left and right ventricular stroke volumes, respectively) than gated (coefficient of variation=15.2% and 13.6%; P<0.01). Cardiac output determined by RT-ungated CMR proved accurate against the direct Fick method with excellent agreement (intraclass correlation coefficient, R=0.96), which was highly reproducible during a second bout of maximal exercise (R=0.98). Conclusions— When RT-ungated CMR is combined with post hoc analysis incorporating compensation for respiratory motion, highly reproducible and accurate biventricular volumes can be measured during maximal exercise.Background— Accurate measures are critical when attempting to distinguish normal from pathological changes in cardiac function during exercise, yet imaging modalities have seldom been assessed against invasive exercise standards. We sought to validate a novel method of biventricular volume quantification by cardiac MRI (CMR) during maximal exercise. Methods and Results— CMR was performed on 34 subjects during exercise and free-breathing with the use of an ungated real-time (RT-ungated) CMR sequence. ECG and respiratory movements were retrospectively synchronized, enabling compensation for cardiac cycle and respiratory phase. Feasibility of RT-ungated imaging was compared with standard exercise CMR imaging with ECG gating (gated); accuracy of RT-ungated CMR was assessed against an invasive standard (direct Fick); and reproducibility was determined after a second bout of maximal exercise. Ventricular volumes were analyzed more frequently during high-intensity exercise with RT-ungated compared with gated CMR (100% versus 47%; P <0.0001) and with better interobserver variability for RT-ungated (coefficient of variation=1.9% and 2.0% for left and right ventricular stroke volumes, respectively) than gated (coefficient of variation=15.2% and 13.6%; P <0.01). Cardiac output determined by RT-ungated CMR proved accurate against the direct Fick method with excellent agreement (intraclass correlation coefficient, R =0.96), which was highly reproducible during a second bout of maximal exercise ( R =0.98). Conclusions— When RT-ungated CMR is combined with post hoc analysis incorporating compensation for respiratory motion, highly reproducible and accurate biventricular volumes can be measured during maximal exercise.

Exercise cardiac magnetic resonance to differentiate athlete’s heart from structural heart disease

Aims The distinction between left ventricular (LV) dilation with mildly reduced LV ejection fraction (EF) in response to regular endurance exercise training and an early cardiomyopathy is a frequently encountered and difficult clinical conundrum. We hypothesized that exercise rather than resting measures would provide better discrimination between physiological and pathological LV remodelling and that preserved exercise capacity does not exclude significant LV damage. Methods and results We prospectively included 19 subjects with LVEF between 40 and 52%, comprising 10 ostensibly healthy endurance athletes (EA-healthy) and nine patients with dilated cardiomyopathy (DCM). In addition, we recruited five EAs with a region of subepicardial LV. Receiver operating characteristic fibrosis (EA-fibrosis). Cardiac magnetic resonance (CMR) imaging was performed at rest and during supine bicycle exercise. Invasive afterload measures were obtained to enable calculations of biventricular function relative to load (an estimate of contractility). In DCM and EA-fibrosis subjects there was diminished augmentation of LVEF (5 ± 6% vs. 4 ± 3% vs. 14 ± 3%; P = 0.001) and contractility [LV end-systolic pressure-volume ratio, LVESPVR; 1.4 (1.3-1.6) vs. 1.5 (1.3-1.6) vs. 1.8 (1.7-2.7); P < 0.001] during exercise relative to EA-healthy. Receiver-operator characteristic curves demonstrated that a cut-off value of 11.2% for ΔLVEF differentiated DCM and EA-fibrosis patients from EA-healthy [area under the curve (AUC) = 0.92, P < 0.001], whereas resting LVEF and VO2max were not predictive. The AUC value for LVESPVR ratio was similar to that of ΔLVEF. Conclusions Functional cardiac evaluation during exercise is a promising tool in differentiating healthy athletes with borderline LVEF from those with an underlying cardiomyopathy. Excellent exercise capacity does not exclude significant LV damage.

Increased Flow, Dam Walls, and Upstream Pressure: The Physiological Challenges and Atrial Consequences of Intense Exercise∗

E xercise impacts atrial fibrillation (AF) risk. Regular low-intensity exercise reduces the risk of incident and recurrent AF (1,2), whereas intense endurance exercise training is associated with a 2to 5-fold increase in AF risk (2,3). The exact reasons for this interaction have yet to be elucidated, but candidate mechanisms include alteration of the atrial substrate with inflammation, ion channel remodelling, and changes in vagal innervation (4–6). Acute hemodynamic factors presumably predispose to many if not all of these secondary events, and in this issue of iJACC, Sanz-de la Garza et al. (7) seek to assess the impact of the sustained hemodynamic stress of prolonged intense exercise on atrial function. To understand the hemodynamic challenges of exercise, it may be reasonable to consider the simple analogy in which the heart is considered a series of dams. The mitral and tricuspid valves are essential for preventing regurgitant blood flow during ventricular systole, but they also serve as a barrier to flow when they are closed. As circulatory flow increases, like a flooded river approaching a dam, there is the potential for consequences upstream of the dam. During intense exercise, circulatory flow is 8-fold increased (8), and the diastolic period decreases to approximate that of systole such that the “dams” are closed for approximately one-half of the time. This potential for