David L. Prior

Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes

AIMS Endurance training may be associated with arrhythmogenic cardiac remodelling of the right ventricle (RV). We examined whether myocardial dysfunction following intense endurance exercise affects the RV more than the left ventricle (LV) and whether cumulative exposure to endurance competition influences cardiac remodelling (including fibrosis) in well-trained athletes. METHODS AND RESULTS Forty athletes were studied at baseline, immediately following an endurance race (3-11 h duration) and 1-week post-race. Evaluation included cardiac troponin (cTnI), B-type natriuretic peptide, and echocardiography [including three-dimensional volumes, ejection fraction (EF), and systolic strain rate]. Delayed gadolinium enhancement (DGE) on cardiac magnetic resonance imaging (CMR) was assessed as a marker of myocardial fibrosis. Relative to baseline, RV volumes increased and all functional measures decreased post-race, whereas LV volumes reduced and function was preserved. B-type natriuretic peptide (13.1 ± 14.0 vs. 25.4 ± 21.4 ng/L, P = 0.003) and cTnI (0.01 ± .03 vs. 0.14 ± .17 μg/L, P < 0.0001) increased post-race and correlated with reductions in RVEF (r = 0.52, P = 0.001 and r = 0.49, P = 0.002, respectively), but not LVEF. Right ventricular ejection fraction decreased with increasing race duration (r = -0.501, P < 0.0001) and VO(2)max (r = -0.359, P = 0.011). Right ventricular function mostly recovered by 1 week. On CMR, DGE localized to the interventricular septum was identified in 5 of 39 athletes who had greater cumulative exercise exposure and lower RVEF (47.1 ± 5.9 vs. 51.1 ± 3.7%, P = 0.042) than those with normal CMR. CONCLUSION Intense endurance exercise causes acute dysfunction of the RV, but not the LV. Although short-term recovery appears complete, chronic structural changes and reduced RV function are evident in some of the most practiced athletes, the long-term clinical significance of which warrants further study.

Navigating the Crossroads of Coronary Artery Disease and Heart Failure

Chronic heart failure (HF) affects 5 million patients in the United States and is responsible for &1 million hospitalizations and 300 000 deaths annually.1 The total annual costs associated with this disorder have been estimated to exceed

Disproportionate Exercise Load and Remodeling of the Athlete's Right Ventricle

40 billion.1,2 Chronic HF is the only category of cardiovascular diseases for which the prevalence, incidence, hospitalization rate, total burden of mortality, and costs have increased in the past 25 years.1,2 Fueling this epidemic is the increasing number of elderly patients developing impaired left ventricular (LV) function as a manifestation of chronic coronary artery disease (CAD).1,2 With the aging of the population and decline in mortality of other forms of cardiovascular diseases, it is likely that the incidence of HF and its impact on public health will continue to increase.1–3 In the past 3 decades, considerable attention has focused on LV dysfunction, loading conditions, neuroendocrine activation, and ventricular remodeling as the principal pathophysiological mechanisms underlying HF progression.4 There has been a fundamental shift, however, in the origin of HF that often is underemphasized.3–5 The Framingham Heart Study suggests that the most common cause of HF is no longer hypertension or valvular heart disease, as it was in previous decades, but rather CAD.4 This shift may be related to improved survival of patients after acute myocardial infarction (MI). Over the past 40 years in the United States, the odds of previous MI as a cause for HF increased by 26% per decade in men and 48% per decade in women. In contrast, there has been a 13% decrease per decade for hypertension as a cause of HF in men and a 25% decrease in women, as well as a decrease in valvular disease by 24% per decade in men and 17% in women. In the 24 …

Biochemical and functional abnormalities of left and right ventricular function after ultra-endurance exercise

PURPOSE There is evolving evidence that intense exercise may place a disproportionate load on the right ventricle (RV) when compared with the left ventricle (LV) of the heart. Using a novel method of estimating end-systolic wall stress (ES-σ), we compared the RV and LV during exercise and assessed whether this influenced chronic ventricular remodeling in athletes. METHODS For this study, 39 endurance athletes (EA) and 14 nonathletes (NA) underwent resting cardiac magnetic resonance (CMR), maximal oxygen uptake (VO2), and exercise echocardiography studies. LV and RV end-systolic wall stress (ES-σ) were calculated using the Laplace relation (ES-σ = Pr/(2h)). Ventricular size and wall thickness were determined by CMR; invasive and Doppler echo estimates were used to measure systemic and pulmonary ventricular pressures, respectively; and stroke volume was quantified by Doppler echocardiography and used to calculate changes in ventricular geometry during exercise. RESULTS In EA, compared with NA, resting CMR measures showed greater RV than LV remodeling. The ratios RV ESV/LV ESV (1.40 ± 0.23 vs 1.26 ± 0.12, P = 0.007) and RV mass/LV mass (0.29 ± 0.04 vs 0.25 ± 0.03, P = 0.012) were greater in EA than in NA. RVES-σ was lower at rest than LVES-σ (143 ± 44 vs 252 ± 49 kdyn · cm, P < 0.001) but increased more with strenuous exercise (125% vs 14%, P < 0.001), resulting in similar peak exercise ES-σ (321 ± 106 vs 286 ± 77 kdyn · cm, P = 0.058). Peak exercise RVES-σ was greater in EA than in NA (340 ± 107 vs 266 ± 82 kdyn · cm, P = 0.028), whereas RVES-σ at matched absolute workloads did not differ (P = 0.79). CONCLUSIONS Exercise induces a relative increase in RVES-σ which exceeds LVES-σ. In athletes, greater RV enlargement and greater wall thickening may be a product of this disproportionate load excess.

Left ventricular strain and strain rate: characterization of the effect of load in human subjects.

Background: There is evidence that ultra-endurance exercise causes myocardial injury. The extent and duration of these changes remains unresolved. Recent reports have speculated that structural adaptations to exercise, particularly of the right ventricle, may predispose to tachyarrhythmias and sudden cardiac death. Objective: To quantify the extent and duration of post-exercise cardiac injury with particular attention to right ventricular (RV) dysfunction. Methods: 27 athletes (20 male, 7 female) were tested 1 week before, immediately after and 1 week after an ultra-endurance triathlon. Tests included cardiac troponin I (cTnI), B-type natriuretic peptide (BNP) and comprehensive echocardiographic assessment. Results: 26 athletes completed the race and testing procedures. Post-race, cTnI was raised in 15 athletes (58%) and the mean value for the entire cohort increased (0.17 vs 0.49 μg/l, p<0.01). BNP rose in every athlete and the mean increased significantly (12.2 vs 42.5 ng/l, p<0.001). Left ventricular ejection fraction (LVEF) was unchanged (60.4% vs 57.5%, p = 0.09), but integrated systolic strain decreased (16.9% vs 15.1%, p<0.01). New regional wall motion abnormalities developed in seven athletes (27%) and LVEF was reduced in this subgroup (57.8% vs 45.9%, p<0.001). RV function was reduced in the entire cohort with decreases in fractional area change (0.47 vs 0.39, p<0.01) and tricuspid annular plane systolic excursion (21.8 vs 19.1 mm, p<0.01). At follow-up, all variables returned to baseline except in one athlete where RV dysfunction persisted. Conclusion: Myocardial damage occurs during intense ultra-endurance exercise and, in particular, there is a significant reduction in RV function. Almost all abnormalities resolve within 1 week.

Pulmonary transit of agitated contrast is associated with enhanced pulmonary vascular reserve and right ventricular function during exercise

AIMS Left ventricular (LV) strain and strain rate have been proposed as novel indices of systolic function; however, there are limited data about the effect of acute changes on these parameters. METHODS AND RESULTS Simultaneous Millar micromanometer LV pressure and echocardiographic assessment were performed on 18 patients. Loading was altered sequentially by the administration of glyceryl trinitrate (GTN) and saline fluid loading. Echocardiographic speckle tracking imaging was used to quantify the peak systolic strain (S) and peak systolic strain rate (SR S) and dp/dt max was recorded from the micromanometer data. GTN administration decreased preload (LV end diastolic pressure [LVEDP]: 15.7 vs. 8.4 mmHg, P < 0.001) and afterload (end systolic wall stress: 74 vs. 43 x 10(3)dyn/cm(2), P < 0.001). Administration of fluid increased preload (LVEDP: 11.3 vs. 18.1 mmHg, P < 0.001) and increased wall stress (53 vs. 62 x 10(3)dyn/cm(2), P < 0.003). Administration of GTN resulted in increased circumferential SR S (-1.2 vs. -1.7s(-1), P < 0.01) and longitudinal SR S (-0.9 vs. -1.0 s(-1), P < 0.001). The administration of fluid resulted in decreased circumferential SR S (-1.5 vs. -1.3s(-1), P < 0.01) and longitudinal SR S (-1.0 vs. -0.9s(-1), P < 0.01). As preload and afterload increased, decrease in circumferential SR S (r = 0.63, P < 0.001; r = 0.56, P<0.001) and longitudinal SR S were observed (r = 0.42, P < 0.003; r = 0.49 P < 0.001). CONCLUSION Circumferential and longitudinal peak strain and systolic strain rate are sensitive to acute changes in load, an important factor that needs to be considered in their application as indices of systolic function.

Left Ventricular Untwisting Is an Important Determinant of Early Diastolic Function

Pulmonary transit of agitated contrast (PTAC) occurs to variable extents during exercise. We tested the hypothesis that the onset of PTAC signifies flow through larger-caliber vessels, resulting in improved pulmonary vascular reserve during exercise. Forty athletes and fifteen nonathletes performed maximal exercise with continuous echocardiographic Doppler measures [cardiac output (CO), pulmonary artery systolic pressure (PASP), and myocardial velocities] and invasive blood pressure (BP). Arterial gases and B-type natriuretic peptide (BNP) were measured at baseline and peak exercise. Pulmonary vascular resistance (PVR) was determined as the regression of PASP/CO and was compared according to athletic and PTAC status. At peak exercise, athletes had greater CO (16.0 ± 2.9 vs. 12.4 ± 3.2 l/min, P < 0.001) and higher PASP (60.8 ± 12.6 vs. 47.0 ± 6.5 mmHg, P < 0.001), but PVR was similar to nonathletes (P = 0.71). High PTAC (defined by contrast filling of the left ventricle) occurred in a similar proportion of athletes and nonathletes (18/40 vs. 10/15, P = 0.35) and was associated with higher peak-exercise CO (16.1 ± 3.4 vs. 13.9 ± 2.9 l/min, P = 0.010), lower PASP (52.3 ± 9.8 vs. 62.6 ± 13.7 mmHg, P = 0.003), and 37% lower PVR (P < 0.0001) relative to low PTAC. Right ventricular (RV) myocardial velocities increased more and BNP increased less in high vs. low PTAC subjects. On multivariate analysis, maximal oxygen consumption (VO(2max)) (P = 0.009) and maximal exercise output (P = 0.049) were greater in high PTAC subjects. An exercise-induced decrease in arterial oxygen saturation (98.0 ± 0.4 vs. 96.7 ± 1.4%, P < 0.0001) was not influenced by PTAC status (P = 0.96). Increased PTAC during exercise is a marker of pulmonary vascular reserve reflected by greater flow, reduced PVR, and enhanced RV function.

Doin’ the twist: new tools for an old concept of myocardial function

OBJECTIVES We sought to establish the relationship between invasive measures of diastolic function and untwisting parameters measured with speckle tracking imaging. BACKGROUND Left ventricular (LV) diastolic function is determined by early diastolic relaxation (which creates suction gradients for LV filling) and myocardial stiffness. Assessment of LV torsion has shown that untwisting begins before aortic valve closure and, in animals, might be an important component of normal diastolic filling. Studies in human subjects using indirect indexes derived from right heart catheterization have suggested a relationship between tau and measures of untwisting, but the relationship between directly measured diastolic function indexes with micromanometer catheters and untwisting parameters has not been established in human subjects. METHODS Simultaneous Millar micromanometer LV pressure and echocardiographic assessment was performed on 18 patients (10 male, mean age 66 years) with normal systolic function and a spectrum of diastolic function. Invasive rate of the rise of LV pressure, dp/dt minimum and tau were recorded as measures of active relaxation, and the LV minimum diastolic pressure was recorded as an index of diastolic suction. The LV stiffness constant and functional chamber stiffness were estimated from hybrid pressure-volume loops. Echocardiographic speckle tracking imaging was used to quantify torsion. RESULTS As relaxation was impaired, (prolonged tau) untwisting was delayed (r = 0.35, p < 0.01). There were nonsignificant associations between reduced untwisting and longer values of tau and lower dp/dt minimum. Reduction in the extent of untwisting before mitral valve opening was associated with increased LV minimum diastolic pressure (r = -0.30, p < 0.034). No relation was observed between the LV stiffness constant (beta: r = 0.11, p = NS) or the functional LV chamber stiffness (b: r = 0.11, p = NS) and untwisting. CONCLUSIONS Untwisting parameters are related to invasive indexes of LV relaxation and suction but not to LV stiffness. These data suggest that untwisting is an important component of early diastolic LV filling but not later diastolic events.

Inhibition of Protein Kinase C–β by Ruboxistaurin Preserves Cardiac Function and Reduces Extracellular Matrix Production in Diabetic Cardiomyopathy

It has been known for some time that the heart rotates during the cardiac cycle in concert with radial and longitudinal motion. With advances in imaging technology, it has been appreciated that the apex and base of the heart rotate in different directions, resulting in a twisting or torsional motion. A new echocardiographic technique, “speckle tracking imaging”, permits accurate quantification of this motion. Torsion as well as the timing and magnitude of the rate of torsion (torsional velocity) may provide important new insights into cardiac physiology and disease.

Exercise Strain Rate Imaging Demonstrates Normal Right Ventricular Contractile Reserve and Clarifies Ambiguous Resting Measures in Endurance Athletes

Background—Heart failure is a common cause of morbidity and mortality in diabetic patients that frequently manifests in the absence of impaired left ventricular systolic function. In contrast to the strong evidence base for the treatment of systolic heart failure, the treatment of heart failure with preserved left ventricular function is uncertain, and therapeutic targets beyond blockade of the renin-angiotensin-aldosterone and β-adrenergic systems are being sought. One such target is the β-isoform of protein kinase C (PKC), implicated in both the complications of diabetes and in cardiac dysfunction in the nondiabetic setting. Methods and Results—Using a hemodynamically validated rodent model of diabetic diastolic heart failure, the (mRen-2)27 transgenic rat, we sought to determine whether selective inhibition of PKC-β would preserve cardiac function and reduce structural injury. Diabetic rats were randomized to receive either vehicle or the PKC-β inhibitor, ruboxistaurin (20 mg/kg per d) and followed for 6 weeks. Compared with untreated animals, ruboxistaurin-treated diabetic rats demonstrated preserved systolic and diastolic function, as measured by the slope of preload recruitable stroke work relationship (P<0.05) and the slope of the end-diastolic pressure volume relationship (P<0.01). Collagen I deposition and cardiomyocyte hypertrophy were both reduced in diabetic animals treated with ruboxistaurin (P<0.01), as was phosphorylated-Smad2, an index of transforming growth factor-β activity (P<0.01 for all, versus untreated diabetic rats). Conclusions—PKC-ß inhibition attenuated diastolic dysfunction, myocyte hypertrophy, and collagen deposition and preserved cardiac contractility. PKC-β inhibition may represent a novel therapeutic strategy for the prevention of diabetes-associated cardiac dysfunction.