Stephen P. Wright

The relationship of pulmonary vascular resistance and compliance to pulmonary artery wedge pressure during submaximal exercise in healthy older adults.

A consistent inverse hyperbolic relationship has been observed between pulmonary vascular resistance and compliance, although changes in pulmonary artery wedge pressure (PAWP) may modify this relationship. This relationship predicts that pulmonary artery systolic, diastolic and mean pressure maintain a consistent relationship relative to the PAWP. We show that, in healthy exercising human adults, both pulmonary vascular resistance and compliance decrease in relation to exercise‐associated increases in PAWP. Pulmonary artery systolic, diastolic and mean pressures maintain a consistent relationship with one another, increasing linearly with increasing PAWP. Increases in PAWP in the setting of exercise are directly related to a decrease in pulmonary vascular compliance, despite small decreases in pulmonary vascular resistance, thereby increasing the pulsatile afterload to the right ventricle.

The pulmonary artery wedge pressure response to sustained exercise is time-variant in healthy adults

Objectives The clinical and prognostic significance of ‘exaggerated’ elevations in pulmonary artery wedge pressure (PAWP) during symptom-limited exercise testing is increasingly recognised. However, the paucity of normative data makes the identification of abnormal responses challenging. Our objectives was to describe haemodynamic responses that reflect normal adaptation to submaximal exercise in a group of community-dwelling, older, non-dyspnoeic adults. Methods Twenty-eight healthy volunteers (16 men/12 women; 55±6 years) were studied during rest and two consecutive stages of cycle ergometry, at targeted heart rates of 100 bpm (light exercise) and 120 bpm (moderate exercise). Right-heart catheterisation was performed to measure pulmonary artery pressures, both early (2 min) and after sustained (7 min) exercise at each intensity. Results End-expiratory PAWP at baseline was 11±3 mm Hg and increased to 22±5 mm Hg at early-light exercise (p<0.01). At sustained-light exercise, PAWP declined to 17±5 mm Hg, remaining elevated versus baseline (p<0.01). PAWP increased again at early-moderate exercise to 20±6 mm Hg but did not exceed the values observed at early-light exercise, and declined further to 15±5 mm Hg at sustained-moderate exercise (p<0.01 vs baseline). When analysed at 30 s intervals, mean and diastolic pulmonary artery pressures peaked at 180 (IQR=30) s and 130 (IQR=90) s, respectively, and both declined significantly by 420 (IQR=30) s (both p<0.01) of light exercise. Similar temporal patterns were observed at moderate exercise. Conclusions The range of PAWP responses to submaximal exercise is broad in health, but also time-variant. PAWP may routinely exceed 20 mm Hg early in exercise. Initial increases in PAWP and mean pulmonary artery pressures do not necessarily reflect abnormal cardiopulmonary physiology, as pressures may normalise within a period of minutes.

Diastolic Pressure Difference to Classify Pulmonary Hypertension in the Assessment of Heart Transplant Candidates

Background: The diastolic pressure difference (DPD) is recommended to differentiate between isolated postcapillary and combined pre-/postcapillary pulmonary hypertension (Cpc-PH) in left heart disease (PH-LHD). However, in usual practice, negative DPD values are commonly calculated, potentially related to the use of mean pulmonary artery wedge pressure (PAWP). We used the ECG to gate late-diastolic PAWP measurements. We examined the method’s impact on calculated DPD, PH-LHD subclassification, hemodynamic profiles, and mortality. Methods and Results: We studied patients with advanced heart failure undergoing right heart catheterization to assess cardiac transplantation candidacy (N=141). Pressure tracings were analyzed offline over 8 to 10 beat intervals. Diastolic pulmonary artery pressure and mean PAWP were measured to calculate the DPD as per usual practice (diastolic pulmonary artery pressure–mean PAWP). Within the same intervals, PAWP was measured gated to the ECG QRS complex to calculate the QRS-gated DPD (diastolic pulmonary artery pressure–QRS-gated PAWP). Outcomes occurring within 1 year were collected retrospectively from chart review. Overall, 72 of 141 cases demonstrated PH-LHD. Within PH-LHD, the QRS-gated DPD yielded higher calculated DPD values (3 [−1 to 6] versus 0 [−4 to 3] mm Hg; P<0.01) and a greater proportion of Cpc-PH (24% versus 8%; P<0.01) versus the usual practice DPD. Cases reclassified as Cpc-PH based on QRS-gated DPD demonstrated higher pulmonary arterial pressures versus isolated postcapillary pulmonary hypertension (P<0.05). One-year mortality was similar between PH-LHD groups. Conclusions: The DPD calculated in usual practice is underestimated in PH-LHD, which may classify Cpc-PH patients as isolated postcapillary pulmonary hypertension. The QRS-gated DPD reclassifies a subset of PH-LHD patients from isolated postcapillary pulmonary hypertension to Cpc-PH, which is characterized by an adverse hemodynamic profile.

Pulmonary Artery Wedge Pressure Relative to Exercise Work Rate in Older Men and Women

Purpose An augmented pulmonary artery wedge pressure (PAWP) response may explain exercise intolerance in some humans. However, routine use of exercise hemodynamic testing is limited by a lack of data from normal older men and women. Our objective was to evaluate the exercise PAWP response and the potential for sexual dimorphism in healthy, nondyspneic older adults. Methods Thirty-six healthy volunteers (18 men [54 ± 7 yr] and 18 women [58 ± 6 yr]) were studied at rest (control) and during two stages of semi-upright cycle ergometry, at heart rates of 100 bpm (light exercise) and 120 bpm (moderate exercise). Right heart catheterization was performed to measure pulmonary pressures. The PAWP response to exercise was assessed in context of exercise work rate and body size. Results At control, PAWP was similar between men and women. Work rates were significantly smaller in women at comparable HR (P < 0.001). PAWP increased similarly at light exercise, with no further increase at moderate exercise. When indexed to work rate alone or work rate adjusted to body weight and height, the PAWP response at light and moderate exercise was significantly elevated in women compared with men (P < 0.05 condition–sex interaction). The change in PAWP relative to the increase in cardiac output did not exceed 2 mm Hg·L−1·min−1 in any volunteer at moderate exercise. Conclusions The similar rise in the PAWP response to submaximal exercise occurs despite lower work rate in healthy older women compared with men, even when adjusted for smaller body size. It is important to consider sex in the development of normal reference ranges for exercise hemodynamic testing.

Pushing it to the limit: enhanced diffusing membrane capacity facilitates greater pulmonary diffusing capacity in athletes during exercise

The capacity to perform aerobic exercise is commonly considered in terms of V̇O2max, the maximum rate at which the body can uptake and utilize oxygen during high intensity exercise. This capacity is in large part determined by oxygen delivery (DO2 ), in turn dependent on both cardiac output (CO) and arterial oxygen content (CaO2 ), as described by the Fick equation. It is generally accepted that CO represents the primary central factor limiting aerobic performance in healthy individuals. While stroke volume and maximal CO increase markedly with endurance training, the effect of training on pulmonary function is less clear. That CaO2 remains high in athletes near maximal exercise despite reduced pulmonary capillary transit time as pulmonary flow increases is a result of exercise-related increases in pulmonary diffusing capacity, as assessed by the diffusing capacity of the lung for carbon monoxide (DLCO). Augmentation of DLCO is secondary to increased pulmonary capillary blood volume (VC) and diffusing membrane capacity (DM), and one or both of these factors may be enhanced in athletes to facilitate blood oxygenation at maximal exercise; however, the challenges associated with data acquisition at near-maximal exercise have left several important questions regarding pulmonary exercise physiology unanswered. In a recent issue of The Journal of Physiology, Tedjasaputra et al. (2016) endeavoured to address these knowledge gaps, and investigated the changes in DLCO, VC and DM during submaximal exercise up to 90% V̇O2max in a group of endurance trained athletes and a group of healthy non-athletes. The authors hypothesized that DLCO, VC, and DM would be higher in athletes compared to non-athletes during incremental cycling exercise. To test this hypothesis, 15 male endurance-trained athletes (V̇O2max = 64.6 ± 1.8 ml kg min) and 14 non-athletes (V̇O2max = 45.0 ± 1.2 ml kg min) were matched for age and height. Subjects performed a graded exercise test to determine V̇O2max, as well as three study visits each consisting of five single-breath determinations of DLCO at exercise intensities corresponding to 30%, 50%, 70%, 80% and 90% of V̇O2max. Study visits were separated by at least 48 h, and the Roughton and Forster method was used to calculate DM and VC. The authors noted that DLCO and DM were higher in the endurance-trained group compared to the untrained group during high-intensity exercise, although VC was not different. From these findings, the authors concluded that differences in the pulmonary alveolar–capillary membrane of endurance-trained athletes allow for increased oxygen diffusion during high-intensity exercise. The study design utilized by Tedjasaputra et al. (2016) has several strengths and limitations which merit discussion. Volunteers were appropriately selected with no history of pulmonary or cardiovascular disease. It is notable that the study did not include female volunteers. Although there are specific considerations associated with the inclusion of pre-menopausal female participants, the necessity of understanding sex differences in cardiorespiratory physiology is increasingly recognized, and the inclusion of such groups would have been a significant strength. Although it appears that exercise assessments may have been performed in a semi-upright position, which may limit V̇O2max, both graded exercise testing and submaximal exercise studies were performed on the same ergometer, limiting the potential for variation in mechanical efficiency. The study consisted of four exercise sessions performed within approximately 7 days. In untrained individuals, the initiation of exercise training results in acute plasma volume expansion that is associated with gains in V̇O2max (Goodman et al. 2005), and which may be observed after even a single training session. However, that the study protocol involved randomization of exercise conditions would mitigate the influence of a training effect on the results. Moreover, randomization of experimental conditions is an important though occasionally overlooked aspect of small human studies, particularly in the context of exercise studies in which there may be time-varying responses (i.e. warm-up effects), and the authors are to be acknowledged for this aspect of their experimental design. The main finding of the current study is that diffusing membrane capacity, DM, appears to be greater in athletes compared to non-athletes during exercise, with group separation occurring at moderate intensities. Interestingly, this difference was independent of either alveolar volume or pulmonary flow, and peak DM was correlated with peak V̇O2 . The authors speculate that augmented DM may represent enhanced capillary recruitment in athletes during exercise. The transfer of oxygen from the alveoli to capillary blood is typically perfusion-limited; however, during strenuous exercise, pulmonary capillary transit time decreases from 0.75 s and can approach 0.25 s, where diffusion may become limited. DM is directly related to the surface area available for gas exchange, which must be both ventilated and perfused, and inversely related to membrane thickness. In humans in an upright or semi-upright position, pulmonary intravascular pressure decreases moving upward from the heart due to the hydrostatic pressure gradient, and blood flow becomes pulsatile when alveolar pressure exceeds intravascular pressure (so-called West Lung Zone 2). While it is possible that increasing pulmonary intravascular pressure may recruit vessels unperfused at rest, capillary recruitment is likely to complete with even mild exercise (Reeves & Taylor, 1996). The current study observed that the greater DM in athletes relative to non-athletes began at moderate intensities and became pronounced at the 90% effort condition, when athletes appeared to augment DM from 70% effort, while conversely, non-athletes trended slightly downward; put differently, DM/Q̇ remained stable in athletes while DM/Q̇ declined in non-athletes. Interestingly, this pattern is similar to that of the stroke volume response

Getting at the heart of the issue: advanced imaging and stem cell-based therapy offer a novel approach to cardiac resynchronization.

The pump function of the left ventricle (LV) is dependent on synchronous depolarization and contraction to expel blood efficiently. The propagation of the apical-to-basal ventricular contraction pattern is controlled by electrical signalling of the fibre system down the interventricular septum and woven through the free walls of the ventricular myocardium. Dyssynchronous contraction results in mechanical inefficiency, decreased external work, and reduced cardiac output. Myocardial infarction (MI) may cause wall motion abnormalities not only through disturbed electrical conduction, but also through myocardial damage and non-viable tissue. Therapy targeted at preventing adverse remodelling and improving the viability of non-contracting tissue may have the potential for great improvement in ventricular synchronization by addressing mechanical disturbances in the myocardium. Recent advances in stem cell therapy hold promise for regenerative cardiac interventions, as the use of undifferentiated stem cells delivered to the myocardium may be effective in forming functional cardiac tissue and restoring global heart function. While the potential use of such therapies has gained recent attention, the administration of stem cell therapy to ameliorate regional dyssynchrony related to MI has not been examined.

Flow-related Right Ventricular – Pulmonary Arterial Pressure Gradients during Exercise

Aims The assumption of equivalence between right ventricular (RV) and pulmonary arterial systolic pressure is fundamental to several assessments of RV or pulmonary vascular haemodynamic function. Our aims were to (i) determine whether systolic pressure gradients develop across the RV outflow tract in healthy adults during exercise, (ii) examine the potential correlates of such gradients, and (iii) consider the effect of such gradients on calculated indices of RV function. Methods and results Healthy untrained and endurance-trained adult volunteers were studied using right-heart catheterization at rest and during submaximal cycle ergometry. RV and pulmonary artery (PA) pressures were simultaneously transduced, and the cardiac output was determined by thermodilution. Systolic pressures, peak and mean gradients, and indices of chamber, vascular, and valve function were analysed offline. Summary data are reported as mean ± standard deviation or median (interquartile range). No significant RV outflow tract gradients were observed at rest [mean gradient = 4 (3-5) mmHg], and the calculated effective orifice area was 3.6 ± 1.0 cm2. The increase in right ventricular systolic pressure during exercise was greater than the PA systolic pressure. Accordingly, mean gradients were developed during light exercise [8 (7-9) mmHg] and increased during moderate exercise [12 (9-14) mmHg, P < 0.001]. The magnitude of the mean gradient was linearly related to the cardiac output (r2 = 0.70, P < 0.001). Conclusions In healthy adults without pulmonic stenosis, systolic pressure gradients develop during exercise, and the magnitude is related to the blood flow rate.

Kept in the loop: longitudinal strain-volume relationships for the assessment of left ventricular mechanical performance

In health, the aortic valve facilitates unidirectional forward flow from the left ventricle (LV) to the systemic circulation. This article is protected by copyright. All rights reserved

Hook, line and sinker: adult zebrafish offer a valid model to study mammalian cardiac contractile mechanics.

On a beat-to-beat basis, cardiac contractile function is driven by a multifaceted and dynamic process that is regulated by both intrinsic (e.g. mechanical loading) and extrinsic (e.g. neuro-hormonal) factors (de Tombe et al. 2010). Specifically, the level of contractile activation of adult mammalian cardiomyocytes is modulated by the magnitude of the Ca2+ transient, the dynamic activation–relaxation kinetic response of the sarcomere to activator Ca2+ and the responsiveness of the myofilament to Ca2+, the last of which is dependent on sarcomere length and is a primary mediator of the Frank–Starling response. While transgenic mouse models have provided important insight into the molecular mechanisms underlying cardiac contractile function in health and disease, they are associated with high cost and relatively long generation times. Recently, the zebrafish has emerged as a promising model for the study of cardiac structure–function relationships, due to short generation times, ease of genetic manipulation and low cost. While multiple studies have characterized zebrafish cardiac electrophysiology, Ca2+ dynamics and myofilament mechanical function, it remains unclear whether the cardiac contractile structure–function relationship of adult zebrafish is comparable to that of the mammalian system.