Right Ventricular Stiffness Research Articles

Poor cardiac output reserve in pulmonary arterial hypertension is associated with right ventricular stiffness and impaired interventricular dependence.

Pulmonary arterial hypertension (PAH) is characterised by poor exercise tolerance. The contribution of right ventricular (RV) diastolic function to the augmentation of cardiac output during exercise is not known. This study leverages pressure-volume (P-V) loop analysis to characterise the impact of RV diastology on poor flow augmentation during exercise in PAH. RV P-V loops were measured in 41 PAH patients at rest and during supine bike exercise. Patients were stratified by median change in cardiac index (CI) during exercise into two groups: high and low CI reserve. Indices of diastolic function (end-diastolic elastance (E ed)) and ventricular interdependence (left ventricular transmural pressure (LVTMP)) were compared at matched exercise stages. Compared to patients with high CI reserve, those with low reserve exhibited lower exercise stroke volume (36 versus 49 mL·m-2; p=0.0001), with higher associated exercise afterload (effective arterial elastance (E a) 1.76 versus 0.90 mmHg·mL-1; p<0.0001), RV stiffness (E ed 0.68 versus 0.26 mmHg·mL-1; p=0.003) and right-sided pressures (right atrial pressure 14 versus 8 mmHg; p=0.002). Higher right-sided pressures led to significantly lower LV filling among the low CI reserve subjects (LVTMP -4.6 versus 3.2 mmHg; p=0.0001). Interestingly, low exercise flow reserve correlated significantly with high afterload and RV stiffness, but not with RV contractility nor RV-PA coupling. Patients with poor exercise CI reserve exhibit poor exercise RV afterload, stiffness and right-sided filling pressures that depress LV filling and stroke work. High afterload and RV stiffness were the best correlates to low flow reserve in PAH. Exercise unmasked significant pathophysiological PAH differences unapparent at rest.

A computational study of right ventricular mechanics in a rat model of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) presents a significant challenge to right ventricular (RV) function due to progressive pressure overload, necessitating adaptive remodeling in the form of increased wall thickness, enhanced myocardial contractility and stiffness to maintain cardiac performance. However, the impact of these remodeling mechanisms on RV mechanics in not clearly understood. In addition, there is a lack of quantitative understanding of how each mechanism individually influences RV mechanics. Utilizing experimental data from a rat model of PAH at three distinct time points, we developed biventricular finite element models to investigate how RV stress and strain evolved with PAH progression. The finite element models were fitted to hemodynamic and morphological data to represent different disease stages and used to analyze the impact of RV remodeling as well as the altered RV pressure. Furthermore, we performed a number of theoretical simulation studies with different combinations of morphological and physiological remodeling, to assess and quantify their individual impact on overall RV load and function. Our findings revealed a substantial 4-fold increase in RV stiffness and a transient 2-fold rise in contractility, which returned to baseline by week 12. These changes in RV material properties in addition to the 2-fold increase in wall thickness significantly mitigated the increase in wall stress and strain caused by the progressive increase in RV afterload. Despite the PAH-induced cases showing increased wall stress and strain at end-diastole and end-systole compared to the control, our simulations suggest that without the observed remodeling mechanisms, the increase in stress and strain would have been much more pronounced. Our model analysis also indicated that while changes in the RV's material properties-particularly increased RV stiffness - have a notable effect on its mechanics, the primary compensatory factor limiting the stress and strain increase in the early stages of PAH was the significant increase in wall thickness. These findings underscore the importance of RV remodeling in managing the mechanical burden on the right ventricle due to pressure overload.

Impact of right ventricular stiffness on discordance between hemodynamic parameter and regurgitant volume in patients with pulmonary regurgitation.

Accurate detection of significant pulmonary regurgitation (PR) is critical in management of patients after right ventricular (RV) outflow reconstruction in Tetralogy of Fallot (TOF) patients, because of its influence on adverse outcomes. Although pressure half time (PHT) of PR velocity is one of the widely used echocardiographic markers of the severity, shortened PHT is suggested to be seen in conditions with increased RV stiffness with mild PR. However, little has been reported about the exact characteristics of patients showing discrepancy between PHT and PR volume in this population. Echocardiography and cardiac magnetic resonance imaging (MRI) were performed in 74 TOF patients after right ventricular outflow tract (RVOT) reconstruction [32 ± 10 years old]. PHT was measured from the continuous Doppler PR flow velocity profile and PHT < 100 ms was used as a sign of significant PR. Presence of end-diastolic RVOT forward flow was defined as RV restrictive physiology. By using phase-contrast MRI, forward and regurgitant volumes through the RVOT were measured and regurgitation fraction was calculated. Significant PR was defined as regurgitant fraction ≥ 25%. Significant PR was observed in 54 of 74 patients. While PHT < 100 ms well predicted significant PR with sensitivity of 96%, specificity of 52%, and c-index of 0.72, 10 patients showed shortened PHT despite regurgitant fraction < 25% (discordant group). Tricuspid annular plane systolic excursion and left ventricular (LV) ejection fraction were comparable between discordant group and patients showing PHT < 100 ms and regurgitant fraction ≥ 25% (concordant group). However, discordant group showed significantly smaller mid RV diameter (30.7 ± 4.5 vs. 39.2 ± 7.3mm, P < 0.001) and higher prevalence of restrictive physiology (100% vs. 42%, P < 0.01) than concordant group. When mid RV diameter ≥ 32mm and presence of restrictive physiology were added to PHT, the predictive value was significantly improved (sensitivity: 81%, specificity: 90%, and c-index: 0.89, P < 0.001 vs. PHT alone by multivariable logistic regression model). Patients with increased RV stiffness and non-enlarged right ventricle showed short PHT despite mild PR. Although it has been expected, this was the first study to demonstrate the exact characteristics of patients showing discrepancy between PHT and PR volume in TOF patients after RVOT reconstruction.

β3 adrenergic agonism: A novel pathway which improves right ventricular-pulmonary arterial hemodynamics in pulmonary arterial hypertension.

Efficacy of therapies that target the downstream nitric oxide (NO) pathway in pulmonary arterial hypertension (PAH) depends on the bioavailability of NO. Reduced NO level in PAH is secondary to "uncoupling" of endothelial nitric oxide synthase (eNOS). Stimulation of β3 adrenergic receptors (β3 ARs) may lead to the recoupling of NOS and therefore be beneficial in PAH. We aimed to examine the efficacy of β3 AR agonism as a novel pathway in experimental PAH. In hypoxia (5 weeks) and Sugen hypoxia (hypoxia for 5 weeks + SU5416 injection) models of PAH, we examined the effects of the selective β3 AR agonist CL316243. We measured echocardiographic indices and invasive right ventricular (RV)-pulmonary arterial (PA) hemodynamics and compared CL316243 with riociguat and sildenafil. We assessed treatment effects on RV-PA remodeling, oxidative stress, and eNOS glutathionylation, an oxidative modification that uncouples eNOS. Compared with normoxic mice, RV systolic pressure was increased in the control hypoxic mice (p < 0.0001) and Sugen hypoxic mice (p < 0.0001). CL316243 reduced RV systolic pressure, to a similar degree to riociguat and sildenafil, in both hypoxia (p < 0.0001) and Sugen hypoxia models (p < 0.03). CL316243 reversed pulmonary vascular remodeling, decreased RV afterload, improved RV-PA coupling efficiency and reduced RV stiffness, hypertrophy, and fibrosis. Although all treatments decreased oxidative stress, CL316243 significantly reduced eNOS glutathionylation. β3 AR stimulation improved RV hemodynamics and led to beneficial RV-PA remodeling in experimental models of PAH. β3 AR agonists may be effective therapies in PAH.

The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary artery pressure leading to right ventricular (RV) failure. While current PAH therapies improve patient outlook, they show limited benefit in attenuating RV dysfunction. Recent investigations demonstrated that the thromboxane (TX) A2 receptor (TP) antagonist NTP42 attenuates experimental PAH across key hemodynamic parameters in the lungs and heart. This study aimed to validate the efficacy of NTP42:KVA4, a novel oral formulation of NTP42 in clinical development, in preclinical models of PAH while also, critically, investigating its direct effects on RV dysfunction. The effects of NTP42:KVA4 were evaluated in the monocrotaline (MCT) and pulmonary artery banding (PAB) models of PAH and RV dysfunction, respectively, and when compared with leading standard-of-care (SOC) PAH drugs. In addition, the expression of the TP, the target for NTP42, was investigated in cardiac tissue from several other related disease models, and from subjects with PAH and dilated cardiomyopathy (DCM). In the MCT-PAH model, NTP42:KVA4 alleviated disease-induced changes in cardiopulmonary hemodynamics, pulmonary vascular remodeling, inflammation, and fibrosis, to a similar or greater extent than the PAH SOCs tested. In the PAB model, NTP42:KVA4 improved RV geometries and contractility, normalized RV stiffness, and significantly increased RV ejection fraction. In both models, NTP42:KVA4 promoted beneficial RV adaptation, decreasing cellular hypertrophy, and increasing vascularization. Notably, elevated expression of the TP target was observed both in RV tissue from these and related disease models, and in clinical RV specimens of PAH and DCM. This study shows that, through antagonism of TP signaling, NTP42:KVA4 attenuates experimental PAH pathophysiology, not only alleviating pulmonary pathologies but also reducing RV remodeling, promoting beneficial hypertrophy, and improving cardiac function. The findings suggest a direct cardioprotective effect for NTP42:KVA4, and its potential to be a disease-modifying therapy in PAH and other cardiac conditions.

Imaging assessment of the right atrium: anatomy and function.

The right atrium (RA) is the cardiac chamber that has been least well studied. Due to recent advances in interventional cardiology, the need for greater understanding of the RA anatomy and physiology has garnered significant attention. In this article, we review how a comprehensive assessment of RA dimensions and function using either echocardiography, cardiac computed tomography, and magnetic resonance imaging may be used as a first step towards a better understanding of RA pathophysiology. The recently published normative data on RA size and function will likely shed light on RA atrial remodelling in atrial fibrillation (AF), which is a complex phenomenon that occurs in both atria but has only been studied in depth in the left atrium. Changes in RA structure and function have prognostic implications in pulmonary hypertension (PH), where the increased right ventricular (RV) afterload first induces RV remodelling, predominantly characterized by hypertrophy. As PH progresses, RV dysfunction and dilatation may begin and eventually lead to RV failure. Thereafter, RV overload and increased RV stiffness may lead to a proportional increase in RA pressure. This manuscript provides an in-depth review of RA anatomy, function, and haemodynamics with particular emphasis on the changes in structure and function that occur in AF, tricuspid regurgitation, and PH.

Externally induced shear waves in the right ventricular free wall during the cardiac cycle

Increased right ventricular (RV) diastolic stiffness is linked to adverse prognosis in pulmonary arterial hypertension. Currently, a non-invasive method for measuring RV stiffness is lacking. In the left ventricle, shear wave (SW) speed is related to diastolic stiffness. We show for the first time that SWs in the RV free wall (RVFW) can be induced and imaged transthoracically with ultrasound. SW imaging was performed using an L7-4 array (ATL, USA) with a Vantage 256 system (Verasonics, USA) in a 5-weeks-old Yorkshire-Landrace pig (±120 beats/min). SWs were induced by a push beam (f0 = 4.5MHz, push duration = 800μs) on the RVFW and its propagation was imaged (f0 = 5.2MHz) using plane wave compounding (-12 deg, 0 deg, +12 deg) at 3 kHz framerate. Three acquisitions of 1 s were performed, where fourteen SWs were sequentially induced during each acquisition. SW propagation speeds were calculated using a semi-automatic pipeline that includes tissue velocity estimation along a manually traced spline on the RVFW, and Radon transform to estimate SW speed. At least 85% of the waves were tracked successfully for all acquisitions. The SW velocities varied during the heart cycle as expected, ranging from 0.58 ± 0.09 m/s at end-diastole to 1.8 ± 0.2 m/s during systole. Pathological increase in stiffness may be demonstrated in longitudinal case/control studies.

RA pressure waveforms as a means for describing right ventricular diastolic stiffness

Introduction Exercise-induced changes in right atrial (RA) pressure associates with morality in patients with pulmonary hypertension (PH). Increased right ventricular (RV) diastolic stiffness impairs right ventricular filling during atrial contraction. Right atrial waveforms consist of the a-wave (atrial contraction) and v-wave (RA passive filling), as well as x and y descents representing atrial relaxation and ventricular filling, respectively. Ventricular distensibility has been associated with the difference between the x- and y-descents (x-y difference) in RA pressure. A positive x-y difference correlates with increased ventricular stiffness. The study aim was to investigate the relationship between RA pressure waveforms and RV diastolic function in patients with pulmonary arterial hypertension (PAH). We hypothesized that exercise-induced increases in RA pressure associate with increased RV diastolic stiffness and a positive x-y difference. Methods Participants (n = 52) with a right heart catheterization (RHC) and invasive cardiopulmonary exercise test were selected from the University of Arizona Pulmonary Hypertension Registry. Resting (REST) and peak exercise (EX) measurements of RA pressure (RAP), pulmonary artery pressure (PAP), cardiac output (CO), and heart rate (HR) were analyzed. Raw RA waveforms were analyzed to identify the a-wave, v-wave, and x- and y-descents using a custom MATLAB program. Single-beat methods were used to calculate end-diastolic elastance (Eed) a measure of RV stiffness. Wilcoxon signed-rank test was used test differences between rest and exercise conditions (R version 4.0.3). Data is presented as mean ± standard deviation or median [IQR]. A p< 0.05 is considered significant. Results Forty-three participants with pulmonary arterial hypertension diagnosis (age: 53 ± 13, sex: 73% female) and 9 participants without PH (age: 61 ± 13 years, sex: 100% female) were included. At rest, patients with pulmonary hypertension have increased PAP (37 ± 11 vs 16 ± 5 mmHg, p < 0.001) but no significant differences in RAP (2.7 [0.5-4.7] vs 0.1 [-0.1 – 3.0] mmHg, p = 0.4). There is a non-significant increase in Eed (0.61 [0.34-0.93] vs. 0.31 [0.26-0.53] mmHg/ml, p = 0.07) compared to controls. At peak exercise (PAH: 20 [10-50] W and controls: 30 [10-60] W), RA pressure significantly increased (Figure 1A). Participants with PAH had an exercise-induced increase in RA x-descent (Figure 1B) and y-descent (Figure 1C). There was an exercise-induced decrease in the x-y descent in participants with PAH but not Controls (Figure 1D). The x-y difference did not correlate with resting Eed at rest (p = 0.58) or peak exercise (p = 0.22). Discussion/Conclusion Exercise significantly increased average RA, x-descent, and y-descent pressure. The RA x-y difference did not correlate with end-diastolic elastance, another measure of ventricular stiffness. Overall, exercise decreased the x-y difference in participants with PAH that suggests an exercise-induced increase in ventricular distensibility. Further investigations are needed to determine if exercise-induced changes in RA pressure can unmask structural or pressure induced changes in RV diastolic function.

Increased MAO-A Activity Promotes Progression of Pulmonary Arterial Hypertension.

Monoamine oxidases (MAOs), a class of enzymes bound to the outer mitochondrial membrane, are important sources of reactive oxygen species. Increased MAO-A activity in endothelial cells and cardiomyocytes contributes to vascular dysfunction and progression of left heart failure. We hypothesized that inhibition of MAO-A can be used to treat pulmonary arterial hypertension (PAH) and right ventricular (RV) failure. MAO-A levels in lung and RV samples from patients with PAH were compared with levels in samples from donors without PAH. Experimental PAH was induced in male Sprague-Dawley rats by using Sugen 5416 and hypoxia (SuHx), and RV failure was induced in male Wistar rats by using pulmonary trunk banding (PTB). Animals were randomized to receive either saline or the MAO-A inhibitor clorgyline at 10 mg/kg. Echocardiography and RV catheterization were performed, and heart and lung tissues were collected for further analysis. We found increased MAO-A expression in the pulmonary vasculature of patients with PAH and in experimental experimental PAH induced by SuHx. Cardiac MAO-A expression and activity was increased in SuHx- and PTB-induced RV failure. Clorgyline treatment reduced RV afterload and pulmonary vascular remodeling in SuHx rats through reduced pulmonary vascular proliferation and oxidative stress. Moreover, clorgyline improved RV stiffness and relaxation and reversed RV hypertrophy in SuHx rats. In PTB rats, clorgyline had no direct clorgyline had no direct effect on the right ventricle effect. Our study reveals the role of MAO-A in the progression of PAH. Collectively, these findings indicated that MAO-A may be involved in pulmonary vascular remodeling and consecutive RV failure.

Simple and noninvasive method to estimate right ventricular operating stiffness based on echocardiographic pulmonary regurgitant velocity and tricuspid annular plane movement measurements during atrial contraction

It was recently shown that invasively determined right ventricular (RV) stiffness was more closely related to the prognosis of patients with pulmonary hypertension than RV systolic function. So far, a completely noninvasive method to access RV stiffness has not been reported. We aimed to clarify the clinical usefulness of our new echocardiographic index of RV operating stiffness using atrial-systolic descent of the pulmonary artery-RV pressure gradient derived from pulmonary regurgitant velocity (PRPGDAC) and tricuspid annular plane movement during atrial contraction (TAPMAC). We studied 81 consecutive patients with various cardiac diseases who underwent echocardiography and cardiac catheterization. We measured PRPGDAC and TAPMAC using continuous-wave Doppler and M-mode echocardiography, respectively, and calculated PRPGDAC/TAPMAC. RV end-diastolic pressure (RVEDP) and RV pressure increase during atrial contraction (ΔRVPAC) were invasively measured, and RV volume change during atrial contraction (ΔVAC) was calculated from echocardiographic late-diastolic transtricuspid flow time-velocity integral and tricuspid annular area; thus ΔRVPAC/ΔVAC was used as the standard index for RV operating stiffness. PRPGDAC/TAPMAC well correlated with ΔRVPAC/ΔVAC (r = 0.84, p < 0.001) and RVEDP (r = 0.80, p < 0.001), and the area under the receiver operating characteristic curve to discriminate RVEDP > 12mmHg was 0.94. Multivariate regression analysis revealed that PRPGDAC/TAPMAC was the single independent determinant of ΔRVPAC/ΔVAC (β = 0.86, p < 0.001). PRPGDAC/TAPMAC is useful to estimate RV operating stiffness and a good practical indicator of RVEDP.

Right atrial-right ventricular coupling in heart failure with preserved ejection fraction.

Right ventricular (RV) function is prognostically relevant in heart failure with preserved ejection fraction (HFpEF) but data on profound assessment of RV and right atrial (RA) interaction in HFpEF are lacking. The current study characterizes RV and RA interaction using invasive pressure-volume-loop analysis and cardiac magnetic resonance imaging (CMR) data. We performed CMR and myocardial feature-tracking in 24 HFpEF patients and 12 patients without HFpEF. Invasive pressure-volume-loops were obtained to evaluate systolic and diastolic RV properties. RV early filling was determined from CMR RV volume-time curves. RV systolic function was slightly increased in HFpEF (RV EF 68 ± 8 vs. 60 ± 9%, p = 0.01), while no differences in RV stroke volume were found (45 ± 7 vs 42 ± 9ml/m2, p = 0.32). RV early filling was decreased in HFpEF (21 ± 11 vs. 40 ± 11% of RV filling volume, p < 0.01) and RV early filling was the strongest predictor for VO2max even after inclusion of invasively derived RV stiffness and relaxation constant (Beta 0.63, p < 0.01). RA conduit-function was lower in HFpEF (RA conduit-strain - 11 ± 5 vs. - 16 ± 4%, p < 0.01) while RA booster-pump-function was increased (RA active-strain - 18 ± 6 vs. - 12 ± 6%, p = 0.01) as a compensation. RV filling was associated with RA conduit-function (r = - 0.55, p < 0.01) but not with invasively derived RV relaxation constant. In compensated HFpEF patients RV early filling was impaired and compensated by increased RA booster pump function, while RV systolic function was preserved. Impaired RV diastology and RA-RV interaction were linked to impaired exercise tolerance and RA-RV-coupling seems to be independent of RV relaxation, suggestive of an independent pathophysiological contribution of RA dysfunction in HFpEF. NCT02459626 (www.clinicaltrials.gov).

Cardiac Magnetic Resonance Imaging-Based Right Ventricular Strain Analysis for Assessment of Coupling and Diastolic Function in Pulmonary Hypertension

ObjectivesThis study sought to compare cardiac magnetic resonance (CMR) imaging-derived right ventricular (RV) strain and invasively measured pressure-volume loop-derived RV contractility, stiffness, and afterload and RV-arterial coupling in pulmonary hypertension (PH). BackgroundIn chronic RV pressure overload, RV-arterial uncoupling is considered the driving cause of RV maladaptation and eventual RV failure. The pathophysiological and clinical value of CMR-derived RV strain relative to that of invasive pressure-volume loop-derived measurements in PH remains incompletely understood. MethodsIn 38 patients with PH, global RV CMR strain was measured within 24 h of diagnostic right heart catheterization and conductance (pressure-volume) catheterization. Associations were evaluated by correlation, multivariate logistic binary regression, and receiver operating characteristic analyses. ResultsLong-axis RV longitudinal and radial strain and short-axis RV radial and circumferential strain were −18.0 ± 7.0%, 28.9% [interquartile range (IQR): 17.4% to 46.6%]; 15.6 ± 6.2%; and −9.8 ± 3.5%, respectively. RV-arterial coupling (end-systolic [Eds]/arterial elastance [Ea]) was 0.76 (IQR: 0.47 to 1.07). Peak RV strain correlated with Ees/Ea, afterload (Ea), RV diastolic dysfunction (Tau), and stiffness (end-diastolic elastance [Eed]) but not with contractility (Ees). In multivariate analysis, long-axis RV radial strain was associated with RV-arterial uncoupling (Ees/Ea: <0.805; odds ratio [OR]: 5.50; 95% confidence interval [CI]: 1.50 to 20.18), whereas long-axis RV longitudinal strain was associated with increased RV diastolic stiffness (Eed: ≥0.124 mm Hg/ml; OR: 1.23; 95% CI: 1.10 to 1.51). The long-axis RV longitudinal strain-to-RV end-diastolic volume/body surface area ratio strongly predicted RV diastolic stiffness (area under receiver operating characteristic curve: 0.908). ConclusionsIn chronic RV overload, CMR-determined RV strain is associated with RV-arterial uncoupling and RV end-diastolic stiffness and represents a promising noninvasive alternative to current invasive methods for assessment of RV-arterial coupling and end-diastolic stiffness in patients with PH. (Right Ventricular Haemodynamic Evaluation and Response to Treatment [Rightheart I]; NCT03403868)

Load-Independent Systolic and Diastolic Right Ventricular Function in Heart Failure With Preserved Ejection Fraction as Assessed by Resting and Handgrip Exercise Pressure–Volume Loops

Although systolic right ventricular (RV) dysfunction has been shown to be a potent predictor for adverse outcomes in patients with heart failure with preserved ejection fraction (HFpEF), RV functional abnormalities in the course of the syndrome are not well characterized. We, therefore, sought to assess load-independent and load-dependent systolic and diastolic characteristics of RV function in stable outpatients with HFpEF. We invasively obtained RV and left ventricular pressure-volume loops in 24 HFpEF patients and 9 patients without heart failure symptoms with a conductance catheter during basal conditions and handgrip exercise. Transient preload reduction was used to extrapolate the RV end-systolic elastance and diastolic stiffness constant. HFpEF patients and controls showed similar left ventricular and RV dimensions and ejection fractions with elevated left ventricular filling pressures. In HFpEF patients, invasively determined load-independent RV contractility (P=0.04) and load-independent passive RV stiffness constant β (P<0.01) were elevated. Although RV relaxation and cardiac output were similar at baseline, HFpEF patients demonstrated a blunted increase in cardiac output under exercise (P=0.01) associated with prolonged RV relaxation (P=0.01), decrease in stroke volume (P<0.01), higher RV-filling pressures (P<0.01), and a marked increase in the end-diastolic pressure-volume relationship (P<0.01). In compensated stages of the HFpEF syndrome, systolic RV function is preserved, but diastolic abnormalities with intrinsic RV stiffness and prolonged RV relaxation are already present. Impaired diastolic RV reserve contributes to a blunted increase in cardiac output during exertion. Because impairments in diastolic function seem to be a biventricular phenomenon, RV diastolic dysfunction warrants further consideration when characterizing HFpEF patients. https://www.clinicaltrials.gov. Unique identifier: NCT02459626.

Contribution of Impaired Parasympathetic Activity to Right Ventricular Dysfunction and Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension.

The beneficial effects of parasympathetic stimulation have been reported in left heart failure, but whether it would be beneficial for pulmonary arterial hypertension (PAH) remains to be explored. Here, we investigated the relationship between parasympathetic activity and right ventricular (RV) function in patients with PAH, and the potential therapeutic effects of pyridostigmine (PYR), an oral drug stimulating the parasympathetic activity through acetylcholinesterase inhibition, in experimental pulmonary hypertension (PH). Heart rate recovery after a maximal cardiopulmonary exercise test was used as a surrogate for parasympathetic activity. RV ejection fraction was assessed in 112 patients with PAH. Expression of nicotinic (α-7 nicotinic acetylcholine receptor) and muscarinic (muscarinic acetylcholine type 2 receptor) receptors, and acetylcholinesterase activity were evaluated in RV (n=11) and lungs (n=7) from patients with PAH undergoing heart/lung transplantation and compared with tissue obtained from controls. In addition, we investigated the effects of PYR (40 mg/kg per day) in experimental PH. PH was induced in male rats by SU5416 (25 mg/kg subcutaneously) injection followed by 4 weeks of hypoxia. In a subgroup, sympathetic/parasympathetic modulation was assessed by power spectral analysis. At week 6, PH status was confirmed by echocardiography, and rats were randomly assigned to vehicle or treatment (both n=12). At the end of the study, echocardiography was repeated, with additional RV pressure-volume measurements, along with lung, RV histological, and protein analyses. Patients with PAH with lower RV ejection fraction (<41%) had a significantly reduced heart rate recovery in comparison with patients with higher RV ejection fraction. In PAH RV samples, α-7 nicotinic acetylcholine receptor was increased and acetylcholinesterase activity was reduced versus controls. No difference in muscarinic acetylcholine type 2 receptor expression was observed. Chronic PYR treatment in PH rats normalized the cardiovascular autonomic function, demonstrated by an increase in parasympathetic activity and baroreflex sensitivity. PYR improved survival, increased RV contractility, and reduced RV stiffness, RV hypertrophy, RV fibrosis, RV inflammation, and RV α-7 nicotinic acetylcholine receptor and muscarinic acetylcholine type 2 receptor expression, as well. Furthermore, PYR reduced pulmonary vascular resistance, RV afterload, and pulmonary vascular remodeling, which was associated with reduced local and systemic inflammation. RV dysfunction is associated with reduced systemic parasympathetic activity in patients with PAH, with an inadequate adaptive response of the cholinergic system in the RV. Enhancing parasympathetic activity by PYR improved survival, RV function, and pulmonary vascular remodeling in experimental PH.

Right ventricular end-diastolic stiffness heralds right ventricular failure in monocrotaline-induced pulmonary hypertension.

Recent studies suggest right ventricular (RV) stiffness is important in pulmonary hypertension (PH) prognosis. Smaller stroke volume (SV) variation after a certain RV end-diastolic pressure (EDP) respiratory variation as assessed by spectral transfer function (STF) may identify RV stiffness. Our aim was to evaluate RV stiffness in monocrotaline (MCT)-induced PH progression and to validate STF gain between EDP and SV as marker of stiffness. Seven-week-old male Wistar rats randomly injected with 60 mg/kg MCT or vehicle were divided into three groups (n = 12 each) according to cardiac index (CI): controls (Ctrl), preserved CI (MCT pCI), and reduced CI (MCT rCI). All underwent RV pressure-volume (PV) evaluation 24-34 days after MCT, under halogenate anesthesia and constant positive-pressure ventilation. End-diastolic stiffness (βi), end-systolic elastance (Eesi), arterial elastance for indexed volumes (Eai), and preload recruitable stroke work (PRSW) were obtained and beat-to-beat fluctuations during ventilation assessed by STF. Eai was the strongest determinant of CI, alongside βi but not PRSW. MCT rCI showed impaired ventricular-vascular coupling (VVC) and higher βi, along with low end-diastolic pressure (EDP) and stroke volume index (SVi) STF gain, denoting impaired preload reserve. On multivariate analysis βi and not Eesi correlated with EDP-SVi STF gain (P < 0.001). Receiver-operating characteristics (ROC) curve analysis of EDP-SVi STF gain showed an area under curve of 0.84 for βi prediction (P = 0.002). Afterload, impaired VVC and RV stiffness are major players in RV failure. RV stiffness can be assessed by STF gain analysis of respiratory fluctuations between EDP and SVi, which may constitute a prognostic tool in PH.

Quantification of myocardial stiffness using magnetic resonance elastography in right ventricular hypertrophy: initial feasibility in dogs

IntroductionMyocardial stiffness is an important determinant of cardiac function and is currently invasively and indirectly assessed by catheter angiography. This study aims to demonstrate the feasibility of quantifying right ventricular (RV) stiffness noninvasively using cardiac magnetic resonance elastography (CMRE) in dogs with severe congenital pulmonary valve stenosis (PVS) causing RV hypertrophy, and compare it to remote myocardium in the left ventricle (LV). Additionally, correlations between stiffness and selected pathophysiologic indicators from transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging were explored. MethodsIn-vivo CMRE was performed on nine dogs presenting severe congenital PVS using a 1.5T MRI scanner. T1-MOLLI, T2-prepared-bSSFP, gated-cine GRE-MRE and LGE (PSIR) sequences were used to acquire a basal short-axis slice. RV and LV-free-wall (FW) stiffness measurements were compared against each other and also correlated to ventricular mass, RV and LV FW thickness, T1 and T2 relaxation times, and extracellular volume fraction (ECV). Peak transpulmonary pressure gradient and myocardial strain were also acquired on eight dogs by TTE and correlated to RV-FW systolic stiffness. Potential correlations were evaluated by Spearman's rho (rs). ResultsRV-FW stiffness was found to be significantly higher than the LV-FW stiffness both during end-systole (ES) (p=0.002) and end-diastole (ED) (p=0.029). Significant correlations were observed between RV-FW ES and LV-FW ED stiffness versus ECV (rs=0.75; p-value=0.05). Non-significant moderate correlations were found between LV-FW ES (rs=0.54) and RV-FW ED (rs=0.61) stiffness versus ECV. Furthermore, non-significant correlations were found between RV or LV-FW stiffness and the remaining variables (rs<0.54; p-value>0.05). ConclusionThis study demonstrates the feasibility of determining RV stiffness. The positive correlations between stiffness and ECV might indicate some interdependence between stiffness and myocardial extracellular matrix alterations. However, further studies are warranted to validate our initial observations.

(373) - Late Diastolic Strain Index Is a Marker of Right Ventricular Fibrosis Content in Precapillary Pulmonary Hypertension

Increased fibrosis content (FC) is a hallmark of right ventricular (RV) remodeling in patients with chronic precapillary pulmonary hypertension (PH). We determined a non-invasive marker of RV FC using RV strain analysis. We induced chronic PH in 9 large white pigs with closed pericardium by progressive pulmonary artery (PA) occlusions (week 0 to week 6). At week 16, we determined, using pressure-volume (PV-) loops, RV stiffness (β); we acquired apical 5 chambers views for RV strain analysis; we quantified the ratio of interstitial fibrosis over myocardium surfaces using picrosirius red staining of RV free wall. The late diastolic strain index (LDSI) was the ratio of RV strain during atrial contraction over total systolic strain. We measured PV-loops, hemodynamic and imaging parameters at baseline and after iterative volume loading (VL) with saline (15 mL/kg = VL1; 15 mL/kg = VL2 and 30 mL/kg = VL3). We determined linear correlations between RV FC, stiffness and imaging parameters. At baseline, mean pulmonary artery pressure (MPAP) was (median, interquartile range) 27 (25; 28) mmHg, pulmonary artery pulse pressure (paPP)/MPAP was 0.54 (0.37; 0.63). We determined the RV stiffness as the mean of the 4 values of β (βm),since β was stable after VL; we indexed βm by the body surface area (βim), βim was 0.026 (0.021; 0.036) mmHg/(mL.m²). The RV FC was 7.4 (5.4; 9.9) %. The LDSI was 56.0 (42.4; 67.2) %. RV FC was correlated to RV stiffness (r = 0.83, P<0.01). The RV LDSI was significantly correlated with RV FC and RV stiffness at baseline (r=-0.81, P<0.01 and P=-0.77, P=0.015, respectively) and after VL1 (r=-0.75, P=0.02 and r=-0.74, P=0.02, respectively). RV FC also correlated significantly with the right atrial active ejection fraction at baseline (r=-0.88, P<0.01) and with RV global longitudinal strain after VL1 (r=0.81, P<0.01). The paPP/MPAP ratio was correlated with FC (r=0.67, P=0.048) and with RV stiffness (r=0.76, P=0.02); whereas MPAP was not (P=NS in all conditions). We validated the significant linear relationship between RV FC content and LDSI in an independent cohort of 3 healthy pigs, 3 pigs with chronic systemic to PA shunt and 3 pigs with chronic PH induced by PA occlusions. We described, for the first time, the RV late diastolic strain index, that may be a non-invasive surrogate of RV fibrosis and stiffness in patients with PH.

Impact of restrictive physiology on intrinsic diastolic right ventricular function and lusitropy in children and adolescents after repair of tetralogy of Fallot

BackgroundRestrictive right ventricular (RV) physiology is a phenomenon considered potentially beneficial when detected in children and adolescents with repaired tetralogy of Fallot (ToF). It is typically characterised by antegrade flow...

Right Atrial and Ventricular Adaptation to Chronic Right Ventricular Pressure Overload

Increased mortality in patients with chronic pulmonary hypertension has been associated with elevated right atrial (RA) pressure. However, little is known about the effects of chronic right ventricular (RV) pressure overload on RA and RV dynamics or the adaptive response of the right atrium to maintain RV filling. In 7 dogs, RA and RV pressure and volume (conductance catheter) were recorded at baseline and after 3 months of progressive pulmonary artery banding. RA and RV elastance (contractility) and diastolic stiffness were calculated, and RA reservoir and conduit function were quantified as RA inflow with the tricuspid valve closed versus open, respectively. With chronic pulmonary artery banding, systolic RV pressure increased from 34+/-7 to 70+/-17 mm Hg (P<0.001), but cardiac output did not change (P>0.78). RV elastance and stiffness both increased (P<0.05), suggesting preserved systolic function but impaired diastolic function. In response, RA contractility improved (elastance increased from 0.28+/-0.12 to 0.44+/-0.13 mm Hg/mL; P<0.04), and the atrium became more distensible, as evidenced by increased reservoir function (49+/-14% versus 72+/-8%) and decreased conduit function (51+/-14% versus 28+/-8%; P<0.002). With chronic RV pressure overload, RV systolic function was preserved, but diastolic function was impaired. To compensate, RA contractility increased, and the atrium became more distensible to maintain filling of the stiffened ventricle. This compensatory response of the right atrium likely plays an important role in preventing clinical failure in chronic pulmonary hypertension.

Right Ventricular Stiffness Measured by a New Method Without Volume Estimation in Coronary Artery Disease

This study was designed to measure the right ventricular (RV) stiffness (ΔP/ΔV) with a new method without estimating the RV volume itself. RV stiffness has rarely been measured due to the difficulty in estimating the RV volume. Without measuring RV volume itself, stiffness can be determined by measuring its volume change (ΔV). Tricuspid filling flow volume, which is the diastolic RV ΔV, is measurable by using Doppler echocardiography. Thus, RV stiffness may possibly be obtained from Doppler echocardiography combined with high-fidelity RV pressure. Subjects consisted of 8 controls, 8 patients with angina pectoris, 8 with anterior, 8 with posterior, and 8 with inferior prior myocardial infarction. Tricuspid annular dimension was measured by 2-dimensional echocardiography and the tricuspid annular area was calculated. Velocity-time integral of the tricuspid filling flow during the late diastole was measured by pulsed Doppler echocardiography. Then, the late diastolic RV ΔV was obtained as the product of the tricuspid annular area and the integral. The late diastolic RV pressure rise (ΔP) was also measured with a micromanometer catheter. The RV elastic chamber stiffness constant ([ΔP/ΔV]/P) was obtained by dividing simple stiffness by the mean RV pressure during late diastole. The RV elastic chamber stiffness constant did not significantly differ among controls, patients with angina pectoris, and those with anterior and posterior myocardial infarction (0.0054 ± 0.0009 vs 0.0057 ± 0.0018 vs 0.0064 ± 0.002 vs 0.0052 ± 0.0019 ml −1). However, it was significantly increased in patients with inferior myocardial infarction (0.010 ± 0.004 ml −1, p <0.01 or 0.05) compared with those in the other 4 groups. These results suggest (1) that RV stiffness can be measured with a new method without RV volume estimation, and (2) that this new method is useful in evaluating RV diastolic pathophysiology in patients with coronary artery disease. (Am J Cardiol 1996;78:298–303)