Publications by authors named "Robert Naeije"

314 Publications

Letter by Naeije Regarding Article, "Oxygen Pathway Limitations in Patients With Chronic Thromboembolic Pulmonary Hypertension".

Authors:
Robert Naeije

Circulation 2021 Nov 22;144(21):e328-e329. Epub 2021 Nov 22.

Free University of Brussels, Faculty of Medicine, Laboratory of Physiology, Belgium.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.055607DOI Listing
November 2021

The physiologic basis of pulmonary arterial hypertension.

Eur Respir J 2021 Nov 4. Epub 2021 Nov 4.

University of California, San Diego, La Jolla, CA, USA.

Pulmonary arterial hypertension (PAH) is a rare dyspnea-fatigue syndrome caused by a progressive increase in pulmonary vascular resistance (PVR) and eventual right ventricular (RV) failure. In spite of extensive pulmonary vascular remodeling, lung function in PAH is generally well preserved, with hyperventilation and increased physiologic dead space, but minimal changes in lung mechanics and only mild to moderate hypoxemia and hypocapnia. Hypoxemia is mainly caused by a low mixed venous PO from a decreased cardiac output. Hypocapnia is mainly caused by an increased chemosensitivity. Exercise limitation in PAH is cardiovascular rather than ventilatory or muscular. The extent of pulmonary vascular disease in PAH is defined by multipoint pulmonary vascular pressure-flow relationships with a correction for hematocrit. Pulsatile pulmonary vascular pressure-flow relationships in PAH allow for the assessment of RV hydraulic load. This analysis is possible either in the frequency-domain or in the time-domain. The RV in PAH adapts to increased afterload by an increased contractility to preserve its coupling to the pulmonary circulation. When this homeometric mechanism is exhausted, the RV dilates to preserve flow output by an additional heterometric mechanism. Right heart failure is then diagnosed by imaging of increased right heart dimensions and clinical systemic congestion signs and symptoms. The coupling of the RV to the pulmonary circulation is assessed by the ratio of end-systolic to arterial elastances, but these measurements are difficult. Simplified estimates of RV-PA coupling can be obtained by magnetic resonance or echocardiographic imaging of ejection fraction.
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http://dx.doi.org/10.1183/13993003.02334-2021DOI Listing
November 2021

Fluid challenge and balloon occlusion testing in patients with atrial septal defects.

Heart 2021 Aug 19. Epub 2021 Aug 19.

Adult Congenital Heart Centre and Centre for Pulmonary Hypertension, Royal Brompton Hospital, London, UK.

Introduction: Careful, stepwise assessment is required in all patients with atrial septal defect (ASD) to exclude pulmonary vascular or left ventricular (LV) disease. Fluid challenge and balloon occlusion may unmask LV disease and post-capillary pulmonary hypertension, but their role in the evaluation of patients with 'operable' ASDs is not well established.

Methods: We conducted a prospective study in three Italian specialist centres between 2018 and 2020. Patients selected for percutaneous ASD closure underwent assessment at baseline and after fluid challenge, balloon occlusion and both.

Results: Fifty patients (46 (38.2, 57.8) years, 72% female) were included. All had a shunt fraction >1.5, pulmonary vascular resistance (PVR) <5 Wood Units (WU) and pulmonary arterial wedge pressure (PAWP) <15 mm Hg. Individuals with a PVR ≥2 WU at baseline (higher PVR group) were older, more symptomatic, with a higher baseline systemic vascular resistance (SVR) than the lower PVR group (all p<0.0001). Individuals with a higher PVR experienced smaller increases in pulmonary blood flow following fluid challenge (0.3 (0.1, 0.5) vs 2.0 (1.5, 2.8) L/min, p<0.0001). Balloon occlusion led to a more marked fall in SVR (p<0.0001) and a larger increase in systemic blood flow (p=0.024) in the higher PVR group. No difference was observed in PAWP following fluid challenge and/or balloon occlusion between groups; four (8%) patients reached a PAWP ≥18 mm Hg following the addition of fluid challenge to balloon occlusion testing.

Conclusions: In adults with ASD without overt LV disease, even small rises in PVR may have significant implications on cardiovascular haemodynamics. Fluid challenge may provide additional information to balloon occlusion in this setting.
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http://dx.doi.org/10.1136/heartjnl-2021-319676DOI Listing
August 2021

Phenotyping long COVID.

Eur Respir J 2021 08 26;58(2). Epub 2021 Aug 26.

Dept of Management, Information and Production Engineering, University of Bergamo, Bergamo, Italy.

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http://dx.doi.org/10.1183/13993003.01763-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287735PMC
August 2021

Sex and the Right Ventricle in Heart Failure With Preserved Ejection Fraction.

Chest 2021 06;159(6):2156-2158

Free University of Brussels, Brussels, Belgium. Electronic address:

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http://dx.doi.org/10.1016/j.chest.2021.02.001DOI Listing
June 2021

Arterial load and right ventricular-vascular coupling in pulmonary hypertension.

J Appl Physiol (1985) 2021 07 27;131(1):424-433. Epub 2021 May 27.

Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale New Haven Hospital and Yale School of Medicine, New Haven, Connecticut.

Right ventricular (RV) functional adaptation to afterload determines outcome in pulmonary hypertension (PH). RV afterload is determined by the dynamic interaction between pulmonary vascular resistance (PVR), characteristic impedance (), and wave reflection. Pulmonary vascular impedance (PVZ) represents the most comprehensive measure of RV afterload; however, there is an unmet need for an easier bedside measurement of this complex variable. Although a recent study showed that and wave reflection can be estimated from RV pressure waveform analysis and cardiac output, this has not been validated. Estimations of and wave reflection coefficient (λ) were validated relative to conventional spectral analysis in an animal model. , λ, and the single-beat ratio of end-systolic to arterial elastance (/) to estimate RV-pulmonary arterial (PA) coupling were determined from right heart catheterization (RHC) data. The study included 30 pulmonary artery hypertension (PAH) and 40 heart failure with preserved ejection fraction (HFpEF) patients [20 combined pre- and postcapillary PH (Cpc-PH) and 20 isolated postcapillary PH, (Ipc-PH)]. Also included were 10 age- and sex-matched controls. There was good agreement with minimal bias between estimated and spectral analysis-derived and λ. in PAH and Cpc-PH groups exceeded that in the Ipc-PH group and controls. λ was increased in Ipc-PH (0.84 ± 0.02), Cpc-PH (0.87 ± 0.05), and PAH groups (0.85 ± 0.04) compared with controls (0.79 ± 0.03); all values were <0.05. λ was the only afterload parameter associated with RV-PA coupling in PAH. In the PH-HFpEF group, RV-PA uncoupling was independent of RV afterload. Our findings indicate that and λ derived from an RV pressure curve can be used to improve estimation of RV afterload. λ is the only afterload measure associated with RV-PA uncoupling in PAH, whereas RV-PA uncoupling in PH-HFpEF appears to be independent of afterload consistent with an inherent abnormality of the RV myocardium. Pulmonary vascular impedance (PVZ) represents the most comprehensive measure of right ventricle (RV) afterload; however, measurement of this variable is complex. We demonstrate that characteristic impedance () and a wave reflection coefficient, λ, can be derived from RV pressure waveform analysis. In addition, RV dysfunction in left heart disease is independent of its afterload. The current study provides a platform for future studies to examine the pharmacotherapeutic effects and prognosis of different measures of RV afterload.
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http://dx.doi.org/10.1152/japplphysiol.00204.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325619PMC
July 2021

Right Heart Phenotype in Heart Failure With Preserved Ejection Fraction.

Circ Heart Fail 2021 04 19;14(4):e007840. Epub 2021 Apr 19.

Erasme Hospital, Free University of Brussels, Belgium (R.N.).

The health burden of heart failure with preserved ejection fraction is increasingly recognized. Despite improvements in diagnostic algorithms and established knowledge on the clinical trajectory, effective treatment options for heart failure with preserved ejection fraction remain limited, mainly because of the high mechanistic heterogeneity. Diagnostic scores, big data, and phenomapping categorization are proposed as key steps needed for progress. In the meantime, advancements in imaging techniques combined to high-fidelity pressure signaling analysis have uncovered right ventricular dysfunction as a mediator of heart failure with preserved ejection fraction progression and as major independent determinant of poor outcome. This review summarizes the current understanding of the pathophysiology of right ventricular dysfunction in heart failure with preserved ejection fraction covering the different right heart phenotypes and offering perspectives on new treatments targeting the right ventricle in its function and geometry.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007840DOI Listing
April 2021

Feasibility of semi-recumbent bicycle exercise Doppler echocardiography for the evaluation of the right heart and pulmonary circulation unit in different clinical conditions: the RIGHT heart international NETwork (RIGHT-NET).

Int J Cardiovasc Imaging 2021 Jul 18;37(7):2151-2167. Epub 2021 Apr 18.

Cardiology Division, A Cardarelli Hospital, Naples, Italy.

Exercise Doppler echocardiography (EDE) is a well-validated tool in ischemic and valvular heart diseases. However, its use in the assessment of the right heart and pulmonary circulation unit (RH-PCU) is limited. The aim of this study is to assess the semi-recumbent bicycle EDE feasibility for the evaluation of RH-PCU in a large multi-center population, from healthy individuals and elite athletes to patients with overt or at risk of developing pulmonary hypertension (PH). From January 2019 to July 2019, 954 subjects [mean age 54.2 ± 16.4 years, range 16-96, 430 women] underwent standardized semi-recumbent bicycle EDE with an incremental workload of 25 watts every 2 min, were prospectively enrolled among 7 centers participating to the RIGHT Heart International NETwork (RIGHT-NET). EDE parameters of right heart structure, function and pressures were obtained according to current recommendations. Right ventricular (RV) function at peak exercise was feasible in 903/940 (96%) by tricuspid annular plane systolic excursion (TAPSE), 667/751 (89%) by tissue Doppler-derived tricuspid lateral annular systolic velocity (S') and 445/672 (66.2%) by right ventricular fractional area change (RVFAC). RV-right atrial pressure gradient [RV-RA gradient = 4 × tricuspid regurgitation velocity (TRV)] was feasible in 894/954 patients (93.7%) at rest and in 816/954 (85.5%) at peak exercise. The feasibility rate in estimating pulmonary artery pressure improved to more than 95%, if both TRV and/or right ventricular outflow tract acceleration time (RVOT AcT) were considered. In high specialized echocardiography laboratories semi-recumbent bicycle EDE is a feasible tool for the assessment of the RH-PCU pressure and function.
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http://dx.doi.org/10.1007/s10554-021-02243-xDOI Listing
July 2021

A novel non-invasive and echocardiography-derived method for quantification of right ventricular pressure-volume loops.

Eur Heart J Cardiovasc Imaging 2021 Feb 28. Epub 2021 Feb 28.

Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Klinikstrasse 32, Giessen 35392, Germany.

Aims: We sought to assess the feasibility of constructing right ventricular (RV) pressure-volume (PV) loops solely by echocardiography.

Methods And Results: We performed RV conductance and pressure wire (PW) catheterization with simultaneous echocardiography in 35 patients with pulmonary hypertension. To generate echocardiographic PV loops, a reference RV pressure curve was constructed using pooled PW data from the first 20 patients (initial cohort). Individual pressure curves were then generated by adjusting the reference curve according to RV isovolumic and ejection phase duration and estimated RV systolic pressure. The pressure curves were synchronized with echocardiographic volume curves. We validated the reference curve in the remaining 15 patients (validation cohort). Methods were compared with correlation and Bland-Altman analysis. In the initial cohort, echocardiographic and conductance-derived PV loop parameters were significantly correlated {rho = 0.8053 [end-systolic elastance (Ees)], 0.8261 [Ees/arterial elastance (Ea)], and 0.697 (stroke work); all P < 0.001}, with low bias [-0.016 mmHg/mL (Ees), 0.1225 (Ees/Ea), and -39.0 mmHg mL (stroke work)] and acceptable limits of agreement. Echocardiographic and PW-derived Ees were also tightly correlated, with low bias (-0.009 mmHg/mL) and small limits of agreement. Echocardiographic and conductance-derived Ees, Ees/Ea, and stroke work were also tightly correlated in the validation cohort (rho = 0.9014, 0.9812, and 0.9491, respectively; all P < 0.001), with low bias (0.0173 mmHg/mL, 0.0153, and 255.1 mmHg mL, respectively) and acceptable limits.

Conclusion: The novel echocardiographic method is an acceptable alternative to invasively measured PV loops to assess contractility, RV-arterial coupling, and RV myocardial work. Further validation is warranted.
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http://dx.doi.org/10.1093/ehjci/jeab038DOI Listing
February 2021

Right ventricular pressure-volume loop shape and systolic pressure change in pulmonary hypertension.

Am J Physiol Lung Cell Mol Physiol 2021 05 3;320(5):L715-L725. Epub 2021 Mar 3.

Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Giessen, Germany.

Right ventricular (RV) function determines outcome in pulmonary arterial hypertension (PAH). RV pressure-volume loops, the gold standard for measuring RV function, are difficult to analyze. Our aim was to investigate whether simple assessments of RV pressure-volume loop morphology and RV systolic pressure differential reflect PAH severity and RV function. We analyzed multibeat RV pressure-volume loops (obtained by conductance catheterization with preload reduction) in 77 patients with PAH and 15 patients without pulmonary hypertension in two centers. Patients were categorized according to their pressure-volume loop shape (triangular, quadratic, trapezoid, or notched). RV systolic pressure differential was defined as end-systolic minus beginning-systolic pressure (ESP - BSP), augmentation index as ESP - BSP/pulse pressure, pulmonary arterial capacitance (PAC) as stroke volume/pulse pressure, and RV-arterial coupling as end-systolic/arterial elastance (Ees/Ea). Trapezoid and notched pressure-volume loops were associated with the highest afterload (Ea), augmentation index, pulmonary vascular resistance (PVR), mean pulmonary arterial pressure, stroke work, B-type natriuretic peptide, and the lowest Ees/Ea and PAC. Multivariate linear regression identified Ea, PVR, and stroke work as the main determinants of ESP - BSP. ESP - BSP also significantly correlated with multibeat Ees/Ea (Spearman's ρ: -0.518, < 0.001). A separate retrospective analysis of 113 patients with PAH showed that ESP - BSP obtained by routine right heart catheterization significantly correlated with a noninvasive surrogate of RV-arterial coupling (tricuspid annular plane systolic excursion/pulmonary arterial systolic pressure ratio; ρ: -0.376, < 0.001). In conclusion, pressure-volume loop shape and RV systolic pressure differential predominately depend on afterload and PAH severity and reflect RV-arterial coupling in PAH.
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http://dx.doi.org/10.1152/ajplung.00583.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174826PMC
May 2021

The Role of Exercise Testing in Pulmonary Vascular Disease: Diagnosis and Management.

Clin Chest Med 2021 03;42(1):113-123

Free University of Brussels, Brussels, Belgium. Electronic address:

Exercise intolerance is the dominant symptom of pulmonary hypertension (PH). The gold standard for the estimation of exercise capacity is a cycle ergometer incremental cardiopulmonary exercise test (CPET). The main clinical variables generated by a CPET are peak oxygen uptake (Vo2peak), ventilatory equivalents for carbon dioxide (VE/Vco), systolic blood pressure, oxygen (O2) pulse, and chronotropic responses. PH is associated with hyperventilation at rest and at exercise, and an increase in physiologic dead space. Maximal cardiac output depends on right ventricular function and critically determines a PH patient's exercise capacity. Dynamic arterial O2 desaturation can also depress the Vo2peak.
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http://dx.doi.org/10.1016/j.ccm.2020.11.003DOI Listing
March 2021

A multicentric quality-control study of exercise Doppler echocardiography of the right heart and the pulmonary circulation. The RIGHT Heart International NETwork (RIGHT-NET).

Cardiovasc Ultrasound 2021 Jan 20;19(1). Epub 2021 Jan 20.

IRCCS SDN, Naples, Italy.

Purpose: This study was a quality-control study of resting and exercise Doppler echocardiography (EDE) variables measured by 19 echocardiography laboratories with proven experience participating in the RIGHT Heart International NETwork.

Methods: All participating investigators reported the requested variables from ten randomly selected exercise stress tests. Intraclass correlation coefficients (ICC) were calculated to evaluate the inter-observer agreement with the core laboratory. Inter-observer variability of resting and peak exercise tricuspid regurgitation velocity (TRV), right ventricular outflow tract acceleration time (RVOT Act), tricuspid annular plane systolic excursion (TAPSE), tissue Doppler tricuspid lateral annular systolic velocity (S'), right ventricular fractional area change (RV FAC), left ventricular outflow tract velocity time integral (LVOT VTI), mitral inflow pulsed wave Doppler velocity (E), diastolic mitral annular velocity by TDI (e') and left ventricular ejection fraction (LVEF) were measured.

Results: The accuracy of 19 investigators for all variables ranged from 99.7 to 100%. ICC was > 0.90 for all observers. Inter-observer variability for resting and exercise variables was for TRV = 3.8 to 2.4%, E = 5.7 to 8.3%, e' = 6 to 6.5%, RVOT Act = 9.7 to 12, LVOT VTI = 7.4 to 9.6%, S' = 2.9 to 2.9% and TAPSE = 5.3 to 8%. Moderate inter-observer variability was found for resting and peak exercise RV FAC (15 to 16%). LVEF revealed lower resting and peak exercise variability of 7.6 and 9%.

Conclusions: When performed in expert centers EDE is a reproducible tool for the assessment of the right heart and the pulmonary circulation.
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http://dx.doi.org/10.1186/s12947-021-00238-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819251PMC
January 2021

Right ventricular-arterial uncoupling independently predicts survival in COVID-19 ARDS.

Crit Care 2020 11 30;24(1):670. Epub 2020 Nov 30.

Department of Cardiology, Monaldi Hospital - "L. Vanvitelli" University, Naples, Italy.

Aim: To investigate the prevalence and prognostic impact of right heart failure and right ventricular-arterial uncoupling in Corona Virus Infectious Disease 2019 (COVID-19) complicated by an Acute Respiratory Distress Syndrome (ARDS).

Methods: Ninety-four consecutive patients (mean age 64 years) admitted for acute respiratory failure on COVID-19 were enrolled. Coupling of right ventricular function to the pulmonary circulation was evaluated by a comprehensive trans-thoracic echocardiography with focus on the tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (PASP) ratio RESULTS: The majority of patients needed ventilatory support, which was noninvasive in 22 and invasive in 37. There were 25 deaths, all in the invasively ventilated patients. Survivors were younger (62 ± 13 vs. 68 ± 12 years, p = 0.033), less often overweight or usual smokers, had lower NT-proBNP and interleukin-6, and higher arterial partial pressure of oxygen (PaO)/fraction of inspired O (FIO) ratio (270 ± 104 vs. 117 ± 57 mmHg, p < 0.001). In the non-survivors, PASP was increased (42 ± 12 vs. 30 ± 7 mmHg, p < 0.001), while TAPSE was decreased (19 ± 4 vs. 25 ± 4 mm, p < 0.001). Accordingly, the TAPSE/PASP ratio was lower than in the survivors (0.51 ± 0.22 vs. 0.89 ± 0.29 mm/mmHg, p < 0.001). At univariate/multivariable analysis, the TAPSE/PASP (HR: 0.026; 95%CI 0.01-0.579; p: 0.019) and PaO/FIO (HR: 0.988; 95%CI 0.988-0.998; p: 0.018) ratios were the only independent predictors of mortality, with ROC-determined cutoff values of 159 mmHg and 0.635 mm/mmHg, respectively.

Conclusions: COVID-19 ARDS is associated with clinically relevant uncoupling of right ventricular function from the pulmonary circulation; bedside echocardiography of TAPSE/PASP adds to the prognostic relevance of PaO/FIO in ARDS on COVID-19.
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http://dx.doi.org/10.1186/s13054-020-03385-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703719PMC
November 2020

Simple imaging of the right heart phenotype in heart failure.

Authors:
Robert Naeije

Eur Heart J Cardiovasc Imaging 2021 01;22(2):177-178

Department of Pathophysiology, Faculty of Medicine, Free University of Brussels, 808 Lennik Road, B-1070 Brussels, Belgium.

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http://dx.doi.org/10.1093/ehjci/jeaa302DOI Listing
January 2021

Right Ventricular Strain Curve Morphology and Outcome in Idiopathic Pulmonary Arterial Hypertension.

JACC Cardiovasc Imaging 2021 01 28;14(1):162-172. Epub 2020 Oct 28.

Department of Cardiovascular and Respiratory Science, Sapienza University of Rome, Italy.

Objectives: The purpose of this study was to explore speckle tracking echocardiographic right ventricular (RV) post-systolic strain patterns and their clinical relevance in idiopathic pulmonary arterial hypertension (PAH).

Background: The imaging of RV diastolic function in PAH remains incompletely understood.

Methods: Speckle tracking echocardiography of RV post-systolic strain recordings were examined in 108 consecutive idiopathic patients with PAH. Each of them underwent baseline clinical, hemodynamic, and complete echocardiographic evaluation and follow-up.

Results: In total, 3 post-systolic strain patterns derived from the mid-basal RV free wall segments were identified. Pattern 1 was characterized by prompt return of strain-time curves to baseline after peak systolic negativity, like in normal control subjects. Pattern 2 was characterized by persisting negativity of strain-time curves well into diastole, before an end-diastolic returning to baseline. Pattern 3 was characterized by a slow return of strain-time curves to baseline during diastole. The 3 patterns corresponded respectively to mild PH, more advanced PH but with still preserved RV function, and PH with obvious end-stage right heart failure. Patterns were characterized by optimal reproducibility when complementary to quantitative measurement of right ventricular longitudinal early diastolic strain rate (RVLSR-E), and right ventricular longitudinal late diastolic strain rate (RVLSR-A) (Cohen's κ = 0.88; p = 0.0001). Multivariable models for clinical worsening prediction demonstrated that the addition of RV post-systolic patterns to clinical and hemodynamic variables significantly increased their prognostic power (0.78 vs. 0.66; p < 0.001). Freedom from clinical worsening rates at 1 and 2 years from baseline were, respectively, 100% and 93% for Pattern 1; 80% and 55% for Pattern 2; and 60% and 33% for Pattern 3.

Conclusions: Speckle tracking echocardiography allows for the identification of 3 phenotypically distinct, reproducible, and clinically meaningful RV strain-derived post-systolic patterns.
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http://dx.doi.org/10.1016/j.jcmg.2020.08.017DOI Listing
January 2021

Systemic vascular distensibility relates to exercise capacity in connective tissue disease.

Rheumatology (Oxford) 2021 03;60(3):1429-1434

Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Objective: Exercise intolerance is a common clinical manifestation of CTD. Frequently, CTD patients have associated cardio-pulmonary disease, including pulmonary hypertension or heart failure that impairs aerobic exercise capacity (pVO2). The contribution of the systemic micro-vasculature to reduced exercise capacity in CTD patients without cardiopulmonary disease has not been fully described. In this study, we sought to examine the role of systemic vascular distensibility, α in reducing exercise capacity (i.e. pVO2) in CTD patients.

Methods: Systemic and pulmonary vascular distensibility, α (%/mmHg) was determined from multipoint systemic pressure-flow plots during invasive cardiopulmonary exercise testing with pulmonary and radial arterial catheters in place in 42 CTD patients without cardiopulmonary disease and compared with 24 age and gender matched normal controls.

Results: During exercise, systemic vascular distensibility, α was reduced in CTD patients compared with controls (0.20 ± 0.12%/mmHg vs 0.30 ± 0.13%/mmHg, P =0.01). The reduced systemic vascular distensibility α, was associated with impaired stroke volume augmentation. On multivariate analysis, systemic vascular distensibility, α was associated with a decreased exercise capacity (pVO2) and decreased systemic oxygen extraction.

Conclusion: Systemic vascular distensibility, α is associated with impaired systemic oxygen extraction and decreased aerobic capacity in patients with CTD without cardiopulmonary disease.
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http://dx.doi.org/10.1093/rheumatology/keaa510DOI Listing
March 2021

Hemodynamics and risk assessment 2 years after the initiation of upfront ambrisentan‒tadalafil in pulmonary arterial hypertension.

J Heart Lung Transplant 2020 12 28;39(12):1389-1397. Epub 2020 Aug 28.

Department of Pathophysiology, Free University of Brussels, Brussels, Belgium.

Background: Upfront combination therapy with ambrisentan and tadalafil has been reported to improve the condition of patients with pulmonary arterial hypertension (PAH) more than with either drug alone. However, little is known about the long-term associated changes in hemodynamics and risk assessment scores.

Methods: This was a multicenter, retrospective analysis of clinical data in 106 patients with newly diagnosed PAH. Clinical evaluations, including demographics, medical history, World Health Organization (WHO) functional class (FC) and 6-minute walk distance (6MWD), right heart catheterization, and Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk score 2.0, were assessed over 48 months of ambrisentan‒tadalafil therapy.

Results: At baseline, 9 patients (9%) showed a low (<7), 48 patients (45%) showed an intermediate (7-8), and 49 patients (46%) showed a high (>8) REVEAL risk score. At a median follow-up of 2 years, 45 patients (43%) showed a low, 47 patients (44%) showed an intermediate, and 14 patients (13%) showed a high REVEAL score, along with improvements in WHO FC, 6MWD and a decrease in mean pulmonary artery pressure and N-terminal pro brain natriuretic peptide (all p < 0.001). Pulmonary vascular resistance (PVR) decreased by 37% from 11.5 ± 6.5 to 7.2 ± 4.1 Wood units (p < 0.001). A total of 61 patients (57%) remained in intermediate-risk or high-risk categories. Low-risk patients had either a decrease in PVR of >50% or a stroke volume within the limits of normal.

Conclusions: Initial combination therapy with ambrisentan and tadalafil in PAH improves the REVEAL risk score in proportion to decreased PVR and preserved stroke volume but still insufficiently so in approximately 50% of the patients.
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http://dx.doi.org/10.1016/j.healun.2020.08.016DOI Listing
December 2020

Risk Reduction and Hemodynamics with Initial Combination Therapy in Pulmonary Arterial Hypertension.

Am J Respir Crit Care Med 2021 02;203(4):484-492

Department of Cardiovascular and Respiratory Sciences, Sapienza University of Rome, Rome, Italy.

An initial oral combination of drugs is being recommended in pulmonary arterial hypertension (PAH), but the effects of this approach on risk reduction and pulmonary vascular resistance (PVR) are not known. To test the hypothesis that a low-risk status would be determined by the reduction of PVR in patients with PAH treated upfront with a combination of oral drugs. The study enrolled 181 treatment-naive patients with PAH (81% idiopathic) with a follow-up right heart catheterization at 6 months (interquartile range, 144-363 d) after the initial combination of endothelin receptor antagonist + phosphodiesterase-5 inhibitor drugs and clinical evaluation and risk assessments by European guidelines and Registry to Evaluate Early and Long-Term PAH Disease Management scores. Initial combination therapy improved functional class and 6-minute-walk distance and decreased PVR by an average of 35% (median, 40%). One-third of the patients had a decrease in PVR <25%. This poor hemodynamic response was independently predicted by age, male sex, pulmonary artery pressure and cardiac index, and at echocardiography, a right/left ventricular surface area ratio of greater than 1 associated with low tricuspid annular plane systolic excursion of less than 18 mm. A low-risk status at 6 months was achieved or maintained in only 34.8% (Registry to Evaluate Early and Long-Term PAH Disease Management score) to 43.1% (European score) of the patients. Adding criteria of poor hemodynamic response improved prediction of a low-risk status. A majority of patients with PAH still insufficiently improved after 6 months of initial combinations of oral drugs is identifiable at initial evaluation by hemodynamic response criteria added to risk scores.
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http://dx.doi.org/10.1164/rccm.202004-1006OCDOI Listing
February 2021

A Fluid Challenge Test for the Diagnosis of Occult Heart Failure.

Chest 2021 02 14;159(2):791-797. Epub 2020 Aug 14.

Department of Pathophysiology, Free University of Brussels, Brussels, Belgium. Electronic address:

A right heart catheterization with measurements of pulmonary artery wedge pressure (PAWP) may be necessary for the diagnosis of left heart failure as a cause of pulmonary hypertension or unexplained dyspnea. Diagnostic cutoff values are a PAWP of ≥ 15 mm Hg at rest or a PAWP of ≥ 25 mm Hg during exercise. However, accurate measurement of PAWP can be challenging and heart failure may be occult. Left heart catheterization, with measurement of left ventricular end-diastolic pressure, may also be indecisive. Measurements are then best repeated in stress conditions. Exercise is an option, but the equipment is not universally available, and interpretation can be difficult in patients with wide respiratory pressure swings. An alternative is offered by a fluid challenge. Studies have gathered data supporting infusion of 500 mL or 7 mL/kg saline and a PAWP of 18 mm Hg as a diagnostic cutoff. The procedure is simple and does not take much catheterization laboratory time. Combining echocardiography with invasive measurements may increase the diagnostic accuracy of diastolic dysfunction. Cardiac output after a fluid challenge may be of prognostic relevance.
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http://dx.doi.org/10.1016/j.chest.2020.08.019DOI Listing
February 2021

An intact animal model for the assessment of coronary blood flow regulation "Coronary blood flow regulation".

Physiol Rep 2020 07;8(14):e14510

Department of Anesthesiology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium.

Coronary blood flow adapts to metabolic demand ("metabolic regulation") and remains relatively constant over a range of pressure changes ("autoregulation"). Coronary metabolic regulation and autoregulation are usually studied separately. We developed an intact animal experimental model to explore both regulatory mechanisms of coronary blood flow. Coronary pressure and flow-velocities were measured in four anesthetized and closed-chest pigs using an intracoronary Doppler wire. Metabolic regulation was assessed by coronary flow reserve defined as the ratio between the maximally vasodilated and the basal flow, with hyperemia achieved using intracoronary administration of adenosine (90 µg) or bradykinin (10  M) as endothelium-independent and -dependent vasodilators respectively. For both vasodilators, we found a healthy coronary flow reserve ≥ 3.0 at baseline, which was maintained at 2.9 ± 0.2 after a 6-hr period. Autoregulation was assessed by the lower breakpoint of coronary pressure-flow relationships, with gradual decrease in coronary pressure through the inflation of an intracoronary balloon. We found a lower limit of autoregulation between 42 and 55 mmHg, which was stable during a 6-hr period. We conclude that this intact animal model is adequate for the study of pharmacological interventions on the coronary circulation in health and disease, and as such suitable for preclinical drug studies.
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http://dx.doi.org/10.14814/phy2.14510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392130PMC
July 2020

Endothelin-1 induces lysyl oxidase expression in pulmonary artery smooth muscle cells.

Can J Physiol Pharmacol 2020 Sep 2;98(9):629-636. Epub 2020 Jul 2.

Division of Cardiovascular Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

The increase in thickening of the arterial wall of pulmonary arterial hypertension (PAH) includes cellular proliferation as well as matrix deposition and interrupted internal elastic lamina (IEL) consisting of a thick homogeneous sheet of elastin. Little is, although, known about the detail of IEL formation in PAH. Endothelin-1 is overexpressed in pulmonary arterioles of PAH. We aimed to examine the expression of genes contributing to IEL formation in pulmonary artery smooth muscle cells (PASMCs) especially focused on lysyl oxidase (LOx), an exreacellular matrix enzyme that catalyzes the cross-linking of collagens or elastin. We quantified mRNA expressions of genes contributing to IEL formation including LOx in PASMCs using real-time quantitative polymerase chain reaction. We stimulated human PASMCs with endothelin-1 with prostacyclin or trapidil. Endothelin-1 significantly increased LOx expression. Prostacyclin and trapidil restored endothelin-1-induced LOx expression to the basal level. Endothelin-1 increased LOx expression strongly in PASMCs from PAH patients compared to those from controls. Trapidil reduced LOx expression only in PASMCs from PAH patients. Overexpressed endothelin-1 in PAH patients can increase expression of LOx and agitate cross-linking of elastin and collagen, resulting in ectopic deposition of these in the vascular media.
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http://dx.doi.org/10.1139/cjpp-2019-0658DOI Listing
September 2020

Transcatheter tricuspid valve repair in patients with pulmonary hypertension.

Eur Heart J 2020 08;41(29):2811-2812

Department of Pathophysiology, Free University of Brussels, Brussels, Belgium.

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http://dx.doi.org/10.1093/eurheartj/ehaa426DOI Listing
August 2020

Right ventricular dyssynchrony: from load-independent right ventricular function to wall stress in severe pulmonary arterial hypertension.

Pulm Circ 2020 Apr-Jun;10(2):2045894020925759. Epub 2020 May 18.

Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.

Right ventricular (RV) dyssynchrony has been related to outcome in pulmonary arterial hypertension. Prospectively, we performed echocardiography with measurement of right ventricular dyssynchrony and pressure-volume loop catheterization in 27 pulmonary arterial hypertension patients. Afterload and diastolic function emerged as determinates of wall stress, which results in dyssynchrony.
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http://dx.doi.org/10.1177/2045894020925759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235672PMC
May 2020

High fat diet altered cardiac metabolic gene profile in Psammomys obesus gerbils.

Lipids Health Dis 2020 Jun 3;19(1):123. Epub 2020 Jun 3.

Laboratory of Physiology and Pharmacology, Faculty of Medicine, Université Libre de Bruxelles, 808, Lennik Road, 1070, Brussels, Belgium.

Background: In metabolic disorders, myocardial fatty infiltration is critically associated with lipotoxic cardiomyopathy.

Methods: Twenty Psammomys obesus gerbils were randomly assigned to normal plant or high fat diet. Sixteen weeks later, myocardium was sampled for pathobiological evaluation.

Results: A sixteen-week high fat diet resulted in myocardial structure disorganization, with collagen deposits, lipid accumulation, cardiomyocyte apoptosis and inflammatory cell infiltration. Myocardial expressions of glucose transporter GLUT1 and pyruvate dehydrogenase (PDH) inhibitor, PDH kinase (PDK)4 increased, while insulin-regulated GLUT4 expression remained unchanged. Myocardial expressions of molecules regulating fatty acid transport, CD36 and fatty acid binding protein (FABP)3, were increased, while expression of rate-controlling fatty acid β-oxidation, carnitine palmitoyl transferase (CPT)1B decreased. Myocardial expression of AMP-activated protein kinase (AMPK), decreased, while expression of peroxisome proliferator activated receptors (PPAR)-α and -γ did not change.

Conclusion: In high fat diet fed Psammomys obesus, an original experimental model of nutritionally induced metabolic syndrome mixing genetic predisposition and environment interactions, a short period of high fat feeding was sufficient to induce myocardial structural alterations, associated with altered myocardial metabolic gene expression in favor of lipid accumulation.
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http://dx.doi.org/10.1186/s12944-020-01301-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271448PMC
June 2020

Identifying potential parameters associated with response to switching from a PDE5i to riociguat in RESPITE.

Int J Cardiol 2020 Oct 24;317:188-192. Epub 2020 May 24.

Clinic for Respiratory Medicine, Hannover Medical School, member of the German Center for Lung Research (DZL), Hannover, Germany.

Background: RESPITE evaluated patients with pulmonary arterial hypertension and an inadequate response to phosphodiesterase type 5 inhibitors (PDE5i) who switched to riociguat. This post hoc analysis assessed response to this switch in parameters associated with clinical improvement.

Methods: RESPITE was a 24-week, uncontrolled pilot study (n = 61). Differences in functional, hemodynamic, and cardiac function parameters, REVEAL risk score (RRS), and biomarkers were compared between responders (free from clinical worsening, World Health Organization functional class I/II, and ≥30 m improvement in 6-min walking distance at Week 24) and non-responders.

Results: Of 51 patients (84%) completing RESPITE, 16 (31%) met the responder endpoint. At baseline, there were significant differences between responders and non-responders in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), growth/differentiation factor 15 (GDF-15), and RRS, whereas there were no differences in hemodynamics or cardiac function. At Week 24, responders had significant improvements in pulmonary arterial compliance, pulmonary vascular resistance, and mean pulmonary arterial pressure, while non-responders showed no significant change. Cardiac efficiency and stroke volume index significantly improved irrespective of responder status.

Conclusions: NT-proBNP, GDF-15, and RRS were identified as potential predictors of response in patients switching from PDE5i to riociguat. Further prospective controlled studies are needed to confirm the association of these parameters with response.
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http://dx.doi.org/10.1016/j.ijcard.2020.05.044DOI Listing
October 2020

Exercise stress echocardiography of the pulmonary circulation and right ventricular-arterial coupling in healthy adolescents.

Eur Heart J Cardiovasc Imaging 2021 05;22(6):688-694

Faculty of Motor Sciences, Cardio-Pulmonary Exercise Laboratory, Université Libre de Bruxelles, Erasmus Campus CP 604, 808 Lennik Road, 1070 Brussels, Belgium.

Aims: To explore the effects of age and sex in adolescents vs. young or middle-aged adults on pulmonary vascular function and right ventricular-arterial (RV-PA) coupling as assessed by exercise stress echocardiography.

Methods And Results: Forty healthy adolescents aged 12-15 years were compared with 40 young adults aged 17-22 years and 40 middle-aged adults aged 30-50 years. Sex distribution was equal in the three groups. All the subjects underwent an exercise stress echocardiography. A pulmonary vascular distensibility coefficient α was determined from multipoint pulmonary vascular pressure-flow relationships. RV-PA coupling was assessed by the tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (PASP) ratio, who has been previously validated by invasive study. While cardiac index and mean PAP were not different, adolescents compared to young and middle-aged adults, respectively had higher pulmonary vascular distensibility coefficients α (1.60 ± 0.31%/mmHg vs. 1.39 ± 0.29%/mmHg vs. 1.20 ± 0.35%/mmHg, P < 0.00001). Adolescents and young adults compared to middle-aged adults, respectively had higher TAPSE/PASP ratios at rest (1.24 ± 0.18 mm/mmHg and 1.22 ± 0.17 mm/mmHg vs. 1.07 ± 0.18 mm/mmHg, P < 0.008) and during exercise (0.86 ± 0.24, 0.80 ± 0.15 and 0.72 ± 0.15 mm/mmHg, P < 0.04). The TAPSE/PASP ratio decreased with exercise. There were no sex differences in α or TAPSE/PASP.

Conclusion: Compared to adults, adolescents present with a sex-independent more distensible pulmonary circulation. Resting and exercise RV-PA coupling is decreased in middle-aged adults.
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http://dx.doi.org/10.1093/ehjci/jeaa085DOI Listing
May 2021
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