Myocardial work across different etiologies of right ventricular dysfunction and healthy controls.

Evaluating right ventricular (RV) function remains a challenge. Recently, novel echocardiographic assessment of RV myocardial work (RVMW) by non-invasive pressure-strain loops was proposed. This enables evaluation of right ventriculoarterial coupling and quantifies RV dyssynchrony and post-systolic shortening. We aimed to assess RVMW in patients with different etiologies of RV dysfunction and healthy controls. We investigated healthy controls (n=17), patients with severe functional tricuspid regurgitation (FTR; n=22), and patients with precapillary pulmonary hypertension (PCPH; n=20). Echocardiography and right heart catheterization were performed to assess 1) RV global constructive work (RVGCW; work needed for systolic myocardial shortening and isovolumic relaxation), 2) RV global wasted work (RVGWW; myocardial shortening following pulmonic valve closure), and 3) RV global work efficiency (RVGWE; describes the relation between RV constructive and wasted work). RVGCW correlated with invasive RV stroke work index (r=0.66, P<0.001) and increased in tandem with higher afterload, i.e., was low in healthy controls (454±73 mmHg%), moderate in patients with FTR (687±203 mmHg%), and highest among patients with PCPH (881±255 mmHg%). RVGWE was lower and RVGWW was higher in patients with FTR (86±8% and 91 mmHg% [53-140]) or PCPH (86±10% and 110 mmHg% [66-159]) as compared with healthy controls (96±3% and 10 mmHg%). RVMW by echocardiography provides a promising index of RV function to discriminate between patients with RV volume or pressure overload. The prognostic value of this measure needs to be settled in future studies.

Biomarkers of collagen turnover and wound healing in chronic thromboembolic pulmonary hypertension patients before and after pulmonary endarterectomy.

BACKGROUND: In chronic thromboembolic pulmonary hypertension (CTEPH), fibrotic remodeling of tissue and thrombi contributes to disease progression. Removal of the thromboembolic mass by pulmonary endarterectomy (PEA) improves hemodynamics and right ventricular function, but the roles of different collagens before as well as after PEA are not well understood. METHODS: In this study, hemodynamics and 15 different biomarkers of collagen turnover and wound healing were evaluated in 40 CTEPH patients at diagnosis (baseline) and 6 and 18 months after PEA. Baseline biomarker levels were compared with a historical cohort of 40 healthy subjects. RESULTS: Biomarkers of collagen turnover and wound healing were increased in CTEPH patients compared with healthy controls, including a 35-fold increase in the PRO-C4 marker of type IV collagen formation and a 55-fold increase in the C3M marker of type III collagen degradation. PEA reduced pulmonary pressures to almost normal levels 6 months after the procedure, with no further improvement at 18 months. There were no changes in any of the measured biomarkers after PEA. CONCLUSIONS: Biomarkers of collagen formation and degradation are increased in CTEPH suggesting a high collagen turnover. While PEA effectively reduces pulmonary pressures, collagen turnover is not significantly modified by surgical PEA.

Hemodynamic Effects of Ketone Bodies in Patients With Pulmonary Hypertension.

Background Pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) are debilitating diseases with a high mortality. Despite emerging treatments, pulmonary vascular resistance frequently remains elevated. However, the ketone body 3-hydroxybutyrate (3-OHB) may reduce pulmonary vascular resistance in these patients. Hence, the aim was to assess the hemodynamic effects of 3-OHB in patients with PAH or CTEPH. Methods and Results We enrolled patients with PAH (n=10) or CTEPH (n=10) and residual pulmonary hypertension. They received 3-OHB infusion and placebo (saline) for 2 hours in a randomized crossover study. Invasive hemodynamic and echocardiography measurements were performed. Furthermore, we investigated the effects of 3-OHB on the right ventricle of isolated hearts and isolated pulmonary arteries from Sprague-Dawley rats. Ketone body infusion increased circulating 3-OHB levels from 0.5±0.5 to 3.4±0.7 mmol/L (P<0.001). Cardiac output improved by 1.2±0.1 L/min (27±3%, P<0.001), and right ventricular annular systolic velocity increased by 1.4±0.4 cm/s (13±4%, P=0.002). Pulmonary vascular resistance decreased by 1.3±0.3 Wood units (18%±4%, P<0.001) with no significant difference in response between patients with PAH and CTEPH. In the rat studies, 3-OHB administration was associated with decreased pulmonary arterial tension compared with saline administration (maximal relative tension difference: 12±2%, P<0.001) and had no effect on right ventricular systolic pressures (P=0.63), whereas pressures rose at a slower pace (dP/dtmax, P=0.02). Conclusions In patients with PAH or CTEPH, ketone body infusion improves cardiac output and decreases pulmonary vascular resistance. Experimental rat studies support that ketone bodies relax pulmonary arteries. Long-term studies are warranted to assess the clinical role of hyperketonemia. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04615754.

Long-Term Prognostic Impact of Pulmonary Hypertension After Venous Thromboembolism.

Pulmonary embolism is a risk factor for chronic thromboembolic pulmonary hypertension (CTEPH), but the prognostic impact of CTEPH on venous thromboembolism (VTE) mortality remains unclear. We examined the impact of CTEPH and other pulmonary hypertension (PH) subtypes on long-term mortality after VTE. We conducted a nationwide, population-based cohort study of all adult Danish patients alive 2 years after incident VTE without previous PH from 1995 to 2020 (n = 129,040). We used inverse probability of treatment weights in a Cox model to calculate standardized mortality rate ratios (SMRs) of the association between receiving a first-time PH diagnosis ≤2 years after incident VTE and mortality (all-cause, cardiovascular, and cancer). We grouped PH as PH associated with left-sided cardiac disease (group II), PH associated with lung diseases and/or hypoxia (group III), CTEPH (group IV), and unclassified (remaining patients). Total follow-up was 858,954 years. The SMR associated with PH overall was 1.99 (95% confidence interval 1.75 to 2.27) for all-cause, 2.48 (1.90 to 3.23) for cardiovascular, and 0.84 (0.60 to 1.17) for cancer mortality. The SMR for all-cause mortality was 2.62 (1.77 to 3.88) for group II, 3.98 (2.85 to 5.56) for group III, 1.88 (1.11 to 3.20) for group IV, and 1.73 (1.47 to 2.04) for unclassified PH. The cardiovascular mortality rate was increased approximately threefold for groups II and III but was not increased for group IV. Only group III was associated with increased cancer mortality. In conclusion, PH diagnosed ≤2 years after incident VTE was associated with an overall twofold increased long-term mortality driven by cardiovascular causes.

Association of residual pulmonary hypertension with survival after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.

This study investigated whether residual pulmonary hypertension (PH), defined as early postoperative mean pulmonary artery pressure (mPAP) of ≥30 mmHg, after undergoing pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) was associated with long-term survival. All patients who underwent PEA for CTEPH at two Scandinavian centers were included in this study. Baseline characteristics and vital statuses were obtained from patient charts and national health-data registers. The patients were then categorized based on residual PH measured via right heart catheterization within 48 h after undergoing PEA. Crude and weighted flexible parametric survival models were used to estimate the association between residual PH and all-cause mortality and to quantify absolute survival differences. From 1992 to 2020, 444 patients underwent surgery. We excluded 6 patients who died on the day of surgery and 12 patients whose early postoperative pulmonary hemodynamic data was unavailable. Of the total study population (n = 426), 174 (41%) and 252 (59%) patients had an early postoperative mPAP <30 and ≥30 mmHg, respectively. After weighting, there was a significant association between residual PH and all-cause mortality (hazard ratio: 2.49; 95% confidence interval [CI]: 1.60-3.87), and the absolute survival difference between the groups at 10 and 20 years was -22% (95% CI: -32% to -12%) and-32% (95% CI: -47% to -18%), respectively. A strong and clinically relevant association of residual PH with long-term survival after PEA for CTEPH was found. After accounting for differences in baseline characteristics, the absolute survival difference at long-term follow-up was clinically meaningful and imply careful surveillance to improve clinical outcomes in these patients. Early postoperative right heart catheter measurements of mPAP seem to be helpful for prognostication following PEA for CTEPH.

Impaired left and right systolic ventricular capacity in corrected atrial septal defect patients.

Resting right ventricular (RV) systolic function has in some studies been shown to be impaired after correction of an atrial septal defect (ASD) whereas impairment of left ventricular (LV) systolic function is uncertain. In the present study we examine the LV and RV systolic response to exercise in patients with a previously corrected ASD in order to investigate the myocardial capacity. Thirty-six adult ASD patients with a corrected isolated secundum ASD and eighteen adult age-matched controls underent a semi-supine exercise stress echocardiographic examination. At rest, LV parameters were comparable between groups, and RV global longitudinal strain (RV-GLS) was lower for the ASD group (-18.5%, 95% CI -20.0--17.0%) compared with controls (-24.5%, 95% CI -27.7--22.4%, p < 0.001). At peak exercise, LV ejection fraction (LVEF) was lower for ASD patients (61%, 95% CI 58-65%) compared with controls (68%, 95% CI 64-73% p = 0.01). Peak LV global longitudinal strain (LV-GLS) was borderline significantly lower (ASD: -18.4%, 95% CI -20.2--16.6%, controls: -21.3%, 95% CI -23.6--19.0%, p = 0.059). Both RVEF (ASD: 64%, 95% CI 60-68%, controls: 73%, 95% CI 65-80%, p = 0.05) and tricuspid annular plane systolic excursion (TAPSE) (ASD: 2.5 cm, 95% CI 2.3-2.7 cm, controls: 3.2 cm, 95% CI 2.9-3.6 cm, p < 0.001) at peak exercise were lower for ASD patients. Exercise assessed peak oxygen uptake was comparable between groups (ASD: 32.8 mL O2/kg/min, 95% CI 30.3-35.5 mL O2/kg/min, controls: 35.2 mL O2/kg/min, 95% CI 31.6-38.8 mL O2/kg/min, p = 0.3). Corrected ASD patients demonstrate a reduced LV and RV systolic exercise response decades after ASD correction whereas resting parameters of LV and RV systolic function were within normal range. The presence of subclinical systolic myocardial dysfunction during exercise might be associated with the long-term morbidities documented in this patient group.

Sex and survival following pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension: a Scandinavian observational cohort study.

Studies have suggested sex-related survival differences in chronic thromboembolic pulmonary hypertension (CTEPH). Whether long-term prognosis differs between men and women following pulmonary endarterectomy for CTEPH remains unclear. We investigated sex-specific survival after pulmonary endarterectomy for CTEPH. We included all patients who underwent pulmonary endarterectomy for CTEPH at two Scandinavian centers and obtained baseline characteristics and vital statuses from patient charts and national health-data registers. Propensity scores and weighting were used to account for baseline differences. Flexible parametric survival models were employed to estimate the association between sex and all-cause mortality and the absolute survival differences. The expected survival in an age-, sex-, and year of surgery matched general population was obtained from the Human Mortality Database, and the relative survival was used to estimate cause-specific mortality. A total of 444 patients were included, comprising 260 (59%) men and 184 (41%) women. Unadjusted 30-day mortality was 4.2% in men versus 9.8% in women (p = 0.020). In weighted analyses, long-term survival did not differ significantly in women compared with men (hazard ratio: 1.36; 95% confidence interval: 0.89-2.06). Relative survival at 15 years conditional on 30-day survival was 94% (79%-107%) in men versus 75% (59%-88%) in women. In patients who underwent pulmonary endarterectomy for CTEPH, early mortality was higher in women compared with men. After adjustment for differences in baseline characteristics, female sex was not associated with long-term survival. However, relative survival analyses suggested that the observed survival in men was close to the expected survival in the matched general population, whereas survival in women deviated notably from the matched general population.

Limited value of pulse wave analysis in assessing arterial wave reflection and stiffness in the pulmonary artery.

We explored the use of the augmentation index (AI) based on pulse wave analysis (PWA) in the pulmonary circulation as a measure of wave reflection and arterial stiffness in individuals with and without pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Right heart catheterization was performed using a pressure and Doppler flow sensor-tipped catheter to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery in 10 controls, 11 PAH patients, and 11 CTEPH patients. PWA was applied to the measured pressure, while wave intensity analysis (WIA) and wave separation analysis (WSA) were performed using both the pressure and velocity to determine the magnitudes and timings of reflected waves. Type C (AI < 0) pressure waveform dominated in controls and type A (AI > 12%) waveform dominated in PAH patients, while there was a mixture of types A, B, and C among CTEPH patients. AI was greater and the inflection time shorter in CTEPH compared to PAH patients. There was a poor correlation between AI and arterial wave speed as well as measures of wave reflection derived from WIA and WSA. The infection point did not match the timing of the backward compression wave in ~50% of the cases. In patients with type C waveforms, the inflection time correlated well to the timing of the late systolic forward decompression wave caused by ventricular relaxation. In conclusion quantifying pulmonary arterial wave reflection and stiffness using AI based on PWA may be inaccurate and should therefore be discouraged.

Reverse remodeling of tricuspid valve morphology and function in chronic thromboembolic pulmonary hypertension patients following pulmonary thromboendarterectomy: a cardiac magnetic resonance imaging and invasive hemodynamic study.

BACKGROUND: To investigate changes in tricuspid annulus (TA) and tricuspid valve (TV) morphology among chronic thromboembolic pulmonary hypertension (CTEPH) patients before and 12 months after pulmonary thromboendarterectomy (PEA) and compare these findings to normal control subjects. METHODS: 20 CTEPH patients and 20 controls were enrolled in the study. The patients were examined with echocardiography, right heart catherization and cardiac magnetic resonance imaging prior to PEA and 12 months after. RESULTS: Right atrium (RA) volume was significantly reduced from baseline to 12 months after PEA (30 ± 9 vs 23 ± 5 ml/m2, p < 0.005). TA annular area in systole remained unchanged (p = 0.11) and was comparable to controls. The leaflet area, tenting volume and tenting height in systole were significantly increased at baseline but decreased significantly with comparable values to controls after 12 months (p < 0.005). There was correlation between the changes of right ventricular-pulmonary artery coupling and changes of TV tenting height (r = - 0.54, p = 0.02), TV tenting volume (r = - 0.73, p < 0.001) and TV leaflet area (- 0.57, p = 0.01) from baseline to 12 months after PEA. Tricuspid regurgitation jet area/RA area was significantly (p < 0.01) reduced from baseline (30 ± 13%) to 12 months after PEA (9 ± 10%). CONCLUSION: In CTEPH patients selected for PEA, TV tenting height, volume and valve area are significantly increased whereas annulus size and shape are less affected. The alterations in TV morphology are fully reversed after PEA and correlates to improvements of right ventricular-pulmonary arterial coupling.

Elevated Left and Right Atrial Pressures Long-Term After Atrial Septal Defect Correction: An Invasive Exercise Hemodynamic Study.

Background Despite correction of the atrial septal defect (ASD), patients experience atrial fibrillation frequently and have increased morbidity and mortality. We examined physical capacity, cardiac performance, and invasive hemodynamics in patients with corrected ASD. Methods and Results Thirty-eight corrected patients with isolated secundum ASD and 19 age-matched healthy controls underwent right heart catheterization at rest and during exercise with simultaneous expired gas assessment and echocardiography. Maximum oxygen uptake was comparable between groups (ASD 32.7±7.7 mL O2/kg per minute, controls 35.2±7.5 mL O2/kg per minute, P=0.3), as was cardiac index at both rest and peak exercise. In contrast, pulmonary artery wedge v wave pressures were increased at rest and peak exercise (rest: ASD 14±4 mm Hg, controls 10±5 mm Hg, P=0.01; peak: ASD 25±9 mm Hg, controls 14±9 mm Hg, P=0.0001). The right atrial v wave pressures were increased at rest but not at peak exercise. The transmural filling pressure gradient (TMFP) was higher at peak exercise among patients with ASD (10±6 mm Hg, controls 7±3 mm Hg, P=0.03). One third of patients with ASD demonstrated an abnormal hemodynamic exercise response defined as mean pulmonary artery wedge pressure ≥25 mm Hg and/or mean pulmonary artery pressure ≥35 mm Hg at peak exercise. These patients had significantly elevated peak right and left atrial a wave pressures, right atrial v wave pressures, pulmonary artery wedge v wave pressures, and transmural filling pressure compared with both controls and patients with ASD with a normal exercise response. Conclusions Patients with corrected ASD present with elevated right and in particular left atrial pressures at rest and during exercise despite preserved peak exercise capacity. Abnormal atrial compliance and systolic atrial function could predispose to the increased long-term risk of atrial fibrillation. Registration Information clinicaltrials.gov. Identifier: NCT03565471.

A systematic approach to weaning from extracorporeal membrane oxygenation in patients with refractory cardiac failure.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is commonly used to provide haemodynamic support for patients with severe cardiac failure. However, timing ECMO weaning remains challenging. We aimed to examine if an integrative weaning approach based on predefined haemodynamic, respiratory and echocardiographic criteria is associated with successful weaning. METHODS: All patients weaned from ECMO between April 2017 and April 2019 at Aarhus University Hospital, Denmark, were consecutively enrolled. Predefined haemodynamic, respiratory and echocardiographic criteria were assessed before and during ECMO flow reduction. A weaning attempt was commenced in haemodynamic stable patients and patients remaining stable at minimal flow were weaned from ECMO. Comparisons were made between patients who met the criteria for weaning at first attempt and patients who did not meet these criteria. Patients completing a full weaning attempt with no further need for mechanical support within 24 h were defined as successfully weaned. RESULTS: A total of 38 patients were included in the study, of whom 26 (68%) patients met the criteria for weaning. Among these patients, 25 (96%) could be successfully weaned. Successfully weaned patients were younger and had less need for inotropic support and ECMO duration was shorter. Fulfilling the weaning criteria was associated with successful weaning and both favourable 30-d survival and survival to discharge. CONCLUSION: An integrative weaning approach based on haemodynamic, respiratory and echocardiographic criteria may strengthen the clinical decision process in predicting successful weaning in patients receiving ECMO for refractory cardiac failure.

Pulmonary vasodilation by sildenafil in acute intermediate-high risk pulmonary embolism: a randomized explorative trial.

BACKGROUND: To investigate if acute pulmonary vasodilation by sildenafil improves right ventricular function in patients with acute intermediate-high risk pulmonary embolism (PE). METHODS: Single center, explorative trial. Patients with PE were randomized to a single oral dose of sildenafil 50 mg (n = 10) or placebo (n = 10) as add-on to conventional therapy. The time from hospital admission to study inclusion was 2.3 ± 0.7 days. Right ventricular function was evaluated immediately before and shortly after (0.5-1.5 h) randomization by right heart catheterization (RHC), trans-thoracic echocardiography (TTE), and cardiac magnetic resonance (CMR). The primary efficacy endpoint was cardiac index measured by CMR. RESULTS: Patients had acute intermediate-high risk PE verified by computed tomography pulmonary angiography, systolic blood pressure of 135 ± 18 (mean ± SD) mmHg, increased right ventricular/left ventricular ratio 1.1 ± 0.09 and increased troponin T 167 ± 144 ng/L. Sildenafil treatment did not improve cardiac index compared to baseline (0.02 ± 0.36 l/min/m2, p = 0.89) and neither did placebo (0.00 ± 0.34 l/min/m2, p = 0.97). Sildenafil lowered mean arterial blood pressure (- 19 ± 10 mmHg, p < 0.001) which was not observed in the placebo group (0 ± 9 mmHg, p = 0.97). CONCLUSION: A single oral dose of sildenafil 50 mg did not improve cardiac index but lowered systemic blood pressure in patients with acute intermediate-high risk PE. The time from PE to intervention, a small patient sample size and low pulmonary vascular resistance are limitations of this study that should be considered when interpreting the results. TRIAL REGISTRATION: The trial was retrospectively registered at www.clinicaltrials.gov (NCT04283240) February 2nd 2020, https://clinicaltrials.gov/ct2/show/NCT04283240?term=NCT04283240&draw=2&rank=1 .

The DANish randomized, double-blind, placebo controlled trial in patients with chronic HEART failure (DANHEART): A 2 × 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic heart failure (H-HeFT) and metformin in patients with chronic heart failure and diabetes or prediabetes (Met-HeFT).

OBJECTIVES: The DANHEART trial is a multicenter, randomized (1:1), parallel-group, double-blind, placebo-controlled study in chronic heart failure patients with reduced ejection fraction (HFrEF). This investigator driven study will include 1500 HFrEF patients and test in a 2 × 2 factorial design: 1) if hydralazine-isosorbide dinitrate reduces the incidence of death and hospitalization with worsening heart failure vs. placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs. placebo in patients with diabetes or prediabetes (Met-HeFT). METHODS: Symptomatic, optimally treated HFrEF patients with LVEF ≤40% are randomized to active vs. placebo treatment. Patients can be randomized in either both H-HeFT and Met-HeFT or to only one of these study arms. In this event-driven study, it is anticipated that 1300 patients should be included in H-HeFT and 1100 in Met-HeFT and followed for an average of 4 years. RESULTS: As of May 2020, 296 patients have been randomized at 20 centers in Denmark. CONCLUSION: The H-HeFT and Met-HeFT studies will yield new knowledge about the potential benefit and safety of 2 commonly prescribed drugs with limited randomized data in patients with HFrEF.

Long-term changes of exercise hemodynamics and physical capacity in chronic thromboembolic pulmonary hypertension after pulmonary thromboendarterectomy.

BACKGROUND: A substantial number of chronic thromboembolic pulmonary hypertension (CTEPH) patients experience dyspnea on exertion and limited exercise capacity despite surgically successful pulmonary endarterectomy (PEA). We sought to prospectively evaluate resting and peak exercise hemodynamics before, 3 and 12 months after PEA in consecutive CTEPH-patients and correlate it to physical functional capacity. METHODS AND RESULTS: Twenty consecutive CTEPH-patients were examined. Twelve months after PEA, 75% of patients with severely increased pre-PEA mean pulmonary arterial pressure (mPAP) at rest had normal or mildly increased mPAP. However, mPAP reduction was less pronounced during exercise where only 45% had normal or mildly increased mPAP at 12 months. Hemodynamic changes during exercise were tested using the pressure-flow relationship (i.e. mPAP/cardiac output (CO) slope). The average mPAP/CO slope was 7.5 ± 4.2 mm Hg/L/min preoperatively and 3.9 ± 3.0 mm Hg/L/min at 12 months (p < .005). CO reserve (CO increase from rest to peak exercise) was increased (5.7 ± 2.9 L/min) 12 months after PEA compared with pre-PEA (2.5 ± 1.8 L/min), p < .0001. However, 12 months after PEA, the CO reserve was only 49% of that of healthy controls, p < .0001. Changes in cardiac output (∆CO), calculated as the difference between CO before PEA and 12 months later, were significantly correlated with six-minute-walk-test and peak oxygen uptake (VO2), both at rest and peak exercise. CONCLUSION: Invasive exercise hemodynamic examination in CTEPH-patients demonstrates that after otherwise successful PEA surgery, >50% of patients have a significant increase in exercise mPAP, and the CO reserve remains compromised 12 months after PEA. Improvement in physical capacity is correlated with ∆CO.

Long-term changes of right ventricular myocardial deformation and remodeling studied by cardiac magnetic resonance imaging in patients with chronic thromboembolic pulmonary hypertension following pulmonary thromboendarterectomy.

BACKGROUND: Right ventricular (RV) afterload in patients with chronic thromboembolic pulmonary hypertension (CTEPH) is associated with reduced myocardial contractility and ventriculoarterial coupling. The impact of increased afterload on RV myocardial deformation was assessed by comparing the characteristics of CTEPH patients to healthy controls at baseline, and by comparing characteristics of CTEPH patients before and 12 months after pulmonary endarterectomy (PEA). METHODS: Cardiac deformation and function of CTEPH patients (n = 20) and healthy controls (n = 20) were assessed by cardiac magnetic resonance (CMR). CTEPH patients were also examined with right heart catheterization before and 12 months after PEA. RESULTS: PEA resulted in significant improvement of invasive hemodynamics and normalization of RV hypertrophy and right atrial, RV and left ventricular dimensions and volumes. RV ejection fraction improved from 30 ±â€¯13% at baseline to 44 ±â€¯10% at 12 months (p < 0.0001) but remained decreased compared with control subjects (54 ±â€¯4%, p < 0.05). RV global circumferential strain (GCS) normalized 12 months after PEA, but RV global longitudinal strain (GLS) remained significantly lower in CTEPH patients than controls (baseline -12.9 ±â€¯3.3% vs. -16.5 ±â€¯3.6% at 12 months p < 0.01, vs. controls -19.3 ±â€¯3.2%, p < 0.05). RV mass changes were significantly correlated with RV-ejection fraction, RV-GLS, and RV-GCS. RV-pulmonary arterial coupling with the volume method improved at 12 months (0.49 ±â€¯0.30 vs. 0.84 ±â€¯0.31, p < 0.0005), but remained significantly reduced compared with healthy controls (1.19 ±â€¯0.20, p < 0.0005). CONCLUSION: RV global longitudinal and circumferential myocardial three-dimensional strain by CMR improved significantly in CTEPH patients 12 months after PEA. Improvements in myocardial deformation were associated with regression of RV hypertrophy and decrease in pulmonary artery pressure.

Long-term changes of resting and exercise right ventricular systolic performance in patients with chronic thromboembolic pulmonary hypertension following pulmonary thromboendarterectomy - A two-dimensional and three-dimensional echocardiographic study.

AIMS: To characterize right ventricular (RV) geometry and function in chronic thromboembolic pulmonary hypertension (CTEPH) patients at rest and during exercise before pulmonary thromboendarterectomy (PEA), and at 3 and 12 months after PEA using two-dimensional and three-dimensional echocardiography with reference to clinical performance and exercise capacity. METHODS AND RESULTS: Forty subjects (20 CTEPH patients and 20 controls) were enrolled between December 2014 and January 2017. Three-dimensional echocardiography demonstrated a significant reduction and normalization of end-diastolic and end-systolic RV volumes in CTEPH patients 12 months after PEA. RV systolic function improved after PEA; however, tricuspid annular plane systolic excursion (TAPSE) (baseline 18 ± 6 mm vs 15 ± 3 mm at 12 months after PEA, P < .05) and tricuspid lateral annular systolic velocity (RV-S') (baseline -8.3 ± 2.1 cm/s vs -7.2 ± 1.3 cm/s at 12 months after PEA, P < .05) declined significantly after PEA. Tricuspid regurgitation gradient was 64 ± 21 mm Hg at baseline, 40 ± 14 mm Hg at 3 months, and 30 ± 13 at 12 months, P < .00001. RV free-wall longitudinal strain at peak exercise was significantly increased from baseline (-10.6 ± 5.5%) to 12 months of follow-up (-15.8 ± 5.2%), P < .005. Physical exercise capacity, measured as peak oxygen uptake, was significantly increased and correlated directly with improvement of resting and exercise-induced RV-EF. CONCLUSION: Improvement of RV geometry and systolic function, along with the reduction of systolic pulmonary pressure, can be expected following PEA in CTEPH patients during long-term follow-up. Improvement of RV myocardial contractility after PEA was only revealed at peak exercise over time. Importantly, physical exercise capacity was significantly increased and was found to be directly correlated with improvement of resting and exercise-induced RV-EF.

Impact of pulmonary endarterectomy on pulmonary arterial wave propagation and reservoir function.

High wave speed and large wave reflection in the pulmonary artery have previously been reported in patients with chronic thromboembolic pulmonary hypertension (CTEPH). We assessed the impact of pulmonary endarterectomy (PEA) on pulmonary arterial wave propagation and reservoir function in patients with CTEPH. Right heart catheterization was performed using a combined pressure and Doppler flow sensor-tipped guidewire to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery in eight patients with CTEPH before and 3 mo after PEA. Wave intensity and reservoir-excess pressure analyses were then performed. Following PEA, mean pulmonary arterial pressure (PAPm; ∼49 vs. ∼32 mmHg), pulmonary vascular resistance (PVR; ∼11.1 vs. ∼5.1 Wood units), and wave speed (∼16.5 vs. ∼8.1 m/s), i.e., local arterial stiffness, markedly decreased. The changes in the intensity of the reflected arterial wave and wave reflection index (pre: ∼28%; post: ∼22%) were small, and patients post-PEA with and without residual pulmonary hypertension (i.e., PAPm ≥ 25 mmHg) had similar wave reflection index (∼20 vs. ∼23%). The reservoir and excess pressure decreased post-PEA, and the changes were associated with improved right ventricular afterload, function, and size. In conclusion, although PVR and arterial stiffness decreased substantially following PEA, large wave reflection persisted, even in patients without residual pulmonary hypertension, indicating lack of improvement in vascular impedance mismatch. This may continue to affect the optimal ventriculoarterial interaction, and further studies are warranted to determine whether this contributes to persistent symptoms in some patients.NEW & NOTEWORTHY We performed wave intensity analysis in the pulmonary artery in patients with chronic thromboembolic pulmonary hypertension before and 3 mo after pulmonary endarterectomy. Despite substantial reduction in pulmonary arterial pressures, vascular resistance, and arterial stiffness, large pulmonary arterial wave reflection persisted 3 mo postsurgery, even in patients without residual pulmonary hypertension, suggestive of lack of improvement in vascular impedance mismatch.

Prognostic value of exercise myocardial deformation and haemodynamics in long-term heart-transplanted patients.

AIMS: The study evaluated exercise left ventricular global longitudinal strain (LVGLS) and invasive haemodynamics for major adverse cardiac events (MACE) prediction in heart-transplanted (HTx) patients. METHODS AND RESULTS: The study comprised 74 stable consecutive HTx patients who were followed at the Department of Cardiology, Aarhus University Hospital, Denmark, from August 2013 to January 2017. All patients were transplanted a minimum of 12 months before study entry and were included at the time of their routine annual coronary angiography. A symptom-limited haemodynamic exercise test with simultaneous echocardiographic study was performed. The primary endpoint was MACE during follow-up defined as heart failure hospitalization, treated rejection episodes, coronary event, or cardiac death. The median time since transplant was 5 years [1:12] and the median follow-up was 1095 days [391;1506]. Thirty patients (41%) experienced MACE during follow-up. Patients who suffered MACE had an impaired resting and peak exercise systolic function in form of a lower LV ejection fraction (Rest: 56 ± 12% vs. 65 ± 7%, P < 0.001; Peak 64 ± 13% vs. 72 ± 6%, P < 0.01) and LVGLS (Rest: 13 ± 4% vs. 16 ± 2%, P < 0.01; Peak: 15 ± 6% vs. 20 ± 4%, P = 0.0001) than patients without MACE episodes. In contrast, resting diastolic filling patterns were comparable between patients suffering from MACE and patients without MACE. At rest, pulmonary capillary wedge pressure (mPCWP) and cardiac index did not predict MACE, whereas increased right atrial pressure (mRAP) was associated with increased MACE risk. Patients with peak exercise mPCWP >23 mmHg [hazard ratio (HR) 2.5, 95% confidence interval (CI): 1.2-5.4], cardiac index <5.9 L/min/m2 (HR 2.7, 95% CI: 1.0-6.3), or mRAP >13 mmHg (HR 2.7, 95% CI: 1.1-6.3) had increased MACE risk. Patients with exercise-induced LVGLS increase <3.5% and peak exercise cardiac index <5.9 L/min/m2 [HR 6.1 (95% CI: 2.2-17.1)] or mPCWP >23 mmHg [HR 6.1 (95% CI: 2.1-17.5)] or mRAP >13 mmHg [HR 7.5 (95% CI: 2.3-23.9)] had the highest MACE risk. CONCLUSIONS: Resting haemodynamic parameters were poor MACE predictors in long-term HTx patients. In contrast, peak exercise mPCWP, mRAP, and CI were significant MACE predictors. LVGLS both at rest and during exercise were significant MACE predictors, and the combined model with peak exercise LVGLS and peak exercise mPCWP, mRAP, and CI clearly identified high-risk HTx patients in relation cardiovascular endpoints independently of time since HTx.

Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients.

BACKGROUND: Myocardial utilization of 3-hydroxybutyrate (3-OHB) is increased in patients with heart failure and reduced ejection fraction (HFrEF). However, the cardiovascular effects of increased circulating plasma-3-OHB levels in these patients are unknown. Consequently, the authors' aim was to modulate circulating 3-OHB levels in HFrEF patients and evaluate: (1) changes in cardiac output (CO); (2) a potential dose-response relationship between 3-OHB levels and CO; (3) the impact on myocardial external energy efficiency (MEE) and oxygen consumption (MVO2); and (4) whether the cardiovascular response differed between HFrEF patients and age-matched volunteers. METHODS: Study 1: 16 chronic HFrEF patients (left ventricular ejection fraction: 37±3%) were randomized in a crossover design to 3-hour of 3-OHB or placebo infusion. Patients were monitored invasively with a Swan-Ganz catheter and with echocardiography. Study 2: In a dose-response study, 8 HFrEF patients were examined at increasing 3-OHB infusion rates. Study 3 to 4: 10 HFrEF patients and 10 age-matched volunteers were randomized in a crossover design to 3-hour 3-OHB or placebo infusion. MEE and MVO2 were evaluated using 11C-acetate positron emission tomography. RESULTS: 3-OHB infusion increased circulating levels of plasma 3-OHB from 0.4±0.3 to 3.3±0.4 mM ( P<0.001). CO rose by 2.0±0.2 L/min ( P<0.001) because of an increase in stroke volume of 20±2 mL ( P<0.001) and heart rate of 7±2 beats per minute (bpm) ( P<0.001). Left ventricular ejection fraction increased 8±1% ( P<0.001) numerically. There was a dose-response relationship with a significant CO increase of 0.3 L/min already at plasma-3-OHB levels of 0.7 mM ( P<0.001). 3-OHB increased MVO2 without altering MEE. The response to 3-OHB infusion in terms of MEE and CO did not differ between HFrEF patents and age-matched volunteers. CONCLUSIONS: 3-OHB has beneficial hemodynamic effects in HFrEF patients without impairing MEE. These beneficial effects are detectable in the physiological concentration range of circulating 3-OHB levels. The hemodynamic effects of 3-OHB were observed in both HFrEF patients and age-matched volunteers. 3-OHB may potentially constitute a novel treatment principle in HFrEF patients.

Wave Intensity Analysis Provides Novel Insights Into Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: In contrast to systemic hypertension, the significance of arterial waves in pulmonary hypertension (PH) is not well understood. We hypothesized that arterial wave energy and wave reflection are augmented in PH and that wave behavior differs between patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS AND RESULTS: Right heart catheterization was performed using a pressure and Doppler flow sensor-tipped catheter to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery. Wave intensity analysis was subsequently applied to the acquired data. Ten control participants, 11 patients with PAH, and 10 patients with CTEPH were studied. Wave speed and wave power were significantly greater in PH patients compared with controls, indicating increased arterial stiffness and right ventricular work, respectively. The ratio of wave power to mean right ventricular power was lower in PAH patients than CTEPH patients and controls. Wave reflection index in PH patients (PAH: ≈25%; CTEPH: ≈30%) was significantly greater compared with controls (≈4%), indicating downstream vascular impedance mismatch. Although wave speed was significantly correlated to disease severity, wave reflection indexes of patients with mildly and severely elevated pulmonary pressures were similar. CONCLUSIONS: Wave reflection in the pulmonary artery increased in PH and was unrelated to severity, suggesting that vascular impedance mismatch occurs early in the development of pulmonary vascular disease. The lower wave power fraction in PAH compared with CTEPH indicates differences in the intrinsic and/or extrinsic ventricular load between the 2 diseases.