Atrial Shunt Device Effects on Cardiac Structure and Function in Heart Failure With Preserved Ejection Fraction: The REDUCE LAP-HF II Randomized Clinical Trial.

Importance: Although the results of A Study to Evaluate the Corvia Medical Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF II) trial were neutral overall, atrial shunt therapy demonstrated potential efficacy in responders (no latent pulmonary vascular disease and no cardiac rhythm management device). Post hoc analyses were conducted to evaluate the effect of shunt vs sham stratified by responder status. Objective: To evaluate the effect of atrial shunt vs sham control on cardiac structure/function in the overall study and stratified by responder status. Design, Setting, and Participants: This was a sham-controlled randomized clinical trial of an atrial shunt device in heart failure with preserved ejection fraction (HFpEF)/HF with mildly reduced EF (HFmrEF). Trial participants with evaluable echocardiography scans were recruited from 89 international medical centers. Data were analyzed from April 2023 to January 2024. Interventions: Atrial shunt device or sham control. Main Outcome Measures: Changes in echocardiographic measures from baseline to 1, 6, 12, and 24 months after index procedure. Results: The modified intention-to-treat analysis of the REDUCE LAP-HF II trial included 621 randomized patients (median [IQR] age, 72.0 [66.0-77.0] years; 382 female [61.5%]; shunt arm, 309 [49.8%]; sham control arm, 312 [50.2%]). Through 24 months, 212 of 217 patients (98%) in the shunt arm with evaluable echocardiograms had patent shunts. In the overall trial population, the shunt reduced left ventricular (LV) end-diastolic volume (mean difference, -5.65 mL; P <.001), left atrial (LA) minimal volume (mean difference, -2.8 mL; P =.01), and improved LV systolic tissue Doppler velocity (mean difference, 0.69 cm/s; P <.001) and LA emptying fraction (mean difference, 1.88 percentage units; P =.02) compared with sham. Shunt treatment also increased right ventricular (RV; mean difference, 9.58 mL; P <.001) and right atrial (RA; mean difference, 9.71 mL; P <.001) volumes but had no effect on RV systolic function, pulmonary artery pressure, or RA pressure compared with sham. In the shunt arm, responders had smaller increases in RV end-diastolic volume (mean difference, 5.71 mL vs 15.18 mL; interaction P =.01), RV end-systolic volume (mean difference, 1.58 mL vs 7.89 mL; interaction P =.002), and RV/LV ratio (mean difference, 0.07 vs 0.20; interaction P <.001) and larger increases in transmitral A wave velocity (mean difference, 5.08 cm/s vs -1.97 cm/s; interaction P =.02) compared with nonresponders randomized to the shunt, suggesting greater ability to accommodate shunted blood through the pulmonary circulation enabling LA unloading. Conclusions and Relevance: In this post hoc analysis of the REDUCE LAP-HF II trial, over 2 years of follow-up, atrial shunting led to reverse remodeling of left-sided chambers and increases in volume of right-sided chambers consistent with the shunt flow but no change in RV systolic function compared with sham. Changes in cardiac structure/function were more favorable in responders compared with nonresponders treated with the shunt, supporting the previously identified responder group hypothesis and mechanism, although further evaluation with longer follow-up is needed. Trial Registration: ClinicalTrials.gov Identifier: NCT03088033.

[Pulmonary hypertension associated with left heart disease (group 2)]. / Pulmonale Hypertonie assoziiert mit Linksherzerkrankungen (Gruppe 2).

Pulmonary hypertension associated with left heart disease (PH-LHD) corresponds to group two of pulmonary hypertension according to clinical classification. Haemodynamically, this group includes isolated post-capillary pulmonary hypertension (IpcPH) and combined post- and pre-capillary pulmonary hypertension (CpcPH). PH-LHD is defined by an mPAP > 20 mmHg and a PAWP > 15 mmHg, pulmonary vascular resistance (PVR) with a cut-off value of 2 Wood Units (WU) is used to differentiate between IpcPH and CpcPH. A PVR greater than 5 WU indicates a dominant precapillary component. PH-LHD is the most common form of pulmonary hypertension, the leading cause being left heart failure with preserved (HFpEF) or reduced ejection fraction (HFmrEF, HFrEF), valvular heart disease and, less commonly, congenital heart disease. The presence of pulmonary hypertension is associated with increased symptom burden and poorer outcome across the spectrum of left heart disease. Differentiating between group 1 pulmonary hypertension with cardiac comorbidities and PH-LHD, especially due to HFpEF, is a particular challenge. Therapeutically, no general recommendation for the use of PDE5 inhibitors in HFpEF-associated CpcPH can be made at this time. There is currently no reliable rationale for the use of PAH drugs in IpcPH, nor is therapy with endothelin receptor antagonists or prostacyclin analogues recommended for all forms of PH-LHD.

Echocardiographic pressure-strain loop-derived stroke work of the right ventricle: validation against the gold standard.

AIMS: Commercially available integrated software for echocardiographic measurement of stroke work (SW) is increasingly used for the right ventricle, despite a lack of validation. We sought to assess the validity of this method [echo-based myocardial work (MW) module] vs. gold-standard invasive right ventricular (RV) pressure-volume (PV) loops. METHODS AND RESULTS: From the prospectively recruiting EXERTION study (NCT04663217), we included 42 patients [34 patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) and 8 patients with absence of cardiopulmonary disease] with RV echocardiography and invasive PV catheterization. Echocardiographic SW was assessed as RV global work index (RVGWI) generated via the integrated pressure-strain MW software. Invasive SW was calculated as the area bounded by the PV loop. An additional parameter derived from the MW module, RV global wasted work (RVGWW), was correlated with PV loop measures. RVGWI significantly correlated with invasive PV loop-derived RV SW in the overall cohort [rho = 0.546 (P < 0.001)] and the PAH/CTEPH subgroup [rho = 0.568 (P < 0.001)]. Overall, RVGWW correlated with invasive measures of arterial elastance (Ea), the ratio of end-systolic elastance (Ees)/Ea, and end-diastolic elastance (Eed) significantly. CONCLUSIONS: Integrated echo measurement of pressure-strain loop-derived SW correlates with PV loop-based assessment of RV SW. Wasted work correlates with invasive measures of load-independent RV function. Given the methodological and anatomical challenges of RV work assessment, evolution of this approach by incorporating more elaborated echo analysis data and an RV reference curve might improve its reliability to mirror invasively assessed RV SW.

Native T2 Predicts Myocardial Inflammation Irrespective of a Patient's Volume Status.

Myocardial inflammation and edema are major pathological features in myocarditis. Myocardial tissue water content and myocardial edema can be quantified via T2 mapping. Thus, cardiac magnetic resonance (CMR) is the noninvasive gold standard for diagnosing myocarditis. Several studies showed an impact of short-term volume changes on T2 relaxation time. Plasma volume status (PVS) is a good surrogate parameter to quantify a patient's volume status, and it is simple to use. The aim of this study was to determine the effect of PVS on the diagnostic value of T2 relaxation time in myocardial inflammation. Between April 2017 and December 2022, patients who were indicated for cardiac CMR were included in our prospective clinical registry. Patients with myocardial inflammation and those with unremarkable findings were analyzed in the present study. A blood sample was drawn, and PVS was calculated. Patients were separated into PVS tertiles to explore a possible nonlinear dose-response relationship. Logistic regression analysis was used to determine whether T2 is an independent predictor of myocardial inflammation. A total of 700 patients (47.43% female) were eligible for analysis. Of these, 551 patients were healthy (78.7%), while 149 (21.3%) showed signs of myocardial inflammation. The T2 relaxation time was elevated in patients with myocardial inflammation (40 ms [IQR 37-42 ms] vs. 38.0 ms [IQR 36-39 ms], p < 0.001). PVS showed no difference between the groups (-12.94 [IQR -18.4--7.28] vs.-12.19 [IQR -18.93--5.87], p = 0.384). T2 showed a clear dose-response relationship with PVS, with increasing T2 values along the PVS tertiles. In spite of this, T2 was found to be an independent marker of myocardial inflammation in logistic regression (OR T2 1.3 [95% CI 1.21-1.39], p < 0.001), even after adjusting for PVS (OR T2 [adj. PVS] 1.31 [95% CI 1.22-1.40], p < 0.001). Despite a dose-response relationship between T2 and the volume status, T2 was found to be an independent indicator of myocardial inflammation.

Simple and safe digitoxin dosing in heart failure based on data from the DIGIT-HF trial.

BACKGROUND: The present study aimed to develop a simple dosing score when starting the cardiac glycoside digitoxin in heart failure with reduced ejection fraction (HFrEF) employing first data from the randomized, double-blinded DIGIT-HF trial. METHODS AND RESULTS: In DIGIT-HF, digitoxin was started with a dose of 0.07 mg once daily (o.d.) in all patients. For score derivation, 317 patients were analyzed who had been randomized to digitoxin. In these patients, after scheduled determination of serum levels at study week 6, the digitoxin dose had remained unchanged or had been reduced to 0.05 mg o.d. (97% of patients) to achieve serum concentrations within a predefined range (10.5-23.6 nmol/l). In logistic regression analyses, sex, age, body mass index (BMI), and estimated glomerular filtration rate (eGFR) were associated with need for dose reduction and, therefore, selected for further developing the dosing score. Optimal cut-points were derived from ROC curve analyses. Finally, female sex, age ≥ 75 years, eGFR < 50 ml/min/1.73 m2, and BMI < 27 kg/m2 each were assigned one point for the digitoxin dosing score. A score of ≥ 1 indicated the need for dose reduction with sensitivity/specificity of 81.6%/49.7%, respectively. Accuracy was confirmed in a validation data set including 64 patients randomized to digitoxin yielding sensitivity/specificity of 87.5%/37.5%, respectively. CONCLUSION: In patients with HFrEF, treatment with digitoxin should be started at 0.05 mg o.d. in subjects with either female sex, eGFR < 50 ml/min/1.73m2, BMI < 27 kg/m2, or age ≥ 75 years. In any other patient, digitoxin may be safely started at 0.07 mg o.d.

Regional extracellular volume within late gadolinium enhancement-positive myocardium to differentiate cardiac sarcoidosis from myocarditis of other etiology: a cardiovascular magnetic resonance study.

BACKGROUND: Cardiovascular magnetic resonance (CMR) plays a pivotal role in diagnosing myocardial inflammation. In addition to late gadolinium enhancement (LGE), native T1 and T2 mapping as well as extracellular volume (ECV) are essential tools for tissue characterization. However, the differentiation of cardiac sarcoidosis (CS) from myocarditis of other etiology can be challenging. Positron-emission tomography-computed tomography (PET-CT) regularly shows the highest Fluordesoxyglucose (FDG) uptake in LGE positive regions. It was therefore the aim of this study to investigate, whether native T1, T2, and ECV measurements within LGE regions can improve the differentiation of CS and myocarditis compared with using global native T1, T2, and ECV values alone. METHODS: PET/CT confirmed CS patients and myocarditis patients (both acute and chronic) from a prospective registry were compared with respect to regional native T1, T2, and ECV. Acute and chronic myocarditis were defined based on the 2013 European Society of Cardiology position paper on myocarditis. All parametric measures and ECV were acquired in standard fashion on three short-axis slices according to the ConSept study for global values and within PET-CT positive regions of LGE. RESULTS: Between 2017 and 2020, 33 patients with CS and 73 chronic and 35 acute myocarditis patients were identified. The mean ECV (± SD) in LGE regions of CS patients was higher than in myocarditis patients (CS vs. acute and chronic, respectively: 0.65 ± 0.12 vs. 0.45 ± 0.13 and 0.47 ± 0.1; p < 0.001). Acute and chronic myocarditis patients had higher global native T1 values (1157 ± 54 ms vs. 1196 ± 63 ms vs. 1215 ± 74 ms; p = 0.001). There was no difference in global T2 and ECV values between CS and acute or chronic myocarditis patients. CONCLUSION: This is the first study to show that the calculation of regional ECV within LGE-positive regions may help to differentiate CS from myocarditis. Further studies are warranted to corroborate these findings.

Hemodynamic markers of pulmonary vasculopathy for prediction of early right heart failure and mortality after heart transplantation.

BACKGROUND: Elevated pulmonary vascular resistance (PVR) is broadly accepted as an imminent risk factor for mortality after heart transplantation (HTx). However, no current HTx recipient risk score includes PVR or other hemodynamic parameters. This study examined the utility of various hemodynamic parameters for risk stratification in a contemporary HTx population. METHODS: Patients from seven German HTx centers undergoing HTx between 2011 and 2015 were included retrospectively. Established risk factors and complete hemodynamic datasets before HTx were analyzed. Outcome measures were overall all-cause mortality, 12-month mortality, and right heart failure (RHF) after HTx. RESULTS: The final analysis included 333 patients (28% female) with a median age of 54 (IQR 46-60) years. The median mean pulmonary artery pressure was 30 (IQR 23-38) mm Hg, transpulmonary gradient 8 (IQR 5-10) mm Hg, and PVR 2.1 (IQR 1.5-2.9) Wood units. Overall mortality was 35.7%, 12-month mortality was 23.7%, and the incidence of early RHF was 22.8%, which was significantly associated with overall mortality (log-rank HR 4.11, 95% CI 2.47-6.84; log-rank p < .0001). Pulmonary arterial elastance (Ea) was associated with overall mortality (HR 1.74, 95% CI 1.25-2.30; p < .001) independent of other non-hemodynamic risk factors. Ea values below a calculated cutoff represented a significantly reduced mortality risk (HR 0.38, 95% CI 0.19-0.76; p < .0001). PVR with the established cutoff of 3.0 WU was not significant. Ea was also significantly associated with 12-month mortality and RHF. CONCLUSIONS: Ea showed a strong impact on post-transplant mortality and RHF and should become part of the routine hemodynamic evaluation in HTx candidates.

Exercise MR-proANP unmasks latent right heart failure in CTEPH.

OBJECTIVE: The present study was designed to investigate the dynamics of right atrial pressure (RAP) and mid-regional pro-atrial natriuretic peptide (MR-proANP) during physical exercise in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and to determine whether these parameters might serve as a tool to measure exercise-dependent atrial stress as an indicator of right heart failure. METHODS: This prospective observational cohort study included 100 CTEPH patients who underwent right heart catheterization during physical exercise (eRHC). Blood samples for MR-proANP measurement were taken prior, during, and after eRHC. MR-proANP levels were correlated to RAP levels at rest, at peak exercise (eRAP), and during recovery. RAP at rest ≤7 mmHg was defined as normal and eRAP >15 mmHg as suggestive of right heart failure. RESULTS: During eRHC mean RAP increased from 6 mmHg (standard deviation, SD 4) to 16 mmHg (SD 7; p < 0.001). MR-proANP levels and dynamics correlated with RAP at rest (rs = 0.61; p < 0.001) and at peak exercise (rs = 0.66; p < 0.001). Logistic regression analysis revealed the peak MR-proANP level (B = 0.058; p = 0.004) and the right atrial area (B = 0.389; p < 0.001) to be associated with eRAP dynamics. A peak MR-proANP level ≥139 pmol/L (AUC = 0.81) and recovery level ≥159 pmol/L (AUC = 0.82) predicted an eRAP >15 mmHg. Physical exercise unmasked right heart failure in 39% of patients with normal RAP at rest; these patients were also characterized by a more distinct increase in MR-proANP levels (p = 0.005) and higher peak (p < 0.001) and recovery levels (p < 0.001). CONCLUSIONS: RAP and MR-proANP dynamics unmask manifest and latent right heart failure in CTEPH patients.

[Implantation of mechanical circulatory support systems and heart transplantation in patients with end-stage heart failure : Consensus paper of the DGK, DGTHG]. / Implantation mechanischer Unterstützungssysteme und Herztransplantation bei Patienten mit terminaler Herzinsuffizienz : Konsensuspapier DGK, DGTHG.

The treatment of patients with advanced heart failure requires interdisciplinary care in a qualified heart failure team, especially prior to and in the follow-up of mechanical circulatory support (MCS) implantation and heart transplantation (HTx). The basic prerequisite is the early specialized evaluation of symptomatic patients even under optimized heart failure treatment. Diagnostics and treatment are initially aimed at improving the prognosis. If the prerequisites for MCS or HTx treatment are present, possible contraindications and problems have to be evaluated in order to achieve an optimal risk-benefit ratio for the abovementioned complex treatments with limited resources. The optimal treatment is still HTx if the conditions are right, so this should be sought in all potential patients. At the same time, the optimal individual transplantation window should not be missed. The provision of a MCS system is a treatment performed with very good results for patients with exclusion criteria for HTx or with hemodynamic instability that prevents a longer waiting time for a donor organ. Short-term and medium-term survival is now comparable to HTx when carefully indicated. Timely implantation before the onset of manifest end-organ damage is crucial. Optimized implementation of advanced treatment requires professional structures that enable effective interdisciplinary cooperation between different sectors of health care.

CILP1 as a biomarker for right ventricular dysfunction in patients with ischemic cardiomyopathy.

The aim of this study was to evaluate the cartilage intermediate layer protein 1 (CILP1) as a biomarker of right ventricular dysfunction in patients with ischemic cardiomyopathy (ICM). CILP1 plasma concentrations were measured in 98 patients with ICM and 30 controls without any cardiac abnormalities. All participants underwent cardiac magnetic resonance imaging. Median CILP1 concentrations were higher in ICM than in controls. In the tertile analysis, low right ventricular ejection fraction (RVEF) and high right ventricular end-systolic volume index and N-terminal pro-brain natriuretic peptide (NT-proBNP) were associated with higher CILP1 levels in ICM. However, there were no associations between CILP1 concentrations and left ventricular (LV) parameters in this group. In receiver-operating characteristic (ROC) analysis CILP1 was a good predictor of RVEF < 40% with an optimal cut-off value of 3545 pg/ml in ICM, whereas it was not predictive of LV ejection fraction (LVEF) < 40% (area under the curve [AUC] = 0.57) There was no significant difference between the ROC curves of CILP1 (AUC = 0.72) and NT-proBNP (AUC = 0.77) for RVEF < 40% (p = 0.42). In multivariable regression analysis, RVEF was the only independent predictor of elevated CILP1. CILP1 and LVEF were the only independent predictors of RVEF < 40% in ICM. Our analysis demonstrates the potential role of CILP1 as a novel cardiac biomarker of prognostically relevant RV dysfunction in patients with ICM.

Prognostic Power of Pulmonary Arterial Compliance Is Boosted by a Hemodynamic Unloading Test With Glyceryl Trinitrate in Heart Failure Patients With Post-capillary Pulmonary Hypertension.

Background: Pulmonary hypertension (PH) is an established risk factor in patients with heart failure (HF). However, right heart catheterisation (RHC) and vasoreactivity testing (VRT) are not routinely recommended in these patients. Methods: The primary objective of the present study was to explore the impact of VRT using sublingual glyceryl trinitrate (GTN) on transplant/ventricular assist device-free survival in HF patients with post-capillary PH. RHC parameters were correlated retrospectively with the primary outcome. Results: The cohort comprised 154 HF patients with post-capillary PH undergoing RHC with GTN-VRT at a tertiary heart failure centre. Multiple parameters were associated with survival. After adjustment for established prognosis-relevant clinical variables from the MAGGIC Score, variables with the most relevant odds ratios (OR) obtained after GTN-VRT were: calculated effective pulmonary arterial (PA) elastance (adjusted OR 2.26, 95%CI 1.30-3.92; p = 0.004), PA compliance (PAC-GTN; adjusted OR 0.45, 95%CI 0.25-0.80; p = 0.006), and total pulmonary resistance (adjusted OR 2.29, 95%CI 1.34-3.93; p = 0.003). Forest plot analysis including these three variables as well as PAC at baseline, delta PAC, and the presence of combined post- and pre-capillary PH revealed prognostic superiority of PAC-GTN, which was confirmed by Kaplan-Meier analysis. Conclusions: In our cohort of symptomatic HF patients with post-capillary PH, improved PAC after administration of GTN was associated with survival independent of established hemodynamic and clinical risk factors. VRT using GTN may be better described as unloading test due to GTN's complex effects on the circulation. This could be used for advanced prognostication and should be investigated in further studies.

Latent Pulmonary Vascular Disease May Alter the Response to Therapeutic Atrial Shunt Device in Heart Failure.

BACKGROUND: In REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure), implantation of an atrial shunt device did not provide overall clinical benefit for patients with heart failure with preserved or mildly reduced ejection fraction. However, prespecified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial volume, and sex. Shunt implantation reduces left atrial pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). On the basis of these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit. METHODS: REDUCE LAP-HF II enrolled 626 patients with heart failure, ejection fraction ≥40%, exercise pulmonary capillary wedge pressure ≥25 mm Hg, and resting pulmonary vascular resistance <3.5 Wood units who were randomized 1:1 to atrial shunt device or sham control. The primary outcome-a hierarchical composite of cardiovascular death, nonfatal ischemic stroke, recurrent HF events, and change in health status-was analyzed using the win ratio. Latent PVD was defined as pulmonary vascular resistance ≥1.74 Wood units (highest tertile) at peak exercise, measured before randomization. RESULTS: Compared with patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated left atrial pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio, 0.60 [95% CI, 0.42, 0.86]; P=0.005) and signal of clinical benefit in patients without PVD (win ratio, 1.31 [95% CI, 1.02, 1.68]; P=0.038). Patients with larger right atrial volumes and men had worse outcomes with the device and both groups were more likely to have pacemakers, heart failure with mildly reduced ejection fraction, and increased left atrial volume. For patients without latent PVD or pacemaker (n=313; 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio, 1.51 [95% CI, 1.14, 2.00]; P=0.004). CONCLUSIONS: In patients with heart failure with preserved or mildly reduced ejection fraction, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit.

Unmasking right ventricular-arterial uncoupling during fluid challenge in pulmonary hypertension.

BACKGROUND: Patients with pulmonary hypertension (PH) frequently show preserved right ventricular (RV) function at rest. However, volume challenge may uncover pending RV dysfunction. We aimed to assess the physiological and prognostic impact of RV-pulmonary arterial (RV-PA) uncoupling during volume challenge in patients with precapillary PH. METHODS: We prospectively assessed 32 patients with PH (pulmonary arterial hypertension, n = 27; inoperable chronic thromboembolic disease, n = 5) and 4 controls using invasive pressure-volume (PV) catheterization. PV loops were recorded during preload reduction (balloon occlusion of inferior vena cava; baseline) and acute volume loading (200 ml saline in 20 s). Contractility (multi-beat end-systolic elastance [Ees]), arterial elastance (Ea), and RV-PA coupling (Ees/Ea) were obtained at baseline and at maximum volume loading (MVL). RESULTS: Median [interquartile range] time to MVL was 19 [18-22] s. Ees/Ea significantly declined from baseline (0.89 [0.69-1.23]) to MVL (0.16 [0.12-0.34]; p < 0.001) in patients with PH but remained stable in controls (baseline: 1.08 [0.94-1.80]; MVL: 1.01 [0.80-2.49]; p = 0.715). The same pattern was observed for Ees, while Ea remained unchanged. The percent decline of RV-PA coupling (ΔEes/Ea) during fluid challenge was significantly associated with pulmonary resting hemodynamics, RV ejection fraction (RVEF), and RV end-diastolic volume. Kaplan-Meier analysis revealed that patients with PH who had a smaller ΔEes/Ea (<-65%) had a significantly better prognosis (log-rank p = 0.0389). In multivariate Cox regression analysis, clinical worsening was predicted by ΔEes/Ea (hazard ratio: 0.96 [95% confidence interval: 0.93-1.00]) and RVEF (hazard ratio: 0.95 [95% confidence interval: 0.92-0.98]). CONCLUSIONS: Assessment of PV loops during fluid challenge uncovers exhausted RV coupling reserve with severely reduced contractility in PH. RV-PA uncoupling during volume challenge can be predicted by pulmonary resting hemodynamics and RVEF. RV-PA uncoupling during fluid challenge and RVEF (as a noninvasive correlate) are predictors of clinical worsening. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03403868 (January 19, 2018).

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

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.

Exercise hemodynamics in heart failure patients with preserved and mid-range ejection fraction: key role of the right heart.

OBJECTIVE: We sought to explore whether classification of patients with heart failure and mid-range (HFmrEF) or preserved ejection fraction (HFpEF) according to their left ventricular ejection fraction (LVEF) identifies differences in their exercise hemodynamic profile, and whether classification according to an index of right ventricular (RV) function improves differentiation. BACKGROUND: Patients with HFmrEF and HFpEF have hemodynamic compromise on exertion. The classification according to LVEF implies a key role of the left ventricle. However, RV involvement in exercise limitation is increasingly recognized. The tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure (TAPSE/PASP) ratio is an index of RV and pulmonary vascular function. Whether exercise hemodynamics differ more between HFmrEF and HFpEF than between TAPSE/PASP tertiles is unknown. METHODS: We analyzed 166 patients with HFpEF (LVEF ≥ 50%) or HFmrEF (LVEF 40-49%) who underwent basic diagnostics (laboratory testing, echocardiography at rest, and cardiopulmonary exercise testing [CPET]) and exercise with right heart catheterization. Hemodynamics were compared according to echocardiographic left ventricular or RV function. RESULTS: Exercise hemodynamics (e.g. pulmonary arterial wedge pressure/cardiac output [CO] slope, CO increase during exercise, and maximum total pulmonary resistance) showed no difference between HFpEF and HFmrEF, but significantly differed across TAPSE/PASP tertiles and were associated with CPET results. N-terminal pro-brain natriuretic peptide concentration also differed significantly across TAPSE/PASP tertiles but not between HFpEF and HFmrEF. CONCLUSION: In patients with HFpEF or HFmrEF, TAPSE/PASP emerged as a more appropriate stratification parameter than LVEF to predict clinically relevant impairment of exercise hemodynamics. Stratification of exercise hemodynamics in patients with HFpEF or HFmrEF according to LVEF or TAPSE/PASP, showing significant distinctions only with the RV-based strategy. All data are shown as median [upper limit of interquartile range] and were calculated using the independent-samples Mann-Whitney U test or Kruskal-Wallis test. PVR pulmonary vascular resistance; max maximum level during exercise.

Application and Validation of the Tricuspid Annular Plane Systolic Excursion/Systolic Pulmonary Artery Pressure Ratio in Patients with Ischemic and Non-Ischemic Cardiomyopathy.

The main aim of this study was to assess the prognostic utility of TAPSE/PASP as an echocardiographic parameter of maladaptive RV remodeling in cardiomyopathy patients using cardiac magnetic resonance (CMR) imaging. Furthermore, we sought to compare TAPSE/PASP to TAPSE. The association of the echocardiographic parameters TAPSE/PASP and TAPSE with CMR parameters of RV and LV remodeling was evaluated in 111 patients with ischemic and non-ischemic cardiomyopathy and cut-off values for maladaptive RV remodeling were defined. In a second step, the prognostic value of TAPSE/PASP and its cut-off value were analyzed regarding mortality in a validation cohort consisting of 221 patients with ischemic and non-ischemic cardiomyopathy. A low TAPSE/PASP (<0.38 mm/mmHg) and TAPSE (<16 mm) were associated with a lower RVEF and a long-axis RV global longitudinal strain (GLS) as well as higher RVESVI, RVEDVI and NT-proBNP. A low TAPSE/PASP, but not TAPSE, was associated with a lower LVEF and long-axis LV GLS, and a higher LVESVI, LVEDVI and T1 relaxation time at the interventricular septum and the RV insertion points. Furthermore, in the validation cohort, low TAPSE/PASP was associated with a higher mortality and TAPSE/PASP was an independent predictor of mortality. TAPSE/PASP is a predictor of maladaptive RV and LV remodeling associated with poor outcomes in cardiomyopathy patients.

Predictive value of overt and non-overt volume overload in patients with high- or low-gradient aortic stenosis undergoing transcatheter aortic valve implantation.

BACKGROUND: The plasma volume status (PVS) is considered a marker of non-overt cardiac congestion and is of prognostic value. Patients with low-flow, low-gradient (LFLG) aortic stenosis (AS) suffer from impaired left ventricular function and show signs of heart failure (HF). We hypothesized that PVS might predict post-interventional rehospitalization and cardiovascular mortality in high-risk patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: In this retrospective, observational analysis, PVS before transfemoral TAVI was calculated by a formula taking into account hematocrit and weight. The predictive performance of PVS was compared with that of prior cardiac decompensation (PCD). RESULTS: In the entire cohort of n=2,458 patients, PVS >-4% (high plasma volume) identified patients (n=1,013) with a higher post-interventional 1-year mortality rate than patients (n=1,445) with a PVS ≤-4% (low plasma volume). However, PVS lost prognostic independence when adjusted for anemia, whereas PCD did not. A high PVS and PCD were not correlated, and both parameters similarly revealed a low sensitivity and specificity but a high negative predictive value (NPV) for future HF events. PVS was not different between control patients (n=1,512) and those with intermediate (paradoxical LFLG-AS, n=327) or high risk scores (LFLG-AS, n=239). The accuracy of high PVS in predicting adverse events in these subpopulations was the same as in the study population overall. Kaplan-Maier analyses demonstrated similar prognostic impacts for PVS and PCD. CONCLUSIONS: PVS and PCD represent two independent parameters of volume overload with unfavorable prognostic significance. Pre-interventional PVS does not appear to be suitable for predicting clinical outcomes in high-risk patients undergoing TAVI.

Hereditary transthyretin-related amyloidosis is frequent in polyneuropathy and cardiomyopathy of no obvious aetiology.

BACKGROUND: Hereditary Transthyretin-Related Amyloidosis, a clinically heterogeneous autosomal dominant disease caused by pathogenic variants in the TTR gene, is characterized by the deposition of insoluble misfolded protein fibrils. The diagnosis, especially in non-endemic areas, is typically delayed by 4-5 years; a misdiagnosis due to clinical heterogeneity is common. The study objective was to define the prevalence of Hereditary Transthyretin-Related Amyloidosis in patients with polyneuropathy and/or cardiomyopathy of no obvious aetiology. METHOD: A multicenter observational "Epidemiological analysis for the hereditary Transthyretin-Related AMyloidosis"-TRAM study was performed in Germany, Austria, and Switzerland. RESULTS: A total of 5141 participants were recruited by 50 neurologic and 27 cardiologic specialized centres. Genetic analysis demonstrated a 1.1% Hereditary Transthyretin-Related Amyloidosis positivity rate among patients with polyneuropathy and/or cardiomyopathy of not obvious aetiology. Twenty-one various TTR variants (TTR-positive) were identified. Body Mass Index was lower in the TTR-positive patients as an indicator for the involvement of the autonomic nervous system; the age of onset of clinical manifestations was higher in TTR-positive patients. There were no other genotype-phenotype correlations or the prevalence of specific clinical manifestations in TTR-positive patients. CONCLUSIONS: Our data support the fact that Hereditary Transthyretin-Related Amyloidosis is underdiagnosed in polyneuropathy and cardiomyopathy patients. Routine implementation of genetic testing is recommended in patients with unexplained polyneuropathy and/or cardiomyopathy to accelerate the earlier diagnosis and the time-sensitive treatment initiation.KEY MESSAGESMore than 5.000 participants with CM and/or PNP of no obvious aetiology were recruited in the observational "Epidemiological analysis for the hereditary Transthyretin-Related AMyloidosis" TRAM study and screened for pathogenic TTR variants.The study demonstrated >1% of patients with CM and/or PNP of unclear aetiology are positive for a pathogenic TTR variant.Routine genetic testing is recommended in patients with unexplained CM and/or PNP to accelerate the initial diagnosis and timely treatment initiation.

Exercise Hemodynamic Profiling Is Associated With Outcome in Patients Undergoing Percutaneous Mitral Valve Repair.

[Figure: see text].