A roadmap for therapeutic discovery in pulmonary hypertension associated with left heart failure. A scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Working Group on Pulmonary Circulation & Right Ventricular Function.

Pulmonary hypertension (PH) associated with left heart failure (LHF) (PH-LHF) is one of the most common causes of PH. It directly contributes to symptoms and reduced functional capacity and negatively affects right heart function, ultimately leading to a poor prognosis. There are no specific treatments for PH-LHF, despite the high number of drugs tested so far. This scientific document addresses the main knowledge gaps in PH-LHF with emphasis on pathophysiology and clinical trials. Key identified issues include better understanding of the role of pulmonary venous versus arteriolar remodelling, multidimensional phenotyping to recognize patient subgroups positioned to respond to different therapies, and conduct of rigorous pre-clinical studies combining small and large animal models. Advancements in these areas are expected to better inform the design of clinical trials and extend treatment options beyond those effective in pulmonary arterial hypertension. Enrichment strategies, endpoint assessments, and thorough haemodynamic studies, both at rest and during exercise, are proposed to play primary roles to optimize early-stage development of candidate therapies for PH-LHF.

Cardiopulmonary Exercise Testing in Evaluating Transthyretin Amyloidosis.

Importance: Cardiopulmonary exercise testing (CPET) has an established role in the assessment of patients with heart failure. However, data are lacking in patients with transthyretin (ATTR) amyloidosis. Objective: To use CPET to characterize the spectrum of functional phenotypes in patients with ATTR amyloidosis and assess their association with the cardiac amyloid burden as well as the association between CPET parameters and prognosis. Design, Setting and Participants: This single-center study evaluated patients diagnosed with ATTR amyloidosis from May 2019 to September 2022 who underwent CPET at the National Amyloidosis Centre. Of 1045 patients approached, 506 were included and completed the study. Patients were excluded if they had an absolute contraindication to CPET or declined participation. The mean (SD) follow-up period was 22.4 (11.6) months. Main Outcomes and Measures: Comparison of CPET parameters across disease phenotypes (ATTR with cardiomyopathy [ATTR-CM], polyneuropathy, or both [ATTR-mixed]), differences in CPET parameters based on degree of amyloid infiltration (as measured by cardiovascular magnetic resonance [CMR] with extracellular volume mapping), and association between CPET parameters and prognosis. Results: Among the 506 patients with ATTR amyloidosis included in this study, the mean (SD) age was 73.5 (10.2) years, and 457 participants (90.3%) were male. Impairment in functional capacity was highly prevalent. Functional impairment in ATTR-CM and ATTR-mixed phenotypes (peak mean [SD] oxygen consumption [VO2], 14.5 [4.3] mL/kg/min and 15.7 [6.2] mL/kg/min, respectively) was observed alongside impairment in the oxygen pulse, with ventilatory efficiency highest in ATTR-CM (mean [SD] ventilatory efficiency/volume of carbon dioxide expired slope, 38.1 [8.6]). Chronotropic incompetence and exercise oscillatory ventilation (EOV) were highly prevalent across all phenotypes, with both the prevalence and severity being higher than in heart failure from different etiologies. Worsening of amyloid burden on CMR was associated with decline in multiple CPET parameters, although chronotropic response and EOV remained abnormal irrespective of amyloid burden. On multivariable Cox regression analysis, peak VO2 and peak systolic blood pressure (SBP) were independently associated with prognosis (peak VO2: hazard ratio, 0.89 [95% CI, 0.81-0.99; P = .03]; peak SBP: hazard ratio, 0.98 [95% CI, 0.97-0.99; P < .001]). Conclusions and Relevance: In this study, ATTR amyloidosis was characterized by distinct patterns of functional impairment between all disease phenotypes. A high prevalence of chronotropic incompetence, EOV, and ventilatory inefficiency were characteristic of this population. CPET parameters were associated with amyloid burden by CMR and with peak VO2, and SBP, which have been shown to be independent predictors of mortality. These findings suggest that CPET may be useful in characterizing distinct patterns of functional impairment across the spectrum of amyloid infiltration and predicting outcomes, and potentially offers a more comprehensive method of evaluating functional capacity for future prospective studies.

Respiratory exchange ratio overshoot during exercise recovery: a promising prognostic marker in HFrEF.

BACKGROUND AND AIMS: Transient increases (overshoot) in respiratory gas analyses have been observed during exercise recovery, but their clinical significance is not clearly understood. An overshoot phenomenon of the respiratory exchange ratio (RER) is commonly observed during recovery from maximal cardiopulmonary exercise testing (CPET), but it has been found reduced in patients with heart failure with reduced ejection fraction (HFrEF). The aim of the study was to analyze the clinical significance of these RER recovery parameters and to understand if these may improve the risk stratification of patients with HFrEF. METHODS: This cross-sectional study includes HFrEF patients who underwent functional evaluation with maximal CPET for the heart transplant checklist at our Sports and Exercise Medicine Division. RER recovery parameters, including RER overshoot as the percentual increase of RER during recovery (RER mag), have been evaluated after CPET with assessment of hard clinical long-term endpoints (MACEs/deaths and transplant/LVAD-free survival). RESULTS: A total of 190 patients with HFrEF and 103 controls were included (54.6 ± 11.9 years; 73% male). RER recovery parameters were significantly lower in patients with HFrEF compared to healthy subjects (RER mag 24.8 ± 14.5% vs 31.4 ± 13.0%), and they showed significant correlations with prognostically relevant CPET parameters. Thirty-three patients with HFrEF did not present a RER overshoot, showing worse cardiorespiratory fitness and efficiency when compared with those patients who showed a detectable overshoot (VO2 peak: 11.0 ± 3.1 vs 15.9 ± 5.1 ml/kg/min; VE/VCO2 slope: 41.5 ± 8.7 vs 32.9 ± 7.9; ΔPETCO2: 2.75 ± 1.83 vs 4.45 ± 2.69 mmHg, respectively). The presence of RER overshoot was associated with a lower risk of cardiovascular events and longer transplant-free survival. CONCLUSION: RER overshoot represents a meaningful cardiorespiratory index to monitor during exercise gas exchange evaluation; it is an easily detectable parameter that could support clinicians to comprehensively interpreting patients' functional impairment and prognosis. CPET recovery analyses should be implemented in the clinical decision-making of advanced HF.

Left atrial strain in acute heart failure: clinical and prognostic insights.

AIMS: In acute heart failure (AHF), the consequences of impaired left atrial (LA) mechanics are not well understood. We aimed to define the clinical trajectory of LA mechanics by left atrial strain (LAS) analysis. METHODS AND RESULTS: Eighty-five consecutive AHF patients with reduced, mildly reduced, and preserved left ventricular ejection fraction (LVEF) were enrolled in the LAS-AHF trial and underwent LA mechanics analysis by speckle tracking echocardiography. Seventy-seven patients were followed-up (FU) at 6 and 12 months. At hospital admission, discharge, 6 and 12 months post-discharge, LA reservoir function (LAS), LA pump strain, LAVi, LA stiffness, indicators of right ventricular (RV) and left ventricular (LV) function, congestion indexes (B lines, inferior vena cava, X-ray congestion score index), and biomarkers (NT-pro-BNP) were measured. The primary outcome was time to first event of re-hospitalization, worsening HF, or cardiovascular death. From admission to discharge, RV function significantly improved after decongestion, whereas no significant differences were observed in LA dynamics and LV function. In sinus rhythm patients with mild or no mitral regurgitation, decongestion was associated with a significant improvement of LAS and LA pump strain rate during hospitalization. At 12 months, 24 CV events occurred and lack of LAS improvement at 12 months FU emerged as the most powerful predictor followed by NT-pro-BNP. Kaplan-Meier curves showed a better survival for LAS >16%, improvement of LAS > 5%, and an LAS/LAVi ratio >0.25%/mL/m2 compared with lower cut-off values [log-rank: heart rate (HR) 3.5, 95% confidence interval (CI) 1.8-7.3, P = 0.004; log-rank: HR 3.6, 95% CI 2-7.9, P < 0.01; log-rank: HR 3.27, 95% CI 1.4-7.7, P = 0.007]. CONCLUSION: In AHF of any LVEF, LA dynamics is highly predictive of re-hospitalization and cardiovascular outcome and allows to ease risk-stratification, potentially becoming an early reference target for improving long-term outcome.

Exercise Stress Echocardiography of the Right Ventricle and Pulmonary Circulation.

BACKGROUND: Exercise echocardiography is used for assessment of pulmonary circulation and right ventricular function, but limits of normal and disease-specific changes remain insufficiently established. OBJECTIVES: The objective of this study was to explore the physiological vs pathologic response of the right ventricle and pulmonary circulation to exercise. METHODS: A total of 2,228 subjects were enrolled: 375 healthy controls, 40 athletes, 516 patients with cardiovascular risk factors, 17 with pulmonary arterial hypertension, 872 with connective tissue diseases without overt pulmonary hypertension, 113 with left-sided heart disease, 30 with lung disease, and 265 with chronic exposure to high altitude. All subjects underwent resting and exercise echocardiography on a semirecumbent cycle ergometer. All-cause mortality was recorded at follow-up. RESULTS: The 5th and 95th percentile of the mean pulmonary artery pressure-cardiac output relationships were 0.2 to 3.5 mm Hg.min/L in healthy subjects without cardiovascular risk factors, and were increased in all patient categories and in high altitude residents. The 5th and 95th percentile of the tricuspid annular plane systolic excursion to systolic pulmonary artery pressure ratio at rest were 0.7 to 2.0 mm/mm Hg at rest and 0.5 to 1.5 mm/mm Hg at peak exercise, and were decreased at rest and exercise in all disease categories and in high-altitude residents. An increased all-cause mortality was predicted by a resting tricuspid annular plane systolic excursion to systolic pulmonary artery pressure <0.7 mm/mm Hg and mean pulmonary artery pressure-cardiac output >5 mm Hg.min/L. CONCLUSIONS: Exercise echocardiography of the pulmonary circulation and the right ventricle discloses prognostically relevant differences between healthy subjects, athletes, high-altitude residents, and patients with various cardio-respiratory conditions. (Right Heart International NETwork During Exercise in Different Clinical Conditions; NCT03041337).

Relationships, Current Issues, Safety and Efficacy of Oral Anticoagulation in Cancer Patients with Atrial Fibrillation.

A relationship between malignancy and impaired hemostasis has been proven, and balancing clotting and bleeding risks can be challenging. Half of cancer patients with atrial fibrillation (AF) do not receive any oral anticoagulation (OAC). Using PubMed on the relationship between cancer and AF and their association with hemostasis, targeting studies comparing vitamin K antagonists (VKAs) and direct OAC (DOAC) strategies in AF cancer patients, three RCTs (>3000 patients) and eight observational studies (>250,000 patients) comparing different OACs were retrieved. The VKA prescribed was always warfarin. Dabigatran was the only DOAC not analyzed in the RCTs but the most used in non-randomized studies, whereas edoxaban-treated patients were the majority in the RCTs. Overall, the DOAC patients showed similar or lower rates of efficacy (thromboembolic) and safety (bleeding) outcomes compared to the VKA patients. DOACs are subject to fewer interactions with antineoplastic agents. DOACs may be preferable to VKAs as a thromboembolic prophylaxis in cancer patients with non-valvular AF.

Phenotyping congestion in acute heart failure by renal flow and right heart to pulmonary circulation coupling.

AIMS: In acute heart failure (AHF), kidney congestion is basic to treatment and prognosis. Its aetiology is manifold and quite unexplored in details mainly regarding the right heart to pulmonary circulation (Pc) coupling. We investigated the right heart to kidney interrelationship by Doppler renal flow pattern, right atrial dynamics, and right ventricular (RV) function to Pc coupling in AHF. METHODS AND RESULTS: In 119 AHF patients, echocardiographic and renal Doppler data were analysed. Univariate and multivariate regression models were performed to define the determinants of a quantitative parameter of renal congestion, the renal venous stasis index (RVSI). When grouped according to different intra-renal venous flow patterns, no differences were observed in haemodynamics and baseline renal function. Nonetheless, patients with renal Doppler evidence of congestion showed a reduced RV function [tricuspid annular plane systolic excursion (TAPSE), S'-wave velocity, and fractional area change], impaired RV to Pc coupling [TAPSE/pulmonary artery systolic pressure (PASP) ratio], and right atrial peak longitudinal strain (RAPLS), along with signs of volume overload [increased inferior vena cava (IVC) diameters and estimated right atrial pressure]. Univariate and multivariate regression analyses confirmed TAPSE/PASP, RAPLS, and IVC diameter as independent determinants of the RVSI. RVSI was the only variable predicting the composite outcome (cardiac death, heart failure hospitalization, and haemodialysis). An easy-to-use echo-derived right heart score of four variables provided good accuracy in identifying kidney congestion. CONCLUSIONS: In AHF, the renal venous flow pattern combined with a right heart study phenotypes congestion and clinical evolution. Keys to renal flow disruption are an impaired right atrial dynamics and RV-Pc uncoupling. Integration of four right heart echocardiographic variables may be an effective tool for scoring the renal congestive phenotype in AHF.

Case Report: A rare homozygous patient affected by TTR systemic amyloidosis with a prominent heart involvement.

Hereditary transthyretin amyloidosis is a severe, adult-onset autosomal dominant inherited systemic disease predominantly affecting the peripheral and autonomic nervous system, heart, kidney, and the eyes. We present a case of a Caucasian 65-year-old man with cardiac amyloidosis and the homozygous mutation Val142Ile (classically, Val122Ile) in the transthyretin gene. We provide a genotype-phenotype correlation regarding the genetic status of both heterozygous and homozygous individuals and their clinical conditions at the time of genetic testing.

Heart failure patients with improved ejection fraction: Insights from the MECKI score database.

AIMS: Improvement of left ventricular ejection fraction is a major goal of heart failure (HF) treatment. However, data on clinical characteristics, exercise performance and prognosis in HF patients who improved ejection fraction (HFimpEF) are scarce. The study aimed to determine whether HFimpEF patients have a distinct clinical phenotype, biology and prognosis than HF patients with persistently reduced ejection fraction (pHFrEF). METHODS AND RESULTS: A total of 7948 patients enrolled in the Metabolic Exercise Cardiac Kidney Indexes (MECKI) score database were evaluated (median follow-up of 1490 days). We analysed clinical, laboratory, electrocardiographic, echocardiographic, exercise, and survival data from HFimpEF (n = 1504) and pHFrEF (n = 6017) patients. The primary endpoint of the study was the composite of cardiovascular death, left ventricular assist device implantation, and urgent heart transplantation. HFimpEF patients had lower HF severity: left ventricular ejection fraction 44.0 [41.0-47.0] versus 29.7 [24.1-34.5]%, B-type natriuretic peptide 122 [65-296] versus 373 [152-888] pg/ml, haemoglobin 13.5 [12.2-14.6] versus 13.7 [12.5-14.7] g/dl, renal function by the Modification of Diet in Renal Disease equation 72.0 [56.7-89.3] versus 70.4 [54.5-85.3] ml/min, peak oxygen uptake 62.2 [50.7-74.1] versus 52.6 [41.8-64.3]% predicted, minute ventilation-to-carbon dioxide output slope 30.0 [26.9-34.4] versus 32.1 [28.0-38.0] in HFimpEF and pHFrEF, respectively (p < 0.001 for all). Cardiovascular mortality rates were 26.6 and 46.9 per 1000 person-years for HFimpEF and pHFrEF, respectively (p < 0.001). Kaplan-Meier analysis showed that HFimpEF had better a long-term prognosis compared with pHFrEF patients. After adjustment for variables differentiating HFimpEF from pHFrEF, except echocardiographic parameters, the Kaplan-Meier curves showed the same prognosis. CONCLUSIONS: Heart failure with improved ejection fraction represents a peculiar group of HF patients whose clinical, laboratory, electrocardiographic, echocardiographic, and exercise characteristics parallel the recovery of systolic function. Nonetheless, these patients remain at risk for adverse outcome.

A new integrative approach combining right heart catheterization and echocardiography to stage aortic stenosis-related cardiac damage.

Introduction: Although staging of the extent of aortic stenosis (AS)-related cardiac damages is usually performed via echocardiography, this technique has considerable limitations in assessing pulmonary artery and right chamber pressures. The present hypothesis-generating study sought to explore the efficacy of a staging system of cardiac damage based on echocardiographic and invasive [right heart catheterization (RHC)] hemodynamic parameters in patients undergoing transcatheter aortic valve implantation (TAVI). Methods: We studied 90 symptomatic patients with severe AS in whom echocardiographic and invasive evaluation by RHC was obtained prior to TAVI. Cardiac damage stages were defined as follows: no cardiac damage (stage 0), left ventricular (LV) damage (stage 1), left atrial or mitral valve damage (stage 2), pulmonary vasculature or tricuspid valve damage (stage 3), and right ventricular (RV) dysfunction or low-flow state (stage 4). With the integrative approach using RHC, pulmonary hypertension (PH) was defined as an mPAP ≥25 mmHg and the low-flow state corresponded to a cardiac index of <1.8 L/min/m2 and a right atrial pressure of >10 mmHg. Results: During follow-up (median: 2.9 years), 43 patients (47.8%) died. The integrative cardiac damage staging was associated with a significant increase in all-cause and cardiovascular mortality per each increase of cardiac damage stage, whereas the outcome was similar according to the echocardiographic staging. Conclusions: A staging system of cardiac lesion based on echocardiographic and invasive hemodynamic parameters in patients with severe AS undergoing TAVI predicts mortality. Patients with pre-existing PH, ≥ moderate tricuspid regurgitation and/or RV dysfunction, and a low-flow state had a markedly increased risk of death. Further larger studies are needed to validate our findings.

Use and Implications of Echocardiography in the Hemodynamic Assessment of Cardiogenic Shock.

Cardiogenic shock (CS) is a complex multisystem syndrome due to pump failure, associated with high mortality and morbidity. Its hemodynamic characterization is key to the diagnostic algorithm and management. Pulmonary artery catheterization is the gold standard for the left and right hemodynamic evaluation, but some concerns exist for invasivity and untoward mechanical and infective complications. Transthoracic echocardiography is a robust noninvasive diagnostic tool for hemodynamic multiparametric assessment that well applies to the management of CS. Its applications expand from etiology definition to the choice of therapeutic intervention and their monitoring. The present review aims at detailing the role of ultrasounds in CS emphasizing the clinical implications of combining cardiac and non-cardiac ultrasounds examinations that may correlate with prognosis.

Pathophysiology of the right ventricle in health and disease: an update.

The contribution of the right ventricle (RV) to cardiac output is negligible in normal resting conditions when pressures in the pulmonary circulation are low. However, the RV becomes relevant in healthy subjects during exercise and definitely so in patients with increased pulmonary artery pressures both at rest and during exercise. The adaptation of RV function to loading rests basically on an increased contractility. This is assessed by RV end-systolic elastance (Ees) to match afterload assessed by arterial elastance (Ea). The system has reserve as the Ees/Ea ratio or its imaging surrogate ejection fraction has to decrease by more than half, before the RV undergoes an increase in dimensions with eventual increase in filling pressures and systemic congestion. RV-arterial uncoupling is accompanied by an increase in diastolic elastance. Measurements of RV systolic function but also of diastolic function predict outcome in any cause pulmonary hypertension and heart failure with or without preserved left ventricular ejection fraction. Pathobiological changes in the overloaded RV include a combination of myocardial fibre hypertrophy, fibrosis and capillary rarefaction, a titin phosphorylation-related displacement of myofibril tension-length relationships to higher pressures, a metabolic shift from mitochondrial free fatty acid oxidation to cytoplasmic glycolysis, toxic lipid accumulation, and activation of apoptotic and inflammatory signalling pathways. Treatment of RV failure rests on the relief of excessive loading.

Extracorporeal veno-venous ultrafiltration in congestive heart failure: What's the state of the art? A mini-review.

Hospitalizations for heart failure exceed 1 million per year in both the United States and Europe and more than 90% are due to symptoms and signs of fluid overload. Rates of rehospitalizations or emergency department visit at 60 days are remarkable regardless of whether loop diuretics were administered at low vs high doses or by bolus injection vs continuous infusion. Ultrafiltration (UF) has been considered a promising alternative to stepped diuretic therapy and it consists in the mechanical, adjustable removal of iso-tonic plasma water across a semipermeable membrane with the application of hydrostatic pressure gradient generated by a pump. Fluid removal with ultrafiltration presents several advantages such as elimination of higher amount of sodium with less neurohormonal activation. However, the conflicting results from UF studies highlight that patient selection and fluid removal targets are not completely understood. The best way to assess fluid status and therefore establish the fluid removal target is also still a matter of debate. Herein, we provide an up-to-date systematic review about the role of ultrafiltration among patients with fluid overload and its gaps in daily practice.

SARS-CoV-2 infection sequelae on exercise response: persistent or reversible? A 2-year perspective.

Post-COVID-19 exercise capacity sequalae on oxygen utilisation and ventilatory efficiency improve over time in most patients. Cardiopulmonary exercise testing is a valuable tool to identify those who may benefit from specific rehabilitative interventions. https://bit.ly/3qFd97x.