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.

[ANMCO/SIC Consensus statement on pulmonary arterial hypertension]. / Documento di consenso ANMCO/SIC sull'ipertensione arteriosa polmonare.

Pulmonary hypertension (PH) is a frequent pathological condition worldwide, mainly secondary to cardiovascular and respiratory diseases, with a poor prognosis. Pulmonary arterial hypertension (PAH) is a rare form that affects the arterial pulmonary vasculature. PH and PAH are characterized by non-specific symptoms and a progressive increase of pulmonary vascular resistance that results in progressive, sometimes irreversible, right ventricular dysfunction. In recent years, a growing medical and social commitment on this disease allowed more accurate diagnosis in shorter times. However, the gap between guidelines and clinical practice remains a challenge for all medical doctors involved in the disease management. Considering the needs to share and describe diagnostic and therapeutic pathways, to measure the results obtained and to address the economical and organizational problems of this disease, all involved figures should collaborate to improve its prognostic impact and health expenses. In this consensus document, the PH experts of the Italian Association of Hospital Cardiologists (ANMCO) together with those of the Italian Society of Cardiology (SIC), address 1) definition, classification and unmet needs of PH and PAH; 2) classification and characteristics of centers involved in the diagnosis and treatment of the disease; 3) proposal of organization of a diagnostic-therapeutic pathway, based on robust and recent scientific evidence.

Right Atrial Remodeling and Outcome in Patients with Secondary Tricuspid Regurgitation.

BACKGROUND: In patients with secondary tricuspid regurgitation (STR), right atrial remodeling (RAR) is a proven marker of disease progression. However, the prognostic value of RAR, assessed by indexed right atrial volume (RAVi) and reservoir strain (RAS), remains to be clarified. Accordingly, the aim of our study is to investigate the association with outcome of RAR in patients with STR. METHODS: We enrolled 397 patients (44% men, 72.7 ± 13 years old) with mild to severe STR. Complete two-dimensional and speckle-tracking echocardiography analysis of right atrial and right ventricular (RV) size and function were obtained in all patients. The primary end point was the composite of death from any cause and heart failure hospitalization. RESULTS: After a median follow-up of 15 months (interquartile range, 6-23), the end point was reached by 158 patients (39%). Patients with RAS <13% and RAVi >48 mL/m2 had significantly lower survival rates compared to patients with RAS ≥13% and RAVi ≤48 mL/m2 (log-rank P < .001). On multivariable analysis, RAS <13% (hazard ratio, 2.11; 95% CI, 1.43-3.11; P < .001) and RAVi > 48 mL/m2 (hazard ratio, 1.49; 95% CI, 1.01-2.18; P = .04) remained associated with the combined end point, even after adjusting for RV free-wall longitudinal strain, significant chronic kidney disease, and New York Heart Association class. Secondary tricuspid regurgitation excess mortality increased exponentially with values of 18.2% and 51.3 mL/m2 for RAS and RAVi, respectively. In nested models, the addition of RAS and RAVi provided incremental prognostic value over clinical, conventional echocardiographic parameters of RV size and function and RV free-wall longitudinal strain. CONCLUSIONS: In patients with STR, RAR was independently associated with mortality and heart failure hospitalization. Assessment of RAR could improve risk stratification of patients with STR, potentially identifying those who may benefit from optimization of medical therapy and a closer follow-up.

[Pulmonary hypertension associated with left heart diseases: pathophysiology, diagnosis, treatment]. / Ipertensione polmonare associata ad insufficienza cardiaca: fisiopatologia, diagnosi, terapia.

Pulmonary hypertension (PH) is a common complication of diseases affecting the left heart, mostly found in patients suffering from heart failure. Left atrial hypertension is the initial driver of post-capillary PH. However, several mechanisms may lead in a subset of patients to structural changes in the pulmonary vessels with development of a pre-capillary component. The right ventricle may be frequently affected, leading to right ventricular failure and a worse outcome. The differential diagnosis of PH associated with left heart disease vs pulmonary arterial hypertension (PAH) is challenging in patients with cardiovascular comorbidities, risk factors for PAH and/or a preserved left ventricular ejection fraction. Multidimensional clinical phenotyping is needed to identify patients in whom hemodynamic confirmation is deemed necessary, that may be completed by provocative testing in the cath lab. In contrast with PAH, management of PH associated with left heart disease should focus on the treatment of the underlying condition. There is currently no approved therapy for PH associated with left heart disease: some PAH-specific treatments have led to an increase in adverse events in these patients.

Exercise in hypoxia: a model from laboratory to on-field studies.

Clinical outcome and quality of life of patients with chronic heart failure (HF) have greatly improved over the last two decades. These results and the availability of modern lifts allow many cardiac patients to spend leisure time at altitude. Heart failure per se does not impede a safe stay at altitude, but exercise at both simulated and real altitudes is associated with a reduction in performance, which is inversely proportional to HF severity. For example, in normal subjects, the reduction in functional capacity is ∼2% every 1000 m altitude increase, whereas it is 4 and 10% in HF patients with normal or slightly diminished exercise capacity and in HF patients with markedly diminished exercise capacity, respectively. Also, the on-field experience with HF patients at altitude confirms safety and shows overall similar data to that reported at simulated altitude. Even 'optimal' HF treatment in patients spending time at altitude or at hypoxic conditions is likely different from optimal treatment at sea level, particularly with regard to the selectivity of ß-blockers. Furthermore, high altitude, both simulated and on-field, represents a stimulating model of hypoxia in HF patients and healthy subjects. Our data suggest that spending time at altitude (<3500 m) can be safe even for HF patients, provided that subjects are free from comorbidities that may directly interfere with the adaptation to altitude and are stable. However, HF patients experience a reduction of exercise capacity directly proportional to HF severity and altitude. Finally, HF patients should be tested for functional capacity and must undergo a specific 'hypoxic-tailored treatment' to avoid pharmacological interference with altitude adaptation mechanisms, particularly with regard to the selectivity of ß-blockers.

Pulmonary artery wedge pressure and left ventricular end-diastolic pressure during exercise in patients with dyspnoea.

Background: Pulmonary artery wedge pressure (PAWP) during exercise, as a surrogate for left ventricular (LV) end-diastolic pressure (EDP), is used to diagnose heart failure with preserved ejection fraction (HFpEF). However, LVEDP is the gold standard to assess LV filling, end-diastolic PAWP (PAWPED) is supposed to coincide with LVEDP and mean PAWP throughout the cardiac cycle (PAWPM) better reflects the haemodynamic load imposed on the pulmonary circulation. The objective of the present study was to determine precision and accuracy of PAWP estimates for LVEDP during exercise, as well as the rate of agreement between these measures. Methods: 46 individuals underwent simultaneous right and left heart catheterisation, at rest and during exercise, to confirm/exclude HFpEF. We evaluated: linear regression between LVEDP and PAWP, Bland-Altman graphs, and the rate of concordance of dichotomised LVEDP and PAWP ≥ or < diagnostic thresholds for HFpEF. Results: At peak exercise, PAWPM and LVEDP, as well as PAWPED and LVEDP, were fairly correlated (R2>0.69, p<0.01), with minimal bias (+2 and 0 mmHg respectively) but large limits of agreement (±11 mmHg). 89% of individuals had concordant PAWP and LVEDP ≥ or <25 mmHg (Cohen's κ=0.64). Individuals with either LVEDP or PAWPM ≥25 mmHg showed a PAWPM increase relative to cardiac output (CO) changes (PAWPM/CO slope) >2 mmHg·L-1·min-1. Conclusions: During exercise, PAWP is accurate but not precise for the estimation of LVEDP. Despite a good rate of concordance, these two measures might occasionally disagree.

Pulmonary Hypertension Associated with Left Heart Disease.

Pulmonary hypertension (PH) is a common complication of diseases affecting the left heart, mostly found in patients suffering from heart failure, with or without preserved left ventricular ejection fraction. Initially driven by a passive increase in left atrial pressure (postcapillary PH), several mechanisms may lead in a subset of patient to significant structural changes of the pulmonary vessels or a precapillary component. In addition, the right ventricle may be independently affected, which results in right ventricular to pulmonary artery uncoupling and right ventricular failure, all being associated with a worse outcome. The differential diagnosis of PH associated with left heart disease versus pulmonary arterial hypertension (PAH) is especially challenging in patients with cardiovascular comorbidities and/or heart failure with preserved ejection fraction (HFpEF). A stepwise approach to diagnosis is proposed, starting with a proper clinical multidimensional phenotyping to identify patients in whom hemodynamic confirmation is deemed necessary. Provocative testing (exercise testing, fluid loading, or simple leg raising) is useful in the cath laboratory to identify patients with abnormal response who are more likely to suffer from HFpEF. In contrast with group 1 PH, management of PH associated with left heart disease must focus on the treatment of the underlying condition. Some PAH-approved targets have been unsuccessfully tried in clinical studies in a heterogeneous group of patients, some even leading to an increase in adverse events. There is currently no approved therapy for PH associated with left heart disease.

Clinical Value of a Novel Three-Dimensional Echocardiography-Derived Index of Right Ventricle-Pulmonary Artery Coupling in Tricuspid Regurgitation.

BACKGROUND: Echocardiographic surrogates of right ventricle-to-pulmonary artery (RV-PA) coupling have been reported to be associated with outcomes in patients with secondary tricuspid regurgitation (STR). However, pulmonary artery systolic pressure (PASP) is difficult to estimate using echocardiography in patients with severe STR. The aim of the present study was to evaluate the predictive power of a surrogate of RV-PA coupling obtained using right ventricular (RV) volumes measured on three-dimensional echocardiography. METHODS: One hundred eight patients (mean age, 73 ± 13 years; 61% women) with moderate or severe STR were included. RESULTS: At a median follow-up of 24 months (interquartile range, 2-48 months), 72 patients (40%) had reached the composite end point of death of any cause and heart failure hospitalization. RV-PA coupling was computed as the ratio between RV forward stroke volume (SV) (i.e., RV SV - regurgitant volume) and RV end-systolic volume (ESV). RV forward SV/ESV was significantly more related to the composite end point than RV ejection fraction (area under the curve, 0.85 [95% CI, 0.78-0.93] vs 0.73 [95% CI, 0.64-0.83], respectively; P = .03). A value of 0.40 was found to best correlate with outcome. On multivariate Cox regression, RV forward SV/ESV, tricuspid annular plane systolic excursion/PASP, and RV free wall longitudinal strain/PASP were all independently associated with the occurrence of the composite end point when added to a group of parameters including STR severity (severe vs moderate), atrial fibrillation, pulmonary arterial hypertension, right atrial volume, RV end-diastolic volume, and RV free wall longitudinal strain. RV forward SV/ESV < 0.40 (HR, 3.36; 95% CI, 1.49-7.56; P < .01) carried higher related risk than RV free wall longitudinal strain/PASP < -0.42%/mm Hg (HR, 3.1; 95% CI, 1.26-7.84; P = .01) and tricuspid annular plane systolic excursion/PASP < 0.36 mm/mm Hg (HR, 2.69; 95% CI, 1.29-5.58; P = .01). RV ejection fraction did not correlate independently with prognosis when added to the same group of variables. CONCLUSIONS: RV forward SV/ESV is associated with the risk for death and heart failure hospitalization in patients with STR.

Haemodynamic validation of the three-step HFA-PEFF algorithm to diagnose heart failure with preserved ejection fraction.

AIMS: The HFA-PEFF algorithm (Heart Failure Association-Pre-test assessment, Echocardiography and natriuretic peptide score, Functional testing in cases of uncertainty, Final aetiology) is a three-step algorithm to diagnose heart failure with preserved ejection fraction (HFpEF). It provides a three-level likelihood of HFpEF: low (score < 2), intermediate (score 2-4), or high (score > 4). HFpEF may be confirmed in individuals with a score > 4 (rule-in approach). The second step of the algorithm is based on echocardiographic features and natriuretic peptide levels. The third step implements diastolic stress echocardiography (DSE) for controversial diagnostic cases. We sought to validate the three-step HFA-PEFF algorithm against a haemodynamic diagnosis of HFpEF based on rest and exercise right heart catheterization (RHC). METHODS AND RESULTS: Seventy-three individuals with exertional dyspnoea underwent a full diagnostic work-up following the HFA-PEFF algorithm, including DSE and rest/exercise RHC. The association between the HFA-PEFF score and a haemodynamic diagnosis of HFpEF, as well as the diagnostic performance of the HFA-PEFF algorithm vs. RHC, was assessed. The diagnostic performance of left atrial (LA) strain < 24.5% and LA strain/E/E' < 3% was also assessed. The probability of HFpEF was low/intermediate/high in 8%/52%/40% of individuals at the second step of the HFA-PEFF algorithm and 8%/49%/43% at the third step. After RHC, 89% of patients were diagnosed as HFpEF and 11% as non-cardiac dyspnoea. The HFA-PEFF score resulted associated with the invasive haemodynamic diagnosis of HFpEF (P < 0.001). Sensitivity and specificity of the HFA-PEFF score for the invasive haemodynamic diagnosis of HFpEF were 45% and 100% for the second step of the algorithm and 46% and 88% for the third step of the algorithm. Neither age, sex, body mass index, obesity, chronic obstructive pulmonary disease, or paroxysmal atrial fibrillation influenced the performance of the HFA-PEFF algorithm, as these characteristics were similarly distributed over the true positive, true negative, false positive, and false negative cases. Sensitivity of the second step of the HFA-PEFF score was non-significantly improved to 60% (P = 0.08) by lowering the rule-in threshold to >3. LA strain alone had a sensitivity and specificity of 39% and 14% for haemodynamic HFpEF, increasing to 55% and 22% when corrected for E/E'. CONCLUSIONS: As compared with rest/exercise RHC, the HFA-PEFF score lacks sensitivity: Half of the patients were wrongly classified as non-cardiac dyspnoea after non-invasive tests, with a minimal impact of DSE in modifying HFpEF likelihood.

Incremental Value of Right Atrial Strain Analysis to Predict Atrial Fibrillation Recurrence After Electrical Cardioversion.

BACKGROUND: Although the assessment of left atrial (LA) mechanics has been reported to refine atrial fibrillation (AF) risk prediction, it doesn't completely predict AF recurrence. The potential added role of right atrial (RA) function in this setting is unknown. Accordingly, this study sought to evaluate the added value of RA longitudinal reservoir strain (RASr) for the prediction of AF recurrence after electrical cardioversion (ECV). METHODS: We retrospectively studied 132 consecutive patients with persistent AF who underwent elective ECV. Complete two-dimensional and speckle-tracking echocardiography analyses of LA and RA size and function were obtained in all patients before ECV. The end point was AF recurrence. RESULTS: During a 12-month follow-up, 63 patients (48%) showed AF recurrence. Both LASr and RASr were significantly lower in patients experiencing AF recurrence than in patients with persistent sinus rhythm (LASr, 10% ± 6% vs 13% ± 7%; RASr, 14% ± 10% vs 20% ± 9%, respectively; P < .001 for both). Right atrial longitudinal reservoir strain (area under the curve = 0.77; 95% CI, 0.69-0.84; P < .0001) was more strongly associated with the recurrence of AF after ECV than LASr (area under the curve = 0.69; 95% CI, 0.60-0.77; P < .0001). Kaplan-Meier curves showed that patients with both LASr ≤ 10% and RASr ≤ 15% had a significantly increased risk for AF recurrence (log-rank, P < .001). However, at multivariable Cox regression, RASr (hazard ratio, 3.26; 95% CI, 1.73-6.13; P < .001) was the only parameter independently associated with AF recurrence. Right atrial longitudinal reservoir strain was more strongly associated with the occurrence of AF relapse after ECV than LASr, and LA and RA volumes. CONCLUSION: Right atrial longitudinal reservoir strain was independently and more strongly associated than LASr with AF recurrence after elective ECV. This study highlights the importance of assessing the functional remodeling of both the RA and LA in patients with persistent AF.

Right Heart Adaptation to Exercise in Pulmonary Hypertension: An Invasive Hemodynamic Study.

BACKGROUND: Right heart failure (RHF) is associated with a dismal prognosis in patients with pulmonary hypertension (PH). Exercise right heart catheterization may unmask right heart maladaptation as a sign of RHF. We sought to (1) define the normal limits of right atrial pressure (RAP) increase during exercise; (2) describe the right heart adaptation to exercise in PH owing to heart failure with preserved ejection fraction (PH-HFpEF) and in pulmonary arterial hypertension (PAH); and (3) identify the factors associated with right heart maladaptation during exercise. METHODS AND RESULTS: We analyzed rest and exercise right heart catheterization from patients with PH-HFpEF and PAH. Right heart adaptation was described by absolute or cardiac output (CO)-normalized changes of RAP during exercise. Individuals with noncardiac dyspnea (NCD) served to define abnormal RAP responses (>97.5th percentile). Thirty patients with PH-HFpEF, 30 patients with PAH, and 21 patients with NCD were included. PH-HFpEF were older than PAH, with more cardiovascular comorbidities, and a higher prevalence of severe tricuspid regurgitation (P < .05). The upper limit of normal for peak RAP and RAP/CO slope in NCD were >12 mm Hg and ≥1.30 mm Hg/L/min, respectively. PH-HFpEF had higher peak RAP and RAP/CO slope than PAH (20 mm Hg [16-24 mm Hg] vs 12 mm Hg [9-19 mm Hg] and 3.47 mm Hg/L/min [2.02-6.19 mm Hg/L/min] vs 1.90 mm Hg/L/min [1.01-4.29 mm Hg/L/min], P < .05). A higher proportion of PH-HFpEF had RAP/CO slope and peak RAP above normal (P < .001). Estimated stressed blood volume at peak exercise was higher in PH-HFpEF than PAH (P < .05). In the whole PH cohort, the RAP/CO slope was associated with age, the rate of increase in estimated stressed blood volume during exercise, severe tricuspid regurgitation, and right atrial dilation. CONCLUSIONS: Patients with PH-HFpEF display a steeper increase of RAP during exercise than those with PAH. Preload-mediated mechanisms may play a role in the development of exercise-induced RHF.

Shedding Light on Latent Pulmonary Vascular Disease in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Among patients with heart failure with preserved ejection fraction (HFpEF), a distinct hemodynamic phenotype has been recently described, ie, latent pulmonary vascular disease (HFpEF-latentPVD), defined by exercise pulmonary vascular resistance (PVR) >1.74 WU. OBJECTIVES: This study aims to explore the pathophysiological significance of HFpEF-latentPVD. METHODS: The authors analyzed a cohort of patients who had undergone supine exercise right heart catheterization with cardiac output (CO) measured by direct Fick method, between 2016 and 2021. HFpEF-latentPVD patients were compared with HFpEF control patients. RESULTS: Out of 86 HFpEF patients, 21% qualified as having HFpEF-latentPVD, 78% of whom had PVR >2 WU at rest. Patients with HFpEF-latentPVD were older, with a higher pretest probability of HFpEF, and more frequently experienced atrial fibrillation and at least moderate tricuspid regurgitation (P < 0.05). PVR trajectories differed between HFpEF-latentPVD patients and HFpEF control patients (Pinteraction = 0.008), slightly increasing in the former and reducing in the latter. HFpEF-latentPVD patients displayed more frequent hemodynamically significant tricuspid regurgitation during exercise (P = 0.002) and had more impaired CO and stroke volume reserve (P < 0.05). Exercise PVR was correlated with mixed venous O2 tension (R2 = 0.33) and stroke volume (R2 = 0.31) in HFpEF-latentPVD patients. The HFpEF-latentPVD patients had had higher dead space ventilation during exercise and higher PaCO2 (P < 0.05), which correlated with resting PVR (R2 = 0.21). Event-free survival was reduced in HFpEF-latentPVD patients (P < 0.05). CONCLUSIONS: The results suggest that when CO is measured by direct Fick, few HFpEF patients have isolated latent PVD (ie, normal PVR at rest, becoming abnormal during exercise). HFpEF-latentPVD patients present with CO limitation to exercise, associated with dynamic tricuspid regurgitation, altered ventilatory control, and pulmonary vascular hyperreactivity, portending a poor prognosis.

Corrigendum: The atrial secondary tricuspid regurgitation is associated to more favorable outcome than the ventricular phenotype.

[This corrects the article DOI: 10.3389/fcvm.2022.1022755.].

[Anticoagulation therapy during pulmonary embolism follow-up in clinical practice]. / Gestione della terapia anticoagulante nel follow-up dell'embolia polmonare nella pratica clinica.

Patients with pulmonary embolism are a heterogeneous population and, after the acute phase and the first 3-6 months, the main issue is whether to continue, and hence how long and at what dose, or to stop anticoagulation therapy. In patients with venous thromboembolism (VTE), direct oral anticoagulants (DOACs) are the recommended treatment (class I, level of evidence B in the latest European guidelines), and in most cases, an "extended" or "long-term" low-dose therapy is warranted. This paper aims to provide a practical management tool to the clinician dealing with pulmonary embolism follow-up: from the evidence behind the most used exams (D-dimer, ultrasound Doppler of the lower limbs, imaging tests, recurrence and bleeding risk scores), and the use of DOACs in the extended phase, to six real clinical scenarios with the relative management in the acute phase and at follow-up. Lastly, a practical algorithm is shown to deal with anticoagulation therapy in the follow-up of VTE patients in a simple, schematic, and pragmatic way.

Impact of severe secondary tricuspid regurgitation on rest and exercise hemodynamics of patients with heart failure and a preserved left ventricular ejection fraction.

Background: Both secondary tricuspid regurgitation (STR) and heart failure with preserved ejection fraction (HFpEF) are relevant public health problems in the elderly population, presenting with potential overlaps and sharing similar risk factors. However, the impact of severe STR on hemodynamics and cardiorespiratory adaptation to exercise in HFpEF remains to be clarified. Aim: To explore the impact of STR on exercise hemodynamics and cardiorespiratory adaptation in HFpEF. Methods: We analyzed invasive hemodynamics and gas-exchange data obtained at rest and during exercise from HFpEF patients with severe STR (HFpEF-STR), compared with 1:1 age-, sex-, and body mass index (BMI)- matched HFpEF patients with mild or no STR (HFpEF-controls). Results: Twelve HFpEF with atrial-STR (mean age 72 years, 92% females, BMI 28 Kg/m2) and 12 HFpEF-controls patients were analyzed. HFpEF-STR had higher (p < 0.01) right atrial pressure than HFpEF-controls both at rest (10 ± 1 vs. 5 ± 1 mmHg) and during exercise (23 ± 2 vs. 14 ± 2 mmHg). Despite higher pulmonary artery wedge pressure (PAWP) at rest in HFpEF-STR than in HFpEF-controls (17 ± 2 vs. 11 ± 2, p = 0.04), PAWP at peak exercise was no more different (28 ± 2 vs. 29 ± 2). Left ventricular transmural pressure and cardiac output (CO) increased less in HFpEF-STR than in HFpEF-controls (interaction p-value < 0.05). This latter was due to lower stroke volume (SV) values both at rest (48 ± 9 vs. 77 ± 9 mL, p < 0.05) and at peak exercise (54 ± 10 vs. 93 ± 10 mL, p < 0.05). Despite these differences, the two groups of patients laid on the same oxygen consumption isophlets because of the increased peripheral oxygen extraction in HFpEF-STR (p < 0.01). We found an inverse relationship between pulmonary vascular resistance and SV, both at rest and at peak exercise (R 2 = 0.12 and 0.19, respectively). Conclusions: Severe STR complicating HFpEF impairs SV and CO reserve, leading to pulmonary vascular de-recruitment and relative left heart underfilling, undermining the typical HFpEF pathophysiology.

Impact of reboxetine plus oxybutynin treatment for obstructive sleep apnea on cardiovascular autonomic modulation.

The combination of noradrenergic (reboxetine) plus antimuscarinic (oxybutynin) drugs (reb-oxy) reduced obstructive sleep apnea (OSA) severity but no data are available on its effects on cardiac autonomic modulation. We sought to evaluate the impact of 1-week reb-oxy treatment on cardiovascular autonomic control in OSA patients. OSA patients were randomized to a double-blind, crossover trial comparing 4 mg reboxetine plus 5 mg oxybutynin to a placebo for OSA treatment. Heart rate (HR) variability (HRV), ambulatory blood pressure (BP) monitoring (ABPM) over 24 h baseline and after treatment were performed. Baroreflex sensitivity was tested over beat-to-beat BP recordings. 16 subjects with (median [interquartile range]) age 57 [51-61] years and body mass index 30 [26-36]kg/m2 completed the study. The median nocturnal HR was 65 [60-69] bpm at baseline and increased to 69 [64-77] bpm on reb-oxy vs 66 [59-70] bpm on placebo (p = 0.02). The mean 24 h HR from ABPM was not different among treatment groups. Reb-oxy administration was not associated with any modification in HRV or BP. Reb-oxy increased the baroreflex sensitivity and did not induce orthostatic hypotension. In conclusion, administration of reb-oxy did not induce clinically relevant sympathetic overactivity over 1-week and, together with a reduction in OSA severity, it improved the baroreflex function.

Concomitant Transcatheter Edge-to-Edge Treatment of Secondary Tricuspid and Mitral Regurgitation: An Expert Opinion.

Secondary (functional) tricuspid regurgitation (sTR) is common in patients with mitral regurgitation (MR). Because combined valvular heart disease affects long-term survival, in comparison with isolated MR or tricuspid regurgitation, it is essential to offer patients adequate treatment. Despite considerable experience, no conclusive data are yet available on the prognostic impact of concomitant tricuspid valve surgery at the time of mitral valve surgery. Emerging transcatheter treatments offer the opportunity to treat both conditions (MR and sTR) simultaneously or in a stepwise fashion. This review provides a clinical overview on available data regarding the rationale for treatment of sTR in patients with relevant MR undergoing mitral transcatheter edge-to-edge repair, focusing on clinical and anatomical selection criteria.