Prognostic value of deep echocardiographic phenotyping in pulmonary arterial hypertension.

Background: A novel approach to derive prognostic information from echocardiography in pulmonary arterial hypertension (PAH) is to define a phenotype of right heart function combining standard echocardiographic parameters which describe right ventricular pump function and systemic venous congestion. We tested the hypothesis that the combination of advanced strain imaging parameters could yield high prognostic accuracy. Methods: This was a prospective observational study with a single centre derivation cohort and a second centre validation cohort. The derivation cohort included 49 naive PAH patients who underwent right heart catheterisation and echocardiographic evaluation at baseline and 4-12 months after diagnosis. The validation cohort included 83 prevalent PAH patients who underwent the same examinations at 12 months after diagnosis. We stratified the risk of the derivation cohort according to three models: Model 1, based on haemodynamic parameters; Model 2, based on standard echocardiographic parameters; and Model 3, based on advanced echocardiographic parameters. The median follow-up period was 21 months; the end point of the analysis was clinical worsening. Results: In the derivation cohort, haemodynamic and echocardiographic parameters obtained at diagnosis were not associated with outcome, whereas a significant association was observed at first reassessment. Model 3 yielded a better predictive accuracy (Harrell's C index 0.832) as compared to Model 2 (Harrell's C index 0.667), and to Model 1 (Harrell's C index 0.713). The validation cohort confirmed the accuracy of Model 3. Conclusions: A comprehensive assessment of right heart function using right ventricular strain, right atrial reservoir strain and degree of tricuspid regurgitation provides accurate prognostic information in prevalent PAH patients.

Sacubitril/valsartan effects on arrhythmias and left ventricular remodelling in heart failure: An observational study.

AIMS: Conflicting results have been reported in the literature on the potential antiarrhythmic effect of sacubitril/valsartan in heart failure patients with reduced ejection fraction (HFrEF). The objectives of this study were: 1- to evaluate the long term effects of sacubitril/valsartan on arrhythmic burden in HFrEF patients; 2- to evaluate the correlation between the reduction of premature ventricular complexes during f-up and reverse remodelling. METHODS: We identified 255 consecutive HFrEF patients treated with sacubitril/valsartan between March 2017 and May 2020 and followed by the Heart Failure and Cardiac Transplant Unit of IRCCS San Matteo Hospital in Pavia (Italy). Within this subgroup, 153 patients underwent 24 h-Holter-ECG or implantable cardioverter defibrillators (ICD) interrogation at baseline, at 12 months (t1) and at 24 months (t2) and transthoracic echocardiography at baseline and after 12 months after the beginning of sacubitril/valsartan. Cardiac-related hospitalizations were analyzed in the 12 months preceding and during 24 months following the drug starting date. RESULTS: Global burden of 24-h premature ventricular complexes (PVC) was significantly reduced at 12 months (t1) and at 24 months (t2) as compared to the same period before treatment (1043 [304-3360] vs 768 [82-2784] at t1 vs 114 [9-333] at t2, P = 0.000). In the subgroup of patients implanted with biventricular ICD (n = 30), the percentage of biventricular pacing increased significantly (96% [94-99] vs 98% [96-99] at t1 vs 98%[97-100] at t2; P = 0.027). The burden of non-sustained ventricular tachycardia and sustained ventricular tachycardia did not change from baseline to t1 and t2, but a reduction of patients with at least one ICD appropriate shock was reported. The correlations between reduction in 24 h PVC and reduction in LV-ESVi or improvement in LVEF were not statistically significant (respectively R = 0.144, P = 0.197 and R = -0.190, P = 0.074). Heart failure related hospitalizations decreased during follow up (11.1% in the year before treatment vs 4.6% at t1 and 4.6% at t2; P = 0.040). CONCLUSION: Sacubitril/valsartan reduced the number of premature ventricular complexes and increased the percentage of biventricular pacing in a cohort of HFrEF patients already on optimal medical therapy. PVC reduction did not correlate with reverse left ventricular remodelling. Whether sacubitril/valsartan has any direct antiarrhythmic effects is an issue to be better explored in future studies.

Hypertrophic Cardiomyopathy and Atrial Fibrillation: A Systematic Review and Meta-analysis of Anticoagulation Strategy.

BACKGROUND: Atrial fibrillation (AF) frequently complicates hypertrophic cardiomyopathy (HCM), and anticoagulation significantly decreases the risk of stroke in this population. To date, no randomized controlled trials (RCTs) have compared direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs). The present study aimed to systematically compare the two anticoagulation strategies in terms of effectiveness and safety. METHOD: We performed a systematic literature search and meta-analysis in the PubMed, MEDLINE, and EMBASE databases for studies reporting all-cause mortality, major bleeding, or thromboembolic events (TEs). Since no RCTs were available, we included observational studies only. The overall hazard ratio (HR) and 95% confidence interval (CI) for each analyzed parameter were pooled using a random-effects model. RESULTS: Five observational studies including 6919 patients were eligible for inclusion. Compared with VKAs, DOACs were associated with statistically significant lower rates of all-cause mortality (HR 0.64, 95% CI 0.35-0.54; p < 0.00001), comparable major bleeding events (HR 0.64, 95% CI 0.40-1.03; p = 0.07), and TEs (HR 0.94, 95% CI 0.73-1.22; p = 0.65). CONCLUSIONS: Compared with VKAs, a DOAC-based strategy might represent an effective and safe strategy regarding all-cause mortality, major/life-threatening bleeding complications, and TEs in HCM patients with concomitant AF. However, further prospective studies are necessary to reinforce a DOAC-based anticoagulation strategy in this population.

Role of cardiac magnetic resonance in the differential diagnosis between arrhythmogenic cardiomyopathy with left ventricular involvement and previous infectious myocarditis.

AIMS: Arrhythmogenic cardiomyopathy with left ventricular involvement (ACM-LV), particularly in case of isolated left ventricular involvement (i.e. left dominant arrhythmogenic cardiomyopathy, LDAC) and previous infectious myocarditis (pIM) may have overlapping clinical and cardiac magnetic resonance (CMR) features. To date, there are no validated CMR criteria for the differential diagnosis between these conditions. The present study aimed to identify CMR characteristics to distinguish ACM-LV from pIM. METHODS AND RESULTS: This observational, retrospective, single-centre study included 30 pIM patients and 30 ACM-LV patients. In ACM-LV patients CMR was performed at diagnosis; in patients with pIM, CMR was performed six months after acute infection. CMR analysis included quantitative assessment of left ventricle (LV) volumes, systolic function and wall thicknesses, qualitative and quantitative assessment of late gadolinium enhancement (LGE) sequences. Compared with pIM, ACM-LV patients showed slightly larger LV volumes, more frequent regional wall motion anomalies and reduced wall thicknesses. ACM-LV patients had higher amounts of LV LGE and extension. Notably, the LDAC subgroup had the highest amount of LV LGE. LV LGE amount > 15 g and a LV LGE percentage > 30% of LV mass discriminated ACM-LV from pIM with a 100% specificity. LGE segmental distribution was superimposable among the groups, except for septal segments that were more frequently involved in ACM-LV and LDAC patients. CONCLUSIONS: A great extension of LV LGE (a cut-off of LGE >15 g and a percentage above 30% of LV LGE in relation to total myocardial mass) discriminates ACM-LV from pIM with extremely high specificity.

First- Versus New-Generation Drug-Eluting Stents in Patients With Heart Transplant With Cardiac Allograft Vasculopathy.

Although several studies have previously reported on the efficacy of percutaneous coronary intervention (PCI) with first-generation drug-eluting stents (DES) in heart transplant patients with cardiac allograft vasculopathy, few data regarding new-generation DES are currently available. We sought to compare the efficacy of new-generation versus first-generation DES in 90 consecutive patients with heart transplant (113 de novo coronary lesions) who underwent urgent or elective PCI with first-generation (28 patients) or new-generation (62 patients) DES. For each patient, the severity of cardiac allograft vasculopathy and postprocedural extent of revascularization were quantified calculating baseline and residual SYNTAX score, respectively. The primary end point was a composite of major adverse cardiac events-myocardial infarction, cardiovascular death, or target vessel revascularization-at 3 years. Overall, the median baseline SYNTAX score was 8 (5 to 15), and a total number of stents per patient of 1.6 ± 0.9 was implanted. Post-PCI residual SYNTAX score was 1.5 (0 to 4), with 13 patients having a score >8. At 3 years, the Kaplan-Meier estimate of freedom from major adverse cardiac events was 64%, with no differences between first-generation and new-generation DES groups (log-rank test p = 0.269). Nevertheless, patients treated with new-generation DES experienced a lower rate of target vessel revascularization (15% vs 31%, log-rank test p = 0.058). In the multivariate Cox regression analysis, a post-PCI residual SYNTAX score >8 (hazard ratio 2.37, confidence interval 0.98 to 5.73, p = 0.054) was identified as an independent predictor of the primary end point.

When you hear hoofbeats, think zebras - pulmonary veno-occlusive disease: A case report.

Pulmonary veno-occlusive disease (PVOD) is a rare disease. It may be idiopathic or associated, in particular, with connective tissue disease, or it may develop after radiation exposure; in heritable forms of PVOD, the inheritance is autosomal recessive due to the presence of homozygous or compound heterozygous pathogenic variants in the EIF2AK4 gene. We describe the case of a young man whose PVOD was initially misdiagnosed as chronic thromboembolic pulmonary hypertension despite worsening after riociguat, nonspecific computed tomography pulmonary angiogram findings, and parental consanguinity could suggest an autosomal recessive disease. The correct diagnosis and the correct treatment are crucial given the high mortality rate of this disease.

[Percutaneous treatment of acute pulmonary embolism: state of the art]. / Trattamento transcatetere dell'embolia polmonare acuta: stato dell'arte.

Acute pulmonary embolism (PE) is a common disease associated with high mortality rates that vary widely according to patient clinical presentation and hemodynamic status. According to international guidelines, systemic thrombolysis (ST) is the mainstem treatment in patients with high risk PE and intermediate-high risk PE evolving towards hemodynamic decompensation, showing lower mortality compared with anticoagulant therapy alone despite a high rate of bleeding events. Considering that a large proportion of patients presents contraindication to ST, catheter-directed therapies (CDTs) could tackle some unsolved issues, targeting the treatment to the pulmonary arteries, avoiding the dreaded complications of ST.The aim of this review is to describe the current indication for CDTs in terms of patient selection and timing of treatment, to describe contemporary available medical devices and techniques, discussing current knowledge of safety and efficacy and the importance of multidisciplinary team in PE management.

Response to acute vasodilator challenge and haemodynamic modifications after MitraClip in patients with functional mitral regurgitation and pulmonary hypertension.

The effectiveness of transcatheter edge-to-edge repair (TEER) in patients with functional mitral regurgitation (FMR) and pulmonary hypertension (PH) is still debated and pre-procedural predictors of haemodynamic improvement after TEER in this setting are currently unknown. We investigated whether normalization of pulmonary artery wedge pressure (PAWP) in response to sodium nitroprusside (SNP) during baseline right heart catheterization might be predictive of a favourable haemodynamic response to MitraClip in patients with FMR and PH. Among 22 patients enrolled, 13 had a positive response to SNP (responders), nine were non-responders. At 6-months follow-up, responders showed a 33% reduction in PAWP and a 25% reduction in mean pulmonary artery pressure (PAP) (P = 0.002 and 0.004, respectively); no significant change occurred in non-responders. In patients with FMR and PH, pre-procedural vasodilator challenge with SNP may help define patients who may have haemodynamic improvement after TEER.

Prevalence, Characteristics, and Outcomes of COVID-19-Associated Acute Myocarditis.

BACKGROUND: Acute myocarditis (AM) is thought to be a rare cardiovascular complication of COVID-19, although minimal data are available beyond case reports. We aim to report the prevalence, baseline characteristics, in-hospital management, and outcomes for patients with COVID-19-associated AM on the basis of a retrospective cohort from 23 hospitals in the United States and Europe. METHODS: A total of 112 patients with suspected AM from 56 963 hospitalized patients with COVID-19 were evaluated between February 1, 2020, and April 30, 2021. Inclusion criteria were hospitalization for COVID-19 and a diagnosis of AM on the basis of endomyocardial biopsy or increased troponin level plus typical signs of AM on cardiac magnetic resonance imaging. We identified 97 patients with possible AM, and among them, 54 patients with definite/probable AM supported by endomyocardial biopsy in 17 (31.5%) patients or magnetic resonance imaging in 50 (92.6%). We analyzed patient characteristics, treatments, and outcomes among all COVID-19-associated AM. RESULTS: AM prevalence among hospitalized patients with COVID-19 was 2.4 per 1000 hospitalizations considering definite/probable and 4.1 per 1000 considering also possible AM. The median age of definite/probable cases was 38 years, and 38.9% were female. On admission, chest pain and dyspnea were the most frequent symptoms (55.5% and 53.7%, respectively). Thirty-one cases (57.4%) occurred in the absence of COVID-19-associated pneumonia. Twenty-one (38.9%) had a fulminant presentation requiring inotropic support or temporary mechanical circulatory support. The composite of in-hospital mortality or temporary mechanical circulatory support occurred in 20.4%. At 120 days, estimated mortality was 6.6%, 15.1% in patients with associated pneumonia versus 0% in patients without pneumonia (P=0.044). During hospitalization, left ventricular ejection fraction, assessed by echocardiography, improved from a median of 40% on admission to 55% at discharge (n=47; P<0.0001) similarly in patients with or without pneumonia. Corticosteroids were frequently administered (55.5%). CONCLUSIONS: AM occurrence is estimated between 2.4 and 4.1 out of 1000 patients hospitalized for COVID-19. The majority of AM occurs in the absence of pneumonia and is often complicated by hemodynamic instability. AM is a rare complication in patients hospitalized for COVID-19, with an outcome that differs on the basis of the presence of concomitant pneumonia.

Immune Response to BNT162b2 in Solid Organ Transplant Recipients: Negative Impact of Mycophenolate and High Responsiveness of SARS-CoV-2 Recovered Subjects against Delta Variant.

The immunogenicity of severe acute respiratory syndrome 2 virus (SARS-CoV-2) vaccines in immunocompromised patients remains to be further explored. Here, we evaluated the immunogenicity elicited by complete vaccination with BNT162b2 vaccine in solid organ transplant recipients (SOTRs). A cohort of 110 SOTRs from Northern Italy were vaccinated with two doses of BNT162b2 mRNA vaccine and prospectively monitored at baseline and after 42 days. Both SARS-CoV-2 naïve and recovered subjects were included. Humoral response elicited by vaccination, including SARS-CoV-2 neutralizing antibodies (SARS-CoV-2 NT Abs), was evaluated; additionally, ex-vivo ELISpot assay was performed for the quantification of Spike-specific T-cell response. Results were compared with those obtained in a cohort of healthy subjects. In a subset of patients, humoral and T-cell responses against delta variant were also evaluated. Less than 20% of transplanted subjects developed a positive humoral and cell-mediated response after complete vaccination schedule. Overall, median levels of immune response elicited by vaccination were significantly lower with respect to controls in SARS-CoV-2 naïve transplant, but not in SARS-CoV-2 recovered transplanted patients. Additionally, a significant impairment of both humoral and cell-mediated response was observed in mycophenolate-treated patients. Positive delta-SARS-CoV-2 NT Abs levels were detected in almost all the SARS-CoV-2 recovered subjects but not in previously uninfected patients. Our study supports previous observations of a low level of seroconversion after vaccination in transplanted patients.

BMPR2 mutations and response to inhaled or parenteral prostanoids: a case series.

Whether mutations in the BMPR2 gene may influence the response to PAH-specific therapies has not yet been investigated. In this study, in 13 idiopathic, heritable or anorexigen-associated PAH patients, in whom treatment escalation was performed by adding a prostanoid, a greater haemodynamic improvement was observed in BMPR2-negative than in BMPR2-positive patients.

Assessment of right ventricle in pulmonary arterial hypertension with three-dimensional echocardiography and cardiovascular magnetic resonance.

AIM: To correlate 3-D Echo and CMR RV parameters and to verify whether they are similarly related to the clinical conditions of patients with pulmonary arterial hypertension (PAH), a disease in which the RV plays a crucial prognostic role. METHODS: We enrolled 34 consecutive PAH patients followed by our PAH clinics. All patients underwent a 3-D Echo and CMR assessment of RV volumes and functions in the same day. The presence or absence of correlation between major findings was investigated; functional RV parameters were also analyzed in relation to 6-min walking test (6MWT) results and BNP/Nt-proBNP plasma levels. Twenty-four subjects served as controls. RESULTS: Good agreement was found between 3-D Echo and CMR measures of RV volumes [RV-end-diastolic volume (r = 0.72, P < 0.0001), RV-end-systolic volume (ESV) (r = 0.80, P < 0.0001)] and function [RV-EF (r = 0.73, P < 0.0001), RV-ESV/SV (r = 0.83, P = 0.001)] for all the subjects of the study. These correlations were stronger in PAH patients than in control subjects. Importantly, 3-D Echo and CMR RV-EF and RV to pulmonary arterial coupling (RV-ESV/SV) similarly correlated with BNP/Nt-proBNP levels and with functional capacity measured at 6MWT in the PAH patients group. CONCLUSIONS: 3-D Echo demonstrated a significant agreement with CMR in the assessment of RV volume and function in PAH patients. Both techniques showed a similar correlation with clinical and prognostic parameters. The use of 3-D Echo should be amply boosted in the real-world clinical evaluation of PAH patients.

[Early diagnosis and management of cardiac allograft vasculopathy: is it time for a standardized approach?] / Individuazione precoce e gestione della coronaropatia nel cuore trapiantato: è tempo per una uniformità di approccio?

Cardiac allograft vasculopathy (CAV) still represents the main cause of long-term graft loss after heart transplantation. Its silent clinical presentation makes an early identification difficult, with relevant implications for a standardized follow-up. Although technological advances have provided sophisticated non-invasive techniques for CAV assessment, intravascular ultrasound in conjunction with coronary angiography is still the gold standard to detect rapidly progressive CAV and to provide prognostic information during follow-up. Current guidelines recommend annual coronary angiography during the first 5 years and every 2 years thereafter. Although commonly performed, coronary angiography has multiple limitations, especially in young patients and in case of chronic kidney disease. This article aims to review the literature about the monitoring of CAV and to propose an ideal and individualized pathway for early diagnosis of CAV in transplanted patients, based on their cardiovascular risk.

Iron deficiency in pulmonary arterial hypertension: prevalence and potential usefulness of oral supplementation.

BACKGROUND: The aim of this study was to evaluate the prevalence of iron depletion in a prevalent population of patients with pulmonary arterial hypertension (PAH) and to gain preliminary insights on the possibility of its treatment with oral drugs. METHODS: Iron status was determined in 31 consecutive prevalent idiopathic patients with PAH. Iron depletion was defined as serum iron <10 mmol/L and decreased transferrin saturation irrespective of the coexistence of anaemia. Patients underwent laboratory examinations, 6-min walking test and echocardiography in the same day. A subgroup of iron depleted patients received one oral capsule/day containing 30 mg of pyrophosphate sucrosomial iron for 16 weeks. After this period all patients were re-evaluated. RESULTS: Iron depletion was observed in 22 patients (71%), of whom 6 were also anaemic and 16 were not anaemic. Iron depletion was associated with higher systolic pulmonary artery pressure (60 [50-90] vs. 45 [40-50] mmHg, p = .007), greater prevalence of moderate to severe tricuspid regurgitation (36% vs. 0%, p = .039), lower tricuspid annular plane systolic excursion (23 [21-24] vs. 19 [18-20] mm; p = .025]) and higher left ventricular eccentricity index (1.35 vs. 1, p = .042). After 16 weeks of treatment, 6-min walking distance significantly improved (500 [390-500] vs. 530 [410-550] metres; p = .043). CONCLUSIONS: Iron deficiency is highly prevalent in patients with PAH and is associated with worse clinical conditions. Treatment with oral sucrosomial iron is a therapeutic option which should be further investigated in future trials.

Pulmonary endarterectomy in the octogenarian population: safety and outcomes.

AIMS: Aim of the study was to verify the feasibility, safety and efficacy of pulmonary endarterectomy (PEA) in octogenarian patients with chronic thromboembolic pulmonary hypertension. METHODS: We retrospectively analyzed 635 chronic thromboembolic pulmonary hypertension patients who underwent PEA at our center and were followed-up for at least 1 year. The end-points of the study were in-hospital mortality, hemodynamic results at 1 year and long-term survival. RESULTS: In-hospital mortality was 4, 10 and 17%, respectively, for 259 patients under the age of 60 years, 352 aged between 60 and 79 years and 24 octogenarians (P = 0.006 octogenarians vs. <60 years). At multivariable analysis, age and pulmonary vascular resistances were independent risk factors for mortality (P = 0.021 and P < 0.001, respectively). At 1 year, the improvement in cardiac index was lower and the distance walked in 6 min was poorer for octogenarians than for the other two groups (both P = 0.001). Survival after hospital discharge was similar over a median follow-up period of 59 months (P = 0.113). Although in-hospital mortality and long-term survival are similar in octogenarians as compared with patients aged between 60 and 79, the improvement in cardiac index and in functional capacity at 1 year are lower in this very elderly population. CONCLUSION: Age over 80 years should not be a contraindication to PEA surgery in selected patients operated on in referral centers.

Galectin-3 Plasma Levels Are Associated with Risk Profiles in Pulmonary Arterial Hypertension.

Galectin-3 is a circulating biomarker of fibrosis whose prognostic role in pulmonary arterial hypertension (PAH) has not been fully explored. We undertook a pilot study to evaluate the relationship between galectin-3 plasma levels and validated risk scores in PAH. The study included 70 PAH patients admitted to a single referral center from June 2016 to June 2018. Patients were stratified according to the REVEAL 2.0 risk score, according to the parameters suggested by the European Society of Cardiology and European Respiratory Society (ESC/ERS) Guidelines, and according to a focused echocardiographic assessment of right heart performance. The association between galectin-3 levels and risk profiles was evaluated by generalized linear regression model with adjustment for etiology. Galectin-3 plasma levels increased linearly in the three risk strata based on the REVEAL 2.0 score (from 16.0 ± 5.7 in low-risk to 22.4 ± 6.3 in intermediate-risk and in 26.9 ± 7.7 ng/mL in high-risk patients (p for trend < 0.001). Galectin-3 levels were significantly lower in low-risk patients defined according to the prognostic parameters of ESC/ERS Guidelines (delta between low-risk and intermediate/high-risk = -9.3, 95% CI -12.8 to -5.8, p < 0.001, p < 0.001). Additionally, galectin-3 levels were lower in the low-risk profile defined on the basis of the echocardiographic evaluation of right heart performance (delta between low-risk and intermediate-/high-risk = -6.3, 95% CI -9.9 to -2.7, p = 0.001). Galectin-3 plasma levels are directly associated with several risk profiles in PAH patients. The prognostic role of this biomarker in PAH is worthwhile to be explored in larger prospective studies.