Publications by authors named "Stefano Ghio"

178 Publications

Current gaps in HFpEF trials: Time to reconsider patients' selection and to target phenotypes.

Prog Cardiovasc Dis 2021 Apr 8. Epub 2021 Apr 8.

Cardiovascular Department, Cardiology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy.

Heart Failure with preserved Ejection Fraction (HFpEF) is an increasingly prevalent clinical condition associated with cardiovascular aging, characterized by different pathophysiological mechanisms and poor outcomes. In this manuscript, we analysed the main differences in terms of updated diagnostic criteria and patients' selection in the most recent HFpEF trials. Recent algorithm purposed for HFpEF diagnosis, does not reflect common criteria adopted in clinical trials. Patients included in the larger studies experienced different characteristics in terms of clinical presentation and echocardiographic features. Current concerns complicate results interpretation and could hypothesize different stages of disease progression, rather than different cardiac phenotypes. Both the lack of diagnostic standardization and the population heterogeneity, might explain why trials investigating the effects of different therapeutic interventions failed to show improved outcomes for patients with HFpEF. Accordingly, we propose to exceed current view mainly based on the morphological adaptations evaluating patients' characterisation, their cardiovascular risk, associated diseases, and structural features consistent with disease progression. Detailed clinical, imaging and biological characterisation of this population, along with the identification of mechanisms linked with disease progression and prognosis, would allow for tailored treatments and provide important mechanistic insights into the complex HFpEF pathophysiology.
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http://dx.doi.org/10.1016/j.pcad.2021.03.007DOI Listing
April 2021

Risk stratification in patients with residual pulmonary hypertension after pulmonary endarterectomy.

Int J Cardiol 2021 Apr 3. Epub 2021 Apr 3.

Division of Cardiac Surgery, Cardiopulmonary Surgery and Pulmonary Hypertension, Foundation "I.R.C.C.S. Policlinico San Matteo", Pavia, Italy; Department of Surgical, Clinical, Diagnostic and Pediatric Sciences, University of Pavia School of Medicine, Pavia, Italy.

Background: Few studies addressed the issue of risk stratification in patients with residual pulmonary hypertension (pH) after pulmonary endarterectomy (PEA). This study tested the potential added value of parameters that have not been included in existing risk models.

Methods: We evaluated 546 consecutive patients with chronic thromboembolic pulmonary hypertension who underwent PEA and were followed-up for a median period of 58 months.

Results: Among the 242 with residual PH, 27 died and had 127 a clinical worsening event. At univariable analysis, the parameters associated with poor survival were pulmonary vascular resistance (PVR) ≥425 dyn·s·cm (p ≤0.001), mean pulmonary artery pressure (mPAP) ≥38 mmHg (p = 0.003) and pulmonary artery compliance (CPA) ≤1.8 ml/mmHg (p = 0.014). In the bivariable models including either PVR or mPAP as first parameter, the addition of CPA was not statistically significant. The parameters associated with poor clinical worsening were CPA ≤1.8 ml/mmHg (p < 0.001), PVR ≥425 dyn·s·cm (p = 0.002), arterial oxygen tension (PaO2) ≤ 75 mmHg (p = 0.003), mPAP ≥38 mmHg (p = 0.008). In a multivariable analysis which included PVR ≥425 as the first parameter, the addition of both CPA ≤1.8 ml/mmHg and of PaO2 ≤ 75 mmHg significantly improved prognostic stratification (Harrel's C of the model = 0.64, p < 0.001). Noticeably, the lower tertile of the model's predictor index identified a subgroup of 91 patients who had an event rate numerically similar to that of patients without residual PH.

Conclusions: Risk stratification in residual PH can be refined if CPA and PaO2 are considered in association with standard hemodynamic parameters.
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http://dx.doi.org/10.1016/j.ijcard.2021.04.003DOI Listing
April 2021

Chronic thromboembolic pulmonary hypertension risk score evaluation and validation (CTEPH Solution): proposal of a study protocol aimed to realize a validated risk score for early diagnosis.

Minerva Cardiol Angiol 2021 Mar 11. Epub 2021 Mar 11.

Department of Cardiovascular and Respiratory Sciences, Sapienza University of Rome, Rome, Italy -

Background: Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is the most serious long-term complication of acute pulmonary embolism (PE) though it is the only potentially reversible form of Pulmonary Hypertension (PH). Its incidence is mainly limited to the first 2 years following the embolic event, however it is often underdiagnosed or misdiagnosed.

Methods: This is a multicenter observational cross-sectional and prospective study. Patients with a prior diagnosis of PE will be enrolled and undergo baseline evaluation for prevalent PH detection through a clinical examination and an echocardiogram as first screening exam. All cases of intermediate-high echocardiographic probability of PH will be confirmed by right heart catheterization and then identified as CTEPH through appropriate imaging and functional examinations in order to exclude other causes of PH. A CTEPH Risk Score will be created using retrospective data from this prevalent cohort of patients and will be then validated on an incident cohort of patients with acute PE.

Results: 1000 retrospective and 218 prospective patients are expected to be enrolled and the study is expected to be completed by the end of 2021. Up to now 841 patients (620 retrospective and 221 prospective) have been enrolled.

Conclusions: This study is the first large prospective study for the prediction of CTEPH development in patients with PE. It aims to create a comprehensive scoring tool that includes echocardiographic data which may allow early detection of CTEPH and the application of targeted follow up screening programs in patients with PE.
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http://dx.doi.org/10.23736/S2724-5683.21.05575-7DOI Listing
March 2021

Nonresponse to Acute Vasodilator Challenge and Prognosis in Heart Failure With Pulmonary Hypertension.

J Card Fail 2021 Feb 5. Epub 2021 Feb 5.

Department of Medicine, Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina.

Background: An acute vasodilator challenge is recommended in patients with heart failure and pulmonary hypertension during heart transplant evaluation. The aim of the study was to assess which hemodynamic parameters are associated with nonresponsiveness to the challenge.

Methods And Results: This study is a retrospective analysis of 402 patients with heart failure with pulmonary hypertension who underwent right heart catheterization and a pulmonary vasodilator challenge. Among the 140 who fulfilled the transplant guidelines eligibility criteria for the vasodilator challenge, 38 were responders and 102 nonresponders. At multivariable analysis, a diastolic blood pressure of <70 mm Hg, pulmonary vascular resistance of >5 Woods units, and pulmonary artery compliance of <1.2 mL/mm Hg were independently associated with poor response to vasodilator challenge (all P < .001). The presence of any 2 of these 3 conditions was associated with a 90% probability of being a nonresponder. The covariate-adjusted hemodynamic predictors of death in the entire population were a low baseline systolic blood pressure (P = .0017) and a low baseline right ventricular stroke work index (P = .0395).

Conclusions: In patients with heart failure and pulmonary hypertension, low pulmonary arterial compliance, high pulmonary vascular resistance, and low diastolic blood pressure predict the nonresponsiveness to acute vasodilator challenge whilst a poor right ventricular function predicts a dismal prognosis.
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http://dx.doi.org/10.1016/j.cardfail.2021.01.021DOI Listing
February 2021

Incidence of Ventricular Arrhythmias and 1-Year Predictors of Mortality in Patients Treated With Implantable Cardioverter-Defibrillator Undergoing Generator Replacement.

J Am Heart Assoc 2021 Feb 30;10(4):e018090. Epub 2021 Jan 30.

Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology Fondazione IRCCS Policlinico San Matteo Pavia Italy.

Background When implantable cardioverter defibrillator (ICD) battery is depleted most patients undergo generator replacement (GR) even in the absence of persistent ICD indication. The aim of this study was to assess the incidence of ventricular arrhythmias and the overall prognosis of patients with and without persistent ICD indication undergoing GR. Predictors of 1-year mortality were also analyzed. Methods and Results Patients with structural heart disease implanted with primary prevention ICD undergoing GR were included. Patients were stratified based on the presence/absence of persistent ICD indication (left ventricular ejection fraction ≤35% at the time of GR and/or history of appropriate ICD therapies during the first generator's life). The study included 371 patients (82% male, 40% with ischemic heart disease). One third of patients (n=121) no longer met ICD indication at the time of GR. During a median follow-up of 34 months after GR patients without persistent ICD indication showed a significantly lower incidence of appropriate ICD shocks (1.9% versus 16.2%, <0.001) and ICD therapies. 1-year mortality was also significantly lower in patients without persistent ICD indication (1% versus 8.3%, =0.009). At multivariable analysis permanent atrial fibrillation, chronic advanced renal impairment, age >80, and persistent ICD indication were found to be significant predictors of 1-year mortality. Conclusions Patients without persistent ICD indication at the time of GR show a low incidence of appropriate ICD therapies after GR. Persistent ICD indication, atrial fibrillation, advanced chronic renal disease, and age >80 are significant predictors of 1-year mortality. Our findings enlighten the need of performing a comprehensive clinical reevaluation of ICD patients at the time of GR.
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http://dx.doi.org/10.1161/JAHA.120.018090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955330PMC
February 2021

Radiological differences between chronic thromboembolic pulmonary disease (CTEPD) and chronic thromboembolic pulmonary hypertension (CTEPH).

Eur Radiol 2021 Jan 28. Epub 2021 Jan 28.

Department of Clinical, Surgical, Pediatric and Diagnostic Sciences, Faculty of Medicine and Surgery, University of Pavia, Pavia, Italy.

Objectives: The aim of this study was to describe the radiological features of chronic thromboembolic pulmonary disease (CTEPD), not yet systematically described in the literature. Furthermore, we compared vascular scores between CTEPD and chronic thromboembolic pulmonary hypertension (CTEPH) patients, trying to explain why pulmonary hypertension does not develop at rest in CTEPD patients.

Methods: Eighty-five patients (40 CTEPD, 45 CTEPH) referred to our centre for pulmonary endarterectomy underwent dual-energy computed tomography pulmonary angiography (DE-CTPA) with iodine perfusion maps; other 6 CTEPD patients underwent single-source CTPA. CT scans were reviewed independently by an experienced cardiothoracic radiologist and a radiology resident to evaluate scores of vascular obstruction, hypoperfusion and mosaic attenuation, signs of pulmonary hypertension and other CT features typical of CTEPH.

Results: Vascular obstruction burden was similar in the two groups (p = 0.073), but CTEPD patients have a smaller extension of perfusion defects in the iodine map (p = 0.009) and a smaller number of these patients had mosaic attenuation (p < 0.001) than CTEPH patients, suggesting the absence of microvascular disease. Furthermore, as expected, the two groups were significantly different considering the indirect signs of pulmonary hypertension (p < 0.001).

Conclusions: CTEPD and CTEPH patients have significantly different radiological characteristics, in terms of signs of pulmonary hypertension, mosaic attenuation and iodine map perfusion extension. Importantly, our results suggest that the absence of peripheral microvascular disease, even in presence of an important thrombotic burden, might be the reason for the absence of pulmonary hypertension in CTEPD.

Key Points: • CTEPD and CTEPH patients have significantly different radiological characteristics. • The absence of peripheral microvascular disease might be the reason for the absence of pulmonary hypertension in CTEPD.
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http://dx.doi.org/10.1007/s00330-020-07556-4DOI Listing
January 2021

A multicentric quality-control study of exercise Doppler echocardiography of the right heart and the pulmonary circulation. The RIGHT Heart International NETwork (RIGHT-NET).

Cardiovasc Ultrasound 2021 Jan 20;19(1). Epub 2021 Jan 20.

Cardiology Division, A Cardarelli Hospital, Naples, Italy.

Purpose: This study was a quality-control study of resting and exercise Doppler echocardiography (EDE) variables measured by 19 echocardiography laboratories with proven experience participating in the RIGHT Heart International NETwork.

Methods: All participating investigators reported the requested variables from ten randomly selected exercise stress tests. Intraclass correlation coefficients (ICC) were calculated to evaluate the inter-observer agreement with the core laboratory. Inter-observer variability of resting and peak exercise tricuspid regurgitation velocity (TRV), right ventricular outflow tract acceleration time (RVOT Act), tricuspid annular plane systolic excursion (TAPSE), tissue Doppler tricuspid lateral annular systolic velocity (S'), right ventricular fractional area change (RV FAC), left ventricular outflow tract velocity time integral (LVOT VTI), mitral inflow pulsed wave Doppler velocity (E), diastolic mitral annular velocity by TDI (e') and left ventricular ejection fraction (LVEF) were measured.

Results: The accuracy of 19 investigators for all variables ranged from 99.7 to 100%. ICC was > 0.90 for all observers. Inter-observer variability for resting and exercise variables was for TRV = 3.8 to 2.4%, E = 5.7 to 8.3%, e' = 6 to 6.5%, RVOT Act = 9.7 to 12, LVOT VTI = 7.4 to 9.6%, S' = 2.9 to 2.9% and TAPSE = 5.3 to 8%. Moderate inter-observer variability was found for resting and peak exercise RV FAC (15 to 16%). LVEF revealed lower resting and peak exercise variability of 7.6 and 9%.

Conclusions: When performed in expert centers EDE is a reproducible tool for the assessment of the right heart and the pulmonary circulation.
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http://dx.doi.org/10.1186/s12947-021-00238-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819251PMC
January 2021

Bayesian Inference Associates Rare Variants with Specific Phenotypes in Pulmonary Arterial Hypertension.

Circ Genom Precis Med 2020 Dec 15. Epub 2020 Dec 15.

Department of Medicine, Department of Haematology, University of Cambridge & NIHR BioResource for Translational Research, Cambridge, United Kingdom.

- Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. - We analyzed 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed. - Heterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor () gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=0.912). We also provide evidence for familial segregation of a rare nonsense variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the five patients harboring these predicted deleterious variants in . Four additional PAH cases with rare likely loss-of-function variants in were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. - The Bayesian inference approach allowed us to independently validate , which encodes for the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.
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http://dx.doi.org/10.1161/CIRCGEN.120.003155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892262PMC
December 2020

Effect of riociguat on pulmonary arterial compliance in the PATENT and CHEST studies.

Pulm Circ 2020 Oct-Dec;10(4):2045894020963836. Epub 2020 Nov 20.

Pulmonary, Critical Care and Sleep Division, Tufts University Medical Center, Boston, MA, USA.

Pulmonary arterial compliance is a measure of the pulsatile afterload of the right ventricle. Lower pulmonary arterial compliance is associated with reduced right ventricular function and worse prognosis in pulmonary hypertension. The effect of pulmonary vasodilators on pulmonary arterial compliance has not been evaluated in detail in pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. In this post hoc analysis of patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension in the PATENT and CHEST studies, we evaluated the change in pulmonary arterial compliance with riociguat versus placebo. Association of pulmonary arterial compliance with clinical outcomes was assessed using Kaplan-Meier and Cox proportional hazards analyses. Compared with placebo, riociguat significantly improved pulmonary arterial compliance in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Pulmonary arterial compliance at baseline was associated with survival and clinical worsening-free survival in pulmonary arterial hypertension but only with clinical worsening-free survival in chronic thromboembolic pulmonary hypertension. In patients with pulmonary arterial hypertension, pulmonary arterial compliance at follow-up ≥1.6 mL/mmHg was associated with better outcomes than pulmonary arterial compliance <1.6 mL/mmHg. In patients with chronic thromboembolic pulmonary hypertension, pulmonary arterial compliance at follow-up did not predict outcomes. Cox proportional hazards analyses showed no association between change in pulmonary arterial compliance and outcomes in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. In conclusion, riociguat improved pulmonary arterial compliance in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Pulmonary arterial compliance at baseline or follow-up, rather than change in pulmonary arterial compliance, is of prognostic importance for outcomes.
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http://dx.doi.org/10.1177/2045894020963836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686638PMC
November 2020

Standardized exercise training is feasible, safe, and effective in pulmonary arterial and chronic thromboembolic pulmonary hypertension: results from a large European multicentre randomized controlled trial.

Eur Heart J 2020 Nov 24. Epub 2020 Nov 24.

Scottish Pulmonary Vascular Unit, Golden Jubilee National Hospital, Glasgow, UK.

Aims: This prospective, randomized, controlled, multicentre study aimed to evaluate efficacy and safety of exercise training in patients with pulmonary arterial (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).

Methods And Results: For the first time a specialized PAH/CTEPH rehabilitation programme was implemented in 11 centres across 10 European countries. Out of 129 enrolled patients, 116 patients (58 vs. 58 randomized into a training or usual care control group) on disease-targeted medication completed the study [85 female; mean age 53.6 ± 12.5 years; mean pulmonary arterial pressure 46.6 ± 15.1 mmHg; World Health Organization (WHO) functional class II 53%, III 46%; PAH n = 98; CTEPH n = 18]. Patients of the training group performed a standardized in-hospital rehabilitation with mean duration of 25 days [95% confidence interval (CI) 17-33 days], which was continued at home. The primary endpoint, change of 6-min walking distance, significantly improved by 34.1 ± 8.3 m in the training compared with the control group (95% CI, 18-51 m; P < 0.0001). Exercise training was feasible, safe, and well-tolerated. Secondary endpoints showed improvements in quality of life (short-form health survey 36 mental health 7.3 ± 2.5, P = 0.004), WHO-functional class (training vs. control: improvement 9:1, worsening 4:3; χ2  P = 0.027) and peak oxygen consumption (0.9 ± 0.5 mL/min/kg, P = 0.048) compared with the control group.

Conclusion: This is the first multicentre and so far the largest randomized, controlled study on feasibility, safety, and efficacy of exercise training as add-on to medical therapy in PAH and CTEPH. Within this study, a standardized specialized training programme with in-hospital start was successfully established in 10 European countries.
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http://dx.doi.org/10.1093/eurheartj/ehaa696DOI Listing
November 2020

Prognostic relevance of Doppler echocardiographic re-assessment in HFrEF patients.

Int J Cardiol 2021 Mar 19;327:111-116. Epub 2020 Nov 19.

Division of Cardiology, Istituti Clinici Scientifici Maugeri, IRCCS, Gattico-Veruno, Italy.

Background: Current guidelines do not recommend periodically repeating echocardiograms in the follow-up of stable heart failure patients with reduced ejection fraction (HFrEF). The objective of the study was to verify the additional prognostic information provided by a comprehensive re-assessment of their cardiac function and hemodynamic profile at Doppler echocardiography in HFrEF patients.

Methods: Retrospective analysis of 769 stable HFrEF outpatients who underwent two complete echocardiograms, at baseline and at re-assessment. Main candidate predictors of prognosis were: left ventricular (LV) filling pattern, pulmonary artery systolic pressure (PASP) and right ventricular function (TAPSE). Age, LV ejection fraction, mitral regurgitation severity, NYHA class, brain natriuretic peptide plasma levels at baseline, and their changes at 12 months, were used as covariates. Median follow-up was 30 months. All-cause death was the study end-point.

Results: At baseline, restrictive filling pattern and low TAPSE were significant predictors of poor prognosis. At re-evaluation, persistently restrictive/worsened filling pattern, persistently-low/worsened TAPSE and worsened PASP, were associated with poorer survival. A significant interaction between changes in TAPSE, PASP and LV filling pattern was observed: in the restrictive pattern subgroup, survival was poorer in worsened/persistently low TAPSE (p < 0.01); in non-restrictive pattern subgroup, survival was poorer in worsened/persistently elevated PASP (p = 0.01). The re-assessment model improved the C-index from 0.69 to 0.74 (P < 0.01) compared to baseline model.

Conclusions: Doppler echocardiographic re-assessment of LV filling pattern, PASP and TAPSE allows a better prognostic stratification of HFrEF outpatients than baseline evaluation and is additional to changes in BNP and NYHA class.
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http://dx.doi.org/10.1016/j.ijcard.2020.11.025DOI Listing
March 2021

Pulmonary endarterectomy in the octogenarian population: safety and outcomes.

J Cardiovasc Med (Hagerstown) 2020 Nov 12. Epub 2020 Nov 12.

Unit of Cardiac Surgery, Intrathoracic Transplantation and Pulmonary Hypertension, University of Pavia School of Medicine, Foundation I.R.C.C.S. Policlinico San Matteo.

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.
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http://dx.doi.org/10.2459/JCM.0000000000001138DOI Listing
November 2020

The haemodynamic assessment of patients with pulmonary arterial hypertension.

Authors:
Stefano Ghio

Glob Cardiol Sci Pract 2020 Apr 30;2020(1):e202004. Epub 2020 Apr 30.

Division of Cardiology, Foundation "I.R.C.C.S. Policlinico San Matteo", Pavia, Italy.

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http://dx.doi.org/10.21542/gcsp.2020.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590935PMC
April 2020

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

Diagnostics (Basel) 2020 Oct 22;10(11). Epub 2020 Oct 22.

Division of Cardiology, Fondazione IRCCS Policlinico S.Matteo, 27100 Pavia, Italy.

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 ( 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, < 0.001, < 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, = 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.
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http://dx.doi.org/10.3390/diagnostics10110857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690258PMC
October 2020

Pulmonary Artery Wedge Pressure Respiratory Variation Increases With Sodium Nitroprusside Vasodilator Challenge.

J Card Fail 2020 Dec 7;26(12):1096-1099. Epub 2020 Oct 7.

Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina. Electronic address:

Background: The physiologic factors leading to pulmonary arterial wedge pressure respiratory variation (PAWP) are underexplored. We hypothesized that PAWP is associated with baseline PAWP and would predict response to sodium nitroprusside (SNP).

Methods And Results: We performed a retrospective study of right heart catheterization studies in 51 subjects with SNP challenge at our institution from 2012 to 2019. PAWP was defined as expiratory minus inspiratory PAWP. Baseline %PAWP was inversely correlated with baseline PAWP (R = -0.5). SNP administration led to increased %PAWP (+27%, P < .01). Subjects with low baseline PAWP (less than the median) had an increase in PAWP with SNP (3 ± 4 mm Hg), whereas those with a high baseline PAWP (greater than the median) did not (-0.6 ± 4 mm Hg, P = .003). Those who had a greater than the median PAWP increase with SNP had greater cardiac output augmentation compared with those who had less than a median increase in PAWP (1.7 ± 1.5 L/min vs 0.9 ± 0.7 L/min, P = .02). An increasing PAWP after SNP was associated with significant discrepancy in the number of subjects achieving transplant-acceptable pulmonary vascular resistance (<2.5 Wood units) when calculated by expiratory versus mean PAWP (37 vs 27 subjects, 20% discrepancy rate). Subjects with a higher PAWP after SNP were more likely to demonstrate discrepant transplant-acceptable pulmonary vascular resistance calculations comparing expiratory versus mean PAWP than those with lower PAWP post-SNP (47% vs 13%, odds ratio 5.5, P = .03).

Conclusions: Our findings indicate that PAWP is a meaningful physiologic parameter that is influenced by the compliance of the left heart/pulmonary vascular system and its relative preload and afterload states.
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http://dx.doi.org/10.1016/j.cardfail.2020.09.476DOI Listing
December 2020

QTc Interval and Mortality in a Population of SARS-2-CoV Infected Patients.

Circ Arrhythm Electrophysiol 2020 11 29;13(11):e008890. Epub 2020 Sep 29.

Cardiac Intensive Care Unit, Arrhythmia and Electrophysiology and Laboratory of Clinical and Experimental Cardiology (A.V., L.M., S.D., E.B., A.S., B.P., L.F., R.R.), Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

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http://dx.doi.org/10.1161/CIRCEP.120.008890DOI Listing
November 2020

Cardiac involvement at presentation in patients hospitalized with COVID-19 and their outcome in a tertiary referral hospital in Northern Italy.

Intern Emerg Med 2020 Nov 22;15(8):1457-1465. Epub 2020 Sep 22.

Emergency Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Pavia, Italy.

The correlation between myocardial injury and clinical outcome in COVID-19 patients is gaining attention in the literature. The aim of the present study was to evaluate the role of cardiac involvement and of respiratory failure in a cohort of COVID-19 patients hospitalized in an academic hospital in Lombardy, one of the most affected Italian (and worldwide) regions by the epidemic. The study included 405 consecutive patients with confirmed COVID-19 admitted to a medical ward from February 25th to March 31st, 2020. Follow-up of surviving patients ended either at hospital discharge or by July 30th, 2020. Myocardial injury was defined on the basis of the presence of blood levels of hs-TnI above the 99th percentile upper reference limit. Respiratory function was assessed as PaO/FiO (P/F) ratio. The primary end-point was death for any cause. During hospitalization, 124 patients died. Death rate increased from 7.9% in patients with normal hs-TnI plasma levels and no cardiac comorbidity to 61.5% in patients with elevated hs-TnI and cardiac involvement (p < 0.001). At multivariable analysis, older age, P/F ratio < 200 (both p < 0.001) and hs-TnI plasma levels were independent predictors of death. However, it must be emphasized that the median values of hs-TnI were within normal range in non-survivors. Cardiac involvement at presentation was associated with poor prognosis in COVID-19 patients, but, even in a population of COVID-19 patients who did not require invasive ventilation at hospital admission, mortality was mainly driven by older age and respiratory failure.
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http://dx.doi.org/10.1007/s11739-020-02493-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505942PMC
November 2020

Hemodynamics and risk assessment 2 years after the initiation of upfront ambrisentan‒tadalafil in pulmonary arterial hypertension.

J Heart Lung Transplant 2020 12 28;39(12):1389-1397. Epub 2020 Aug 28.

Department of Pathophysiology, Free University of Brussels, Brussels, Belgium.

Background: Upfront combination therapy with ambrisentan and tadalafil has been reported to improve the condition of patients with pulmonary arterial hypertension (PAH) more than with either drug alone. However, little is known about the long-term associated changes in hemodynamics and risk assessment scores.

Methods: This was a multicenter, retrospective analysis of clinical data in 106 patients with newly diagnosed PAH. Clinical evaluations, including demographics, medical history, World Health Organization (WHO) functional class (FC) and 6-minute walk distance (6MWD), right heart catheterization, and Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk score 2.0, were assessed over 48 months of ambrisentan‒tadalafil therapy.

Results: At baseline, 9 patients (9%) showed a low (<7), 48 patients (45%) showed an intermediate (7-8), and 49 patients (46%) showed a high (>8) REVEAL risk score. At a median follow-up of 2 years, 45 patients (43%) showed a low, 47 patients (44%) showed an intermediate, and 14 patients (13%) showed a high REVEAL score, along with improvements in WHO FC, 6MWD and a decrease in mean pulmonary artery pressure and N-terminal pro brain natriuretic peptide (all p < 0.001). Pulmonary vascular resistance (PVR) decreased by 37% from 11.5 ± 6.5 to 7.2 ± 4.1 Wood units (p < 0.001). A total of 61 patients (57%) remained in intermediate-risk or high-risk categories. Low-risk patients had either a decrease in PVR of >50% or a stroke volume within the limits of normal.

Conclusions: Initial combination therapy with ambrisentan and tadalafil in PAH improves the REVEAL risk score in proportion to decreased PVR and preserved stroke volume but still insufficiently so in approximately 50% of the patients.
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http://dx.doi.org/10.1016/j.healun.2020.08.016DOI Listing
December 2020

Pre-existing type 2 diabetes is associated with increased all-cause death independently of echocardiographic predictors of poor prognosis only in ischemic heart disease.

Nutr Metab Cardiovasc Dis 2020 10 15;30(11):2036-2040. Epub 2020 Jul 15.

Division of Cardiology, Fondazione Salvatore Maugeri, IRCCS, Veruno, Italy.

Background And Aims: It is unknown whether the prognostic role of diabetes (T2DM) in outpatients with chronic heart failure (CHF) is independent of the most important echocardiographic markers of poor prognosis. The aims of this analysis were to evaluate whether T2DM modifies the risk of mortality in CHF patients stratified by etiology of disease or by right-ventricular to pulmonary arterial coupling at echocardiography and to evaluate how T2DM interacts with the prognostic role of cardiac plasma biomarkers.

Methods And Results: This is a retrospective analysis of 1627 CHF outpatients who underwent a complete echocardiographic examination. During a median follow-up period of 63 months 255 patients died. Poor right-ventricular to pulmonary arterial coupling and reduced left ventricular ejection fraction were independent predictors of outcome, whereas ischemic etiology and T2DM were not. T2DM interacted with etiology increasing the risk of mortality by 32% among patients with ischemic disease (p = 0.003). Elevated hsTNI plasma levels were associated with poor survival in T2DM but not in non-diabetic patients.

Conclusion: T2DM signals a worse outcome in ischemic CHF patients regardless of the echocardiographic phenotype. High plasma levels of hsTNI are stronger predictors of mortality in CHF patients with T2DM than in patients without diabetes.
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http://dx.doi.org/10.1016/j.numecd.2020.07.008DOI Listing
October 2020

Risk Reduction and Hemodynamics with Initial Combination Therapy in Pulmonary Arterial Hypertension.

Am J Respir Crit Care Med 2021 02;203(4):484-492

Department of Cardiovascular and Respiratory Sciences, Sapienza University of Rome, Rome, Italy.

An initial oral combination of drugs is being recommended in pulmonary arterial hypertension (PAH), but the effects of this approach on risk reduction and pulmonary vascular resistance (PVR) are not known. To test the hypothesis that a low-risk status would be determined by the reduction of PVR in patients with PAH treated upfront with a combination of oral drugs. The study enrolled 181 treatment-naive patients with PAH (81% idiopathic) with a follow-up right heart catheterization at 6 months (interquartile range, 144-363 d) after the initial combination of endothelin receptor antagonist + phosphodiesterase-5 inhibitor drugs and clinical evaluation and risk assessments by European guidelines and Registry to Evaluate Early and Long-Term PAH Disease Management scores. Initial combination therapy improved functional class and 6-minute-walk distance and decreased PVR by an average of 35% (median, 40%). One-third of the patients had a decrease in PVR <25%. This poor hemodynamic response was independently predicted by age, male sex, pulmonary artery pressure and cardiac index, and at echocardiography, a right/left ventricular surface area ratio of greater than 1 associated with low tricuspid annular plane systolic excursion of less than 18 mm. A low-risk status at 6 months was achieved or maintained in only 34.8% (Registry to Evaluate Early and Long-Term PAH Disease Management score) to 43.1% (European score) of the patients. Adding criteria of poor hemodynamic response improved prediction of a low-risk status. A majority of patients with PAH still insufficiently improved after 6 months of initial combinations of oral drugs is identifiable at initial evaluation by hemodynamic response criteria added to risk scores.
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http://dx.doi.org/10.1164/rccm.202004-1006OCDOI Listing
February 2021

Pulmonary Hypertension in HFpEF and HFrEF: JACC Review Topic of the Week.

J Am Coll Cardiol 2020 09;76(9):1102-1111

Pulmonary Division, Lady Davis Carmel Medical Center, Faculty of Medicine, The Technion, Institute of Technology, Haifa, Israel.

Pulmonary hypertension (PH) associated with left heart disease, or Group 2 PH, includes heart failure, valvular heart diseases, and congenital heart diseases. Although it is axiomatic that in PH due to heart failure the increase in pulmonary pressure is directly related to an enhanced left atrial pressure, which is common to both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF), there has been limited attention over the years on the potential differences in terms of driving mechanisms, pathophysiology, and clinical phenotypes. Major differences between HFpEF and HFrEF are the underlying causes, associated comorbidities, and cardiac remodeling. This suggests that despite similar hemodynamic profiles, there may be some disparities in PH development. A focused knowledge on the differences between the 2 syndromes has relevant implications to seek new, personalized, and timely treatments for Group 2 PH. The purpose of the present review is to highlight the mechanisms and clinical phenotypes of PH in HFpEF and HFrEF.
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http://dx.doi.org/10.1016/j.jacc.2020.06.069DOI Listing
September 2020

Is the fear of COVID-19 infection the same in all subjects?

Int J Infect Dis 2020 08 15;97:331-333. Epub 2020 Jun 15.

Microbiology and Virology Unit, San Matteo Hospital, University of Pavia, Pavia, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.ijid.2020.06.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295515PMC
August 2020

A comprehensive echocardiographic method for risk stratification in pulmonary arterial hypertension.

Eur Respir J 2020 09 24;56(3). Epub 2020 Sep 24.

University Hospital Giessen und Marburg GmbH, Pulmonary Hypertension Division, Medical Clinic II, Giessen, Germany.

Question Addressed: Echocardiography is not currently considered as providing sufficient prognostic information to serve as an integral part of treatment goals in pulmonary arterial hypertension (PAH). We tested the hypothesis that incorporation of multiple parameters reflecting right heart function would improve the prognostic value of this imaging modality.

Methods And Main Results: We pooled individual patient data from a total of 517 patients (mean age 52±15 years, 64.8% females) included in seven observational studies conducted at five European and United States academic centres. Patients were subdivided into three groups representing progressive degrees of right ventricular dysfunction based on a combination of echocardiographic measurements, as follows. Group 1 (low risk): normal tricuspid annular plane systolic excursion (TAPSE) and nonsignificant tricuspid regurgitation (TR) (n=129); group 2 (intermediate risk): normal TAPSE and significant TR or impaired TAPSE and nondilated inferior vena cava (IVC) (n=256); group 3 (high risk): impaired TAPSE and dilated IVC (n=132). The 5-year cumulative survival rate was 82% in group 1, 63% in group 2 and 43% in group 3. Low-risk patients had better survival rates than intermediate-risk patients (log-rank Chi-squared 12.25; p<0.001) and intermediate-risk patients had better survival rates than high-risk patients (log-rank Chi-squared 26.25; p<0.001). Inclusion of other parameters such as right atrial area and pericardial effusion did not provide added prognostic value.

Answer To The Question: The proposed echocardiographic approach integrating the evaluation of TAPSE, TR grade and IVC is effective in stratifying the risk for all-cause mortality in PAH patients, outperforming the prognostic parameters suggested by current guidelines.
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http://dx.doi.org/10.1183/13993003.00513-2020DOI Listing
September 2020

[COVID-19 pandemic: the need to reorganize a Cardiology Department in a hospital of the Lombardy Region, Italy].

G Ital Cardiol (Rome) 2020 05;21(5):358-359

U.O.C. Cardiologia - U.O.C Unità Coronarica - Ricerca e Sperimentazione Cardiologica, Dipartimento Scienze Mediche e Malattie Infettive, Fondazione IRCCS Policlinico San Matteo, Pavia.

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http://dx.doi.org/10.1714/3343.33134DOI Listing
May 2020

Long-Term Effects of the Replacement of Calcineurin Inhibitors With Everolimus and Mycophenolate in Patients With Calcineurin Inhibitor-Related Nephrotoxicity.

Transplant Proc 2020 Apr 27;52(3):836-842. Epub 2020 Feb 27.

Division of Cardiology, Fondazione IRCCS San Matteo Hospital, Pavia, Italy.

Background: There is little evidence on the long-term effects of calcineurin inhibitor (CNI) withdrawal and substitution with everolimus and mycophenolate mofetil in maintenance therapy of patients who have received heart transplants and have concurrent CNI nephrotoxicity. Aims of this study were to evaluate the progression of renal dysfunction after discontinuation of CNIs and to monitor for major adverse events after therapy change.

Methods: Data from 41 patients who underwent heart transplant and have different degrees of renal dysfunction (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m), without evidence of proteinuria, and in whom CNI therapy was replaced by everolimus, were analyzed. At the time of CNI withdrawal, clinical parameters, echocardiographic data, blood tests of renal function, and monitoring of adverse events were recorded. The median follow-up period was 5 years ± 28 months.

Results: In 52% of patients, there was a clear improvement in renal function (10.5 mL/min/1.73 m of extra eGFR on average). The former were characterized by less advanced age and a short time from the heart transplant. The echocardiographic parameters showed a significant reduction in septum thickness (11.58 ± 2 mm vs 10.29 ± 2 mm; P = .0001) and in left ventricle posterior wall thickness (10.74 ± 1 mm vs 9.74 ± 1 mm; P = .0004). The incidence of late acute rejection and cardiac allograft vasculopathy was similar in our population compared to literature data.

Conclusions: A therapeutic switch from CNIs to everolimus and mycophenolate mofetil can improve renal function in patients with CNI nephrotoxicity, especially in those with a shorter time period from transplantation, without exposing them to a higher incidence of late acute rejection and cardiac allograft vasculopathy.
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http://dx.doi.org/10.1016/j.transproceed.2020.01.030DOI Listing
April 2020