Does pulmonary endarterectomy improve the clinical conditions of patients with chronic thromboembolic pulmonary disease without pulmonary hypertension?

To verify whether the new hemodynamic definition of pulmonary hypertension (PH) has any implication in treatment of Chronic Thrombo-Embolic Pulmonary Disease (CTEPD) patients without PH, we retrospectively analysed the clinical and functional changes determined by pulmonary endarterectomy (PEA) in 63 CTEPD patients without PH who underwent surgery at our center, comparing those in whom the hemodynamic diagnosis of PH met recent guideline recommendations versus those in whom the diagnosis only met previous hemodynamic thresholds. The results show that the vast majority of CTEPD patients without PH operated at our center would now be defined as chronic thromboembolic pulmonary hypertension (CTEPH) patients. PEA did not result in any improvement in exercise capacity nor in right ventricular function or lung function test in patients with mean pulmonary artery pressure (mPAP) ≤ 20 mm Hg and pulmonary vascular resistance (PVR) ≤ 2 WU; on the contrary, hemodynamic parameters, exercise capacity, right ventricular function and lung function significantly improved in patients with mPAP between 21 and 24 mm Hg.

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

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-5 (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-5 (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.

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

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.

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

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 m2), 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 m2 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.

High preoperative plasma endothelin-1 levels are associated with increased acute kidney injury risk after pulmonary endarterectomy.

OBJECTIVES: The only curative treatment for chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA). PEA requires cardiopulmonary bypass (CPB) which is associated with a high acute kidney injury (AKI) risk. Circulating endothelin-1 (ET-1) levels are elevated in CTEPH, and ET-1 plays a pivotal role in AKI. Because AKI is burdened by high morbidity and mortality, we aimed to evaluate the association between preoperative ET-1 and the risk to develop AKI in CTEPH individuals who undergo PEA. We also evaluated the association of AKI and ET-1 with kidney function and mortality at 1 year after PEA. METHODS: In 385 consecutive patients diagnosed with CTEPH who underwent PEA at the Foundation IRCC Policlinico San Matteo (Pavia, Italy) from January 2009 to April 2015, we assessed preoperative circulating ET-1 by ELISA and identified presence of AKI based on 2012 KDIGO criteria. RESULTS: AKI occurred in 26.5% of the 347 patients included in the analysis, and was independently associated with preoperative ET-1 (p = 0.008), body mass index (BMI) (p = 0.022), male gender (p = 0.005) and duration of CPB (p = 0.002). At 1-year post PEA, estimated glomerular filtration rate (eGFR) significantly improved in patients who did not develop AKI [ΔeGFR 5.6 ml/min/1.73 m2 (95% CI 3.6-7.6), p < 0.001] but not in those with perioperative AKI. AKI (p < 0.001), age (p < 0.001), preoperative eGFR (p < 0.001) and systemic hypertension diagnosis (p = 0.015) were independently associated with 1-year ΔeGFR. Neither perioperative AKI nor preoperative ET-1 was associated with 1-year survival. CONCLUSION: Perioperative AKI is associated with higher preoperative circulating ET-1 and it negatively influences long-term kidney function in patients with CTEPH who undergo PEA.

Advanced native-kidney carcinoma in a heart- and kidney-transplanted patient: a case report.

Malignancies are one of the leading causes of death in long-term surviving transplant recipients. Dose and prolonged durations of immunosuppressive regimens are considered the main cause, through a direct oncogenic effect and a renowned interaction on physiological anti-viral and anti-oncogenic immune response. Specific neoplasms are known to occur with different frequencies according to the transplanted organ. As a consequence, imaging screenings have been implemented in many graft surveillance programs, although a wide consensus on the timing and modality has not been concurred. There are little data available in the literature regarding incidence of de-novo malignancies in multi-organ recipients. We report the case of a 66-year-old man who developed a renal mass 10 years after a combined heart-kidney transplant.

Pavia Experience in Reoperative Pulmonary Endarterectomy.

In our experience, we reperformed pulmonary endarterectomy (PEA) in 10 patients who previously underwent a first PEA. We analyzed this cohort of patients to investigate the main causes of recurrence of symptomatic pathology and the clinical and hemodynamic results of redo surgery. Between 1994 and April 2016, 10 of 716 patients were reoperated at our institution. Available postoperative data were analyzed, and a comparison between first and second PEA hemodynamic and clinical results was carried out. In-hospital mortality rate was also evaluated. After reoperation, mean pulmonary arterial pressure decreased from 45?±?9 to 34?±?10?mm Hg, and pulmonary vascular resistance reduced from 932?±?346?dyne*s*cm?5 to 428?±?207?dyne*s*cm?5. Hemodynamic data revealed worthy results of redo PEA, although they are less important than after first PEA. The World Health Organization (WHO) functional class improvement demonstrated satisfactory clinical results. In-hospital mortality of repeat PEA is 40%. Reoperative PEA operative candidacy should be assessed in case of young patients, no other risk factor, and recent medical history of pulmonary hypertension. In the other cases, in-hospital mortality rate is very high and pulmonary hypertension-specific drug therapy or interventional approach should be previously considered.

ANMCO Position Paper: long-term follow-up of patients with pulmonary thromboembolism.

Venous thromboembolism (VTE), including pulmonary embolism and deep venous thrombosis, is the third most common cause of cardiovascular death. The management of the acute phase of VTE has already been described in several guidelines. However, the management of the follow-up (FU) of these patients has been poorly defined. This consensus document, created by the Italian cardiologists, wants to clarify this issue using the currently available evidence in VTE. Clinical and instrumental data acquired during the acute phase of the disease are the cornerstone for planning the FU. Acquired or congenital thrombophilic disorders could be identified in apparently unprovoked VTE during the FU. In other cases, an occult cancer could be discovered after a VTE. The main targets of the post-acute management are to prevent recurrence of VTE and to identify the patients who can develop a chronic thromboembolic pulmonary hypertension. Knowledge of pathophysiology and therapeutic approaches is fundamental to decide the most appropriate long-term treatment. Moreover, prognostic stratification during the FU should be constantly updated on the basis of the new evidence acquired. Currently, the cornerstone of VTE treatment is represented by both the oral and the parenteral anticoagulation. Novel oral anticoagulants should be an interesting alternative in the long-term treatment.

Analysis of long term CD4+CD25highCD127- T-reg cells kinetics in peripheral blood of lung transplant recipients.

BACKGROUND: The role of CD4+CD25highCD127- T-reg cells in solid-organ Transplant (Tx) acceptance has been extensively studied. In previous studies on kidney and liver recipients, peripheral T-reg cell counts were associated to graft survival, while in lung Tx, there is limited evidence for similar findings. This study aims to analyze long term peripheral kinetics of T-reg-cells in a cohort of lung recipients and tests its association to several clinical variables. METHODS: From jan 2009 to dec 2014, 137 lung Tx recipients were submitted to an immunological follow up (median: 105.9 months (6.7-310.5)). Immunological follow up consisted of a complete blood peripheral immuno-phenotype, inclusive of CD4+CD25highCD127- T and FOXP3+ cells. We tested the association between T-reg and relevant variables by linear OR regression models for repeated measures, adjusting for time from Tx. Also, by ordered logistic models for panel data, the association between Chronic Lung Allograft Dysfuncton (CLAD) onset/progression and T-reg counts in the previous 3 months was tested. RESULTS: Among all variables analyzed at multivariate analysis: Bronchiolitis Obliterans Syndrome (OR -6.51, p < 0.001), Restrictive Allograft Syndrome (OR -5.19, p = 0.04) and Extracorporeal photopheresis (OR -5.65, p < 0.001) were significantly associated to T-reg cell. T-reg cell counts progressively decreased according to the severity of CLAD. Furthermore, patients with higher mean T-reg counts in a trimester had a significantly lower risk (OR 0.97, p = 0.012) of presenting CLAD or progressing in the graft dysfunction in the following trimester. CONCLUSIONS: Our present data confirm animal observations on the possible role of T-reg in the evolution of CLAD.

Pulmonary endarterectomy in the management of chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a type of pulmonary hypertension, resulting from fibrotic transformation of pulmonary artery clots causing chronic obstruction in macroscopic pulmonary arteries and associated vascular remodelling in the microvasculature.Pulmonary endarterectomy (PEA) offers the best chance of symptomatic and prognostic improvement in eligible patients; in expert centres, it has excellent results. Current in-hospital mortality rates are <5% and survival is >90% at 1 year and >70% at 10 years. However, PEA, is a complex procedure and relies on a multidisciplinary CTEPH team led by an experienced surgeon to decide on an individual's operability, which is determined primarily by lesion location and the haemodynamic parameters. Therefore, treatment of patients with CTEPH depends largely on subjective judgements of eligibility for surgery by the CTEPH team.Other controversies discussed in this article include eligibility for PEA versus balloon pulmonary angioplasty, the new treatment algorithm in the European Society of Cardiology/European Respiratory Society guidelines and the definition of an "expert centre" for the management of this condition.

Patent foramen ovale diagnosis: The importance of provocative maneuvers.

Patent foramen ovale (PFO) is a frequent congenital anomaly, but massive right-to-left shunt (RTLS) is normally prevented by higher pressures in left heart chambers. However, mechanical ventilation with positive end-expiratory pressure (PEEP) can significantly increase right atrial pressure, accentuating the RTLS, mainly after major cardiothoracic surgery. We report a patient admitted to the intensive care unit after cardiac surgery. Pre- and intraoperative transesophageal echocardiography only described an aneurysmal interatrial septum with no shunt. However, high-PEEP ventilation induced a paradoxical response with life-threatening hypoxemia, triggering further echocardiographic evaluation, revealing massive RTLS across a stretch PFO. Provocative maneuvers (Valsalva/PEEP) significantly increase echocardiographic sensitivity, unmasking silent PFO. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:58-61, 2017.

[ANMCO Position paper: Recommendations for the follow-up of patients with pulmonary thromboembolism]. / Position paper ANMCO: Raccomandazioni per il follow-up del paziente con tromboembolia polmonare.

Venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism, is the third most common cause of cardiovascular death. The management of the acute phase of VTE is well described in several papers and guidelines, whereas the management of the follow-up of the patients affected from VTE is less defined. This position paper of the Italian Association of Hospital Cardiologists (ANMCO) tries to fill the gap using currently available evidence and the opinion of the experts to suggest the most useful way to manage patients in the chronic phase.The clinical and laboratory tests acquired during the acute phase of the disease drives the decision of the following period. Acquired or congenital thrombophilic factors may be identified to explain an apparently not provoked VTE. In some patients, a not yet clinically evident cancer could be the trigger of VTE and this could lead to a different strategy. The main target of the post-acute management is to prevent relapse of the disease and to identify those patients who could worsen or develop chronic thromboembolic pulmonary hypertension. The knowledge of the etiopathogenetic ground is important to address the therapeutic approach, choosing the best antithrombotic strategy and deciding how long therapy should last. During the follow-up period, prognostic stratification should be updated on the basis of new evidences eventually acquired.Treatment of VTE is mainly based on oral or parenteral anticoagulation. Oral direct inhibitors of coagulation represent an interesting new therapy for the acute and extended period of treatment.

Changes in surface electrocardiogram in patients with chronic thromboembolic pulmonary hypertension undergoing pulmonary endarterectomy. Correlations with hemodynamic and echocardiographic improvements after surgery.

BACKGROUND: The aim of the present study was to evaluate the changes of electrocardiographic (ECG) markers of right ventricular (RV) hypertrophy/overload in patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing pulmonary endarterectomy (PEA). METHODS AND RESULTS: We evaluated 99 CTEPH patients who underwent PEA. P wave amplitude in DII, R wave amplitude in V1 and the number of patients with negative T wave in V1-V3 decreased significantly at 1month after surgery with no further change at 1year, in parallel with the rapid improvement in right heart hemodynamics. S wave amplitude in V1, R:S wave ratio in lead V6 and prevalence of SIQIII pattern improved significantly at 1year, in parallel with the progressive reverse remodeling of the right ventricle at echocardiography. CONCLUSIONS: The study shows that some of the ECG markers of RV hypertrophy/overload better reflect RV hemodynamic overload while others better reflect the pathologic remodeling of the right ventricle.

Pulmonary endarterectomy in the elderly: safety, efficacy and risk factors.

AIMS: Pulmonary endarterectomy (PEA) is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension, but there are few data in the literature about the results of this procedure in the elderly. In this study, we aimed to assess whether this type of surgery is effective and well tolerated for the elderly. METHODS: A total of 264 consecutive patients who underwent PEA between January 2008 and December 2012 were reviewed. PEA was performed under cardiopulmonary bypass and hypothermic ventricular fibrillation, with the aorta left unclamped. The population was dichotomized according to age into the following two groups: below 70 years (n = 176, younger patients) and at least 70-year-olds (n = 88, elderly patients). Regression models were used to identify predictors of hospital mortality and postoperative adverse events, and their interaction with age was tested. RESULTS: Hospital mortality was slightly, but not significantly higher in elderly patients (9.1 vs. 5.1%; P = 0.22). Effect modification by history of smoking and preoperative O2 therapy was present. The cumulative survival at 1, 2, and 4 years was 93, 92, and 91% among younger patients; and 88, 86, and 86% among older patients (P = 0.19). Clinical and hemodynamic improvement was similar in the two groups. CONCLUSION: Despite a slightly higher short-term mortality, PEA is feasible and well tolerated for the vast majority of the elderly patients. Clinical and hemodynamic improvements are outstanding, with satisfactory long-term survival rates.

Urgent lung transplant programme in Italy: analysis of the first 14 months.

OBJECTIVES: Lung transplantation (LTx) is the only effective treatment for end-stage lung disease. In rapidly deteriorating patients awaiting transplant, supportive strategies for lung function allow only a short period of support and lung transplantation remains the definitive therapy. An urgent transplant programme may reduce the waiting time, allowing lung transplantation in these patients. METHODS: Since November 2010 a nation-wide urgent lung transplant programme has been established in Italy and patients on the waiting list dependent on mechanical ventilation and/or extracorporeal lung support (ECLS) can be transplanted on an emergency basis with the first available graft in the country. Results of the first 14 months of this programme are analysed here. RESULTS: From November 2010 to December 2011, 28 patients (14 males, mean age 33.6 ± 14.4 years) were considered for urgent LTx. Rapidly deteriorating lung function was supported with mechanical ventilation alone in 4 patients (14.3%), ECLS in 13 patients (46.4%) and mechanical ventilation plus ECLS in the remaining 11 patients (39.3%). Three patients (10.7%) were excluded because of worsening conditions, 3 patients (10.7%) while on the urgent listed and 22 patients (78.6%) underwent transplantation after 9.8 ± 6.2 days of being on the urgent list. The 30-day mortality rate after LTx was 18%, and the 1-year survival rate was 71.4%. CONCLUSIONS: The urgent lung transplant programme allowed transplantation in a significant percentage of prioritized patients with acceptable 30-day and 1-year mortality rates. An accurate selection of recipients may further improve the clinical impact of this programme, reducing the ethical concerns about transplantation in high-risk patients.

Heart transplantation in patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

BACKGROUND: Heart involvement is the leading cause of death of patients with eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome) and is more frequent in anti-neutrophil cytoplasm antibody (ANCA)-negative patients. Post-transplant outcome has only been reported once. METHODS: We conducted a retrospective international multicenter study. Patients satisfying the criteria of the American College of Rheumatology and/or revised Chapel Hill Consensus Conference Nomenclature were identified by collaborating vasculitis and transplant specialists, and the help of the Churg-Strauss Syndrome Association. RESULTS: Nine ANCA(-) patients who received transplants between October 1987 and December 2009 were identified. The vasculitis and cardiomyopathy diagnoses were concomitant for 5 patients and separated by 12 to 288 months for the remaining 4 patients. Despite ongoing immunosuppression, histologic examination of 7 (78%) patients' explanted hearts showed histologic patterns suggestive of active vasculitis. The overall 5-year survival rate was low (57%), but rose to 80% when considering only the 6 patients transplanted during the last decade. After survival lasting 3 to 60 months, 4 (44%) patients died sudden deaths. CONCLUSIONS: The search for EGPA-related cardiomyopathy is mandatory early in the course of this type of vasculitis. Indeed, prompt treatment with corticosteroids and cyclophosphamide may achieve restore cardiac function. Most patients in this series were undertreated. For patients with refractory EGPA, heart transplantation should be performed, which carries a fair prognosis. No optimal immunosuppressive strategy has yet been identified.

Leukocytoclastic vasculitis as a complication of recombinant granulocyte colony-stimulating factor therapy in a heart transplant patient.

Recombinant granulocyte colony-stimulating factor (rG-CSF) is a myeloid growth factor that is widely used in haematology to recover neutropenia secondary to myelosuppressive chemotherapy. Leukocytoclastic vasculitis is an acknowledged side effect of the above therapy. Its pathogenesis involves many mechanisms that collectively induce an increase in neutrophil function and a subsequent release of cytokines. Here, we report a case of leukocytoclastic vasculitis proven by skin biopsy, following the use of rG-CSF in a heart transplant patient with leukopenia secondary to immunosuppressive therapy.

Pulmonary arterial compliance and exercise capacity after pulmonary endarterectomy.

Patients with chronic thromboembolic pulmonary hypertension (CTEPH), despite successful pulmonary endarterectomy (PEA), can continue to suffer from a limitation in exercise capacity. The objective of this study was to assess whether pulmonary arterial compliance is a predictor of exercise capacity after PEA. Right heart haemodynamics, treadmill incremental exercise test, spirometry, carbon monoxide transfer factor, arterial blood gas and echocardiographic examinations were retrospectively analysed in a population of CTEPH patients who underwent PEA at a single centre. Baseline and 3-month haemodynamic data were available in 296 patients; 5-year follow-up data were available in 68 patients. In a multivariable model the following parameters were found to be independent predictors of exercise capacity after surgery: age, sex, pulmonary arterial compliance, tricuspid annular plane excursion, arterial oxygen tension and carbon monoxide transfer factor (p<0.0001); the model showed good discrimination (Harrell's c=0.84) and calibration (shrinkage coefficient=0.91). Poor exercise capacity at 3 months was loosely associated with higher death rate during subsequent survival (Harrell's c=0.61). In conclusion, after successful PEA, reduced pulmonary arterial compliance is an important determinant of exercise capacity in association with the age and sex of the patients, and the extent of recovery of both cardiac and respiratory function. However, exercise capacity does not explain a large proportion of the effect of surgery on subsequent survival.