Right ventricular dysfunction in left ventricular assist device candidates: is it time to change our prospective?

The use of left ventricular assist devices (LVAD) has significantly increased in the last years, trying to offer a therapeutic alternative to heart transplantation, in light also to the significant heart donor shortage compared to the growing advanced heart failure population. Despite technological improvements in the devices, LVAD-related mortality is still fairly high, with right heart failure being one of the predominant predictors. Therefore, many efforts have been made toward a thorough right ventricular (RV) evaluation prior to LVAD implant, considering clinical, laboratory, echocardiographic, and invasive hemodynamic parameters. However, there is high heterogeneity regarding both which predictor is the strongest as well as the relative cut-off values, and a consensus has not been reached yet, increasing the risk of facing patients in which the distinction between good or poor RV function cannot be surely reached. In parallel, due to technological development and availability of mechanical circulatory support of the RV, LVADs are being considered even in patients with suboptimal RV function. The aim of our review is to analyze the current evidence regarding the role of RV function prior to LVAD and its evaluation, pointing out the extreme variability in parameters that are currently assessed and future prospective regarding new diagnostic tools. Finally, we attempt to gather the available information on the therapeutic strategies to use in the peri-operative phase, in order to reduce the incidence of RV failure, especially in patients in which the preoperative evaluation highlighted some conflicting results with regard to ventricular function.

Hydrogeological characteristics and water availability in the mountainous aquifer systems of Italian Central Alps: A regional scale approach.

Groundwater resources in mountain areas are strategically important to maintain adequate water supply for domestic uses, farming, industrial activities, and energy production, also considering the expected growing demand due to ongoing climate changes. Within this framework, the objective of the study is to develop a regional approach, compliant with the European requirements of the Water Framework Directive 2000/60/EC and Groundwater Directive 2006/118/EC, that could support public agencies and water companies to efficiently manage and protect the available water resources in mountainous environments. The proposed approach identifies and delineates groundwater bodies by coupling a 3D hydro-stratigraphic model with the definition of the water budget and water hydrochemical fingerprints in a geologically complex Alpine environment in Northern Italy. Sixteen groundwater bodies (GWBs) have been identified all over the 10.290 km2 area, showing an average storage capacity of more than 500 Mm³ y-1 (about 3% of the average total inflow from precipitation and snowmelt), with differences up to four times between GWBs mainly constituted of carbonate rocks and those prevalently composed of crystalline or terrigenous rocks. Groundwater quality in the study domain is generally excellent, with few exceptions due to geogenic (i.e., natural) or anthropogenic sources of contamination. The results of this study show the advantages of coupling 3D hydro-stratigraphic modelling combined with meteorological, hydrological and hydrogeological information, which consist in: i) identifying the most Strategic Storage Reservoir both in terms of quality and storage capacity; ii) evaluating the present ground- and surface water availability; iii) detecting areas of specific interest for implementing groundwater monitoring networks; iv) recognising recharge areas of the most relevant springs, to implement protection strategies of the resource.

Pretransplant Right Ventricular Dysfunction Is Associated With Increased Mortality After Heart Transplantation: A Hard Inheritance to Overcome.

BACKGROUND: Right ventricular dysfunction (RVD) is a major issue in patients with advanced heart failure because it precludes the implantation of left ventricular assist device, usually leaving heart transplantation (HTx) as the only available treatment option. The pulmonary artery pulsatility index (PAPi) is a hemodynamic parameter integrating information of right ventricular function and of pulmonary circulation. Our aim is to evaluate the association of preoperative RVD, hemodynamically defined as a low PAPi, with post-HTx survival. METHODS AND RESULTS: Consecutive adult HTx recipient at 2 Italian transplant centers between 2000 and 2018 with available data on pre-HTx right heart catheterization were included retrospectively. RVD was defined as a value of PAPi lower than the 25th percentile of the study population. The association of RVD with the 1-year post-HTx mortality and other secondary end points were evaluated. Multivariate logistic regression was used to adjust for clinical and hemodynamic variables. Analyses stratified by pulmonary vascular resistance (PVR) status (≥3 Woods units vs <3 Woods units) were also performed. Among 657 HTx recipients (female 31.1%, age 53 ± 11 years), patients with pre-HTx RVD (PAPi of <1.68) had significantly lower 1-year survival rates (77.8% vs 87.1%, P = .005), also after adjusting for estimated glomerular filtration rate, total bilirubin, PVR, serum sodium, inotropes, and mechanical circulatory support at HTx (hazard ratio 2.0, 95% confidence interval, 1.3-3.1). RVD was also associated with post-HTx renal replacement therapy (hazard ratio 2.0, 95% confidence interval 1.05-3.30) and primary graft dysfunction (hazard ratio 1.7, , 95% confidence interval 1.02-3.30). When stratifying patients by estimated PVR status, RVD was associated with worse 1-year survival among patients with normal PVR (76.9% vs 88.3%, P = .003), but not in those with increased PVR (78.6% vs 83.2%, P = .49). CONCLUSIONS: Preoperative RVD, evaluated through PAPi, is associated with mortality and morbidity after HTx, providing incremental prognostic value over traditional clinical and hemodynamic parameters.

Longest reported support (7.5 years) with postauricular type of Jarvik 2000 axial-flow left ventricular assist device.

Mechanical circulatory supports with left ventricular assist devices (LVAD) are nowadays an established treatment in end-stage heart failure for those patients who are waiting for an organ donation or are unsuitable for transplantation. The duration of LVAD support is variable, depending on the device, the intention to treat and the issues occurring during treatment, which can change the purpose treatment or accelerate the transplantation. Moreover, length of reported supports in the literature is heterogenous. In here, we present the clinical and surgical case of the longest LVAD support reported in the literature, as a bridge to transplantation, with axial pump Jarvik 2000 (Jarvik Heart, Inc, New York, NY).

Postoperative outcomes following rehabilitation in patients with left ventricular assist devices.

Postoperative rehabilitation is a cornerstone of the recovery pathway following left ventricular assist device implantation (LVAD), and patients are expected to conduct an autonomous life thanks to improved technology and increased knowledge of mechanical circulatory support. The primary purpose of the present study was to quantify clinical changes related to rehabilitation, in patients with LVAD: functional capacity, disability, and quality of life were identified as reliable outcomes to detect such changes. The current study was a scoping review conducted searching three primary databases, namely PubMed, Scopus, and Cochrane Library, from their inception until January 2020. After the selection process was completed, 12 citations were included in the present study. Three hundred eight three patients were included in the current analysis. Functional capacity, disability, and quality of life were investigated in 157, 215, 18 patients, respectively. Significant differences were found before and after rehabilitation. The mean walked distance at 6-Minute Walk Test improved from 319±96 to 412.8±86.2 metres (p<0.001), the mean score of the Functional Independence Measure from 68.4±11.8 to 92.5±10.8 points (p<0.001), the mean score of the Short Form-36 physical component from 32.7±29.9 to 55.5±24.7 points (p=0.009) and the mental component from 55.8±19.8 to 75.4±21.4 points (p=0.002). Postoperative rehabilitation is effective at improving functional capacity, disability, and quality of life in patients with left ventricular assist device; all these three domains are particularly expressive of the entity of patients' functional recovery.

Coronary artery disease in heart transplantation: new concepts for an old disease.

Cardiac allograft vasculopathy (CAV) remains one of the main long-term complications after heart transplantation. We performed a systematic review focused on articles published in the previous 6 years to reappraise the novel evidences supporting risk factors, pathology, prevention, and treatment of CAV. We identified a search string for a literature search on PubMed. We excluded articles specifically focused on diagnosis/biomarkers/imaging only or complications of other diseases. We included 98 studies out of our search. Forty-eight articles describe risk factors for CAV, 13 pathology, 24 prevention, and 13 treatment for CAV. While confirming known concepts, we found supportive evidence that CAV pathophysiology may vary according to the time post-transplant and the prevalence of metabolic versus immune-mediated risk factors. Selective revascularization of focal lesions in patients with CAV may result in some clinical benefit, but CAV prevention, rather than treatment, by controlling risk factors and by using targeted immunosuppressive therapies is the most evidence-based approach to reduce disease progression.

Diminished impact of cytomegalovirus infection on graft vasculopathy development in the antiviral prophylaxis era - a retrospective study.

Evidence concerning an association between cytomegalovirus (CMV) infection and accelerated cardiac allograft vasculopathy (CAV) is inconclusive. Data were analyzed retrospectively from 297 consecutive heart transplants between 1.1.2002 and 31.12.2012. Patients ≤18 years of age, survival, and follow-up ≤1-year post-transplant and patients with early CAV were excluded. CMV-infection was diagnosed and monitored closely in the first year. CAV was diagnosed by coronary angiography via left heart catheterization, and results were categorized according to the International Society of Heart and Lung Transplantation (ISHLT) scoring system. Risk factors for CAV were tested in a multivariable model. Median follow-up was 7.5 years (IQR: 5.6-10.3). CMV infection in the first year after transplantation occurred in 26% of patients (n = 78), CMV disease in 5% (n = 15). CAV ≥1 ISHLT was detected in 36% (n = 108). Incidence of CAV >1 ISHLT and severity of CAV increased over time. No statistically significant association between CMV infection and disease within the first year and risk of CAV after 1-year post-HTx was detected in the univariate (P = 0.16) and multivariable [hazard ratio (HR), 1.36; confidence interval (CI), 0.89-2.07; P = 0.16] Cox regression. In the multivariable Cox regression, donor age (HR, 1.04; 95% CI, 1.02-1.06; P < 0.01) and acute cellular rejection (ACR) ≥2R in the first year after HTx (HR, 1.77; 95% CI, 1.06-2.95; P = 0.03) were independent risk factors for CAV development. In our cohort, CMV infection and disease in the first year after transplantation did not significantly influence the risk of CAV in the long-term follow-up.

The recipient's heme oxygenase-1 promoter region polymorphism is associated with cardiac allograft vasculopathy.

Heme oxygenase-1 (HO-1) catalyses the degradation of heme to biliverdin, free iron, and carbon monoxide. The promoter region contains a highly polymorphic (GT)n repeat, where shorter (GT)n repeat sequences are linked to higher transcriptional activity, which was shown to correlate with a cytoprotective effect. Higher HO-1 levels may protect from cardiac allograft vasculopathy. Cardiac allograft recipients transplanted between 1988 and 2012 were analyzed for the HO-1 (GT)n repeat polymorphism using PCR and DNA fragment analysis with capillary electrophoresis. A relation to cardiac allograft vasculopathy (CAV) was analyzed using Cox regression including common risk factors for CAV and the occurrence of rejection episodes as explanatory variables. A total of 344 patients were analyzed, of which 127 patients were positive for CAV (36.9%). In our multivariable Cox regression analysis, the short homozygous HO-1 (GT)n genotype with <27 repeats (S/S) revealed a higher risk for CAV (P = 0.032). Donor age (P = 0.001) and donor weight (P = 0.005) were significant predictors for CAV. A potential risk for CAV was associated with rejection episodes (P = 0.058) and history of smoking (P = 0.06). The recipient HO-1 (GT)n genotype may contribute to CAV development. This finding has to be evaluated in larger series including studies targeting the underlying disease mechanism.

A versatile method for groundwater vulnerability projections in future scenarios.

Water scarcity and associated risks are serious societal problems. A major challenge for the future will be to ensure the short-term and long-term provision of accessible and safe freshwater to meet the needs of the rapidly growing human population and changes in land cover and land use, where conservation and protection play a key role. Through a Bayesian spatial statistical method, a time-dependent approach for groundwater vulnerability assessment is developed to account for both the recent status of groundwater contamination and its evolution, as required by the European Union (Groundwater Directive, 2006/118/EC). This approach combines natural and anthropogenic factors to identify areas with a critical combination of high levels and increasing trends of nitrate concentrations, together with a quantitative evaluation of how different future scenarios would impact the quality of groundwater resources in a given area. In particular, the proposed approach can determine potential impacts on groundwater resources if policies are maintained at the status quo or if new measures are implemented for safeguarding groundwater quality, as natural factors are changing under climatic or anthropogenic stresses.

Adipocyte-fatty acid binding protein and non-alcoholic fatty liver disease in the elderly.

BACKGROUND: Adipocyte-fatty acid binding protein (A-FABP) is an intracellular lipid transporter that mediates metabolically triggered inflammation, and it is associated with insulin resistance, atherogenic dyslipidemia, and cardiovascular risk. AIMS: The aim of this study was to evaluate A-FABP behavior in elderly people, and especially its association with liver steatosis at abdominal ultrasound. METHOD: Cross-sectional study of two cohort of individuals with and without steatosis, with assessment of several clinical and laboratory variables. Prospective evaluation of liver steatosis remodeling after six years of follow-up. One hundred and fifty-six subjects aged over 65 years were enrolled. RESULTS: Serum A-FABP positively correlated with body fat percentage, total cholesterol, serum triglycerides and erythrocyte sedimentation rate. Unlike expected, high A-FABP levels were associated with absence of liver steatosis, while there was no evidence of association with steatosis grade changes after 6 years of follow-up. CONCLUSION: Among individuals aging more than 65 years included in the study, A-FABP was inversely associated with liver steatosis. It can be argued, that still uncovered mechanisms modify A-FABP behavior in elderly people, especially its association with multifactorial diseases.

The impact of environmental factors and contaminants on thyroid function and disease from fetal to adult life: current evidence and future directions.

The thyroid gland regulates most of the physiological processes. Environmental factors, including climate change, pollution, nutritional changes, and exposure to chemicals, have been recognized to impact thyroid function and health. Thyroid disorders and cancer have increased in the last decade, the latter increasing by 1.1% annually, suggesting that environmental contaminants must play a role. This narrative review explores current knowledge on the relationships among environmental factors and thyroid gland anatomy and function, reporting recent data, mechanisms, and gaps through which environmental factors act. Global warming changes thyroid function, and living in both iodine-poor areas and volcanic regions can represent a threat to thyroid function and can favor cancers because of low iodine intake and exposure to heavy metals and radon. Areas with high nitrate and nitrite concentrations in water and soil also negatively affect thyroid function. Air pollution, particularly particulate matter in outdoor air, can worsen thyroid function and can be carcinogenic. Environmental exposure to endocrine-disrupting chemicals can alter thyroid function in many ways, as some chemicals can mimic and/or disrupt thyroid hormone synthesis, release, and action on target tissues, such as bisphenols, phthalates, perchlorate, and per- and poly-fluoroalkyl substances. When discussing diet and nutrition, there is recent evidence of microbiome-associated changes, and an elevated consumption of animal fat would be associated with an increased production of thyroid autoantibodies. There is some evidence of negative effects of microplastics. Finally, infectious diseases can significantly affect thyroid function; recently, lessons have been learned from the SARS-CoV-2 pandemic. Understanding how environmental factors and contaminants influence thyroid function is crucial for developing preventive strategies and policies to guarantee appropriate development and healthy metabolism in the new generations and for preventing thyroid disease and cancer in adults and the elderly. However, there are many gaps in understanding that warrant further research.

Right heart failure with left ventricular assist devices: Preoperative, perioperative and postoperative management strategies. A clinical consensus statement of the Heart Failure Association (HFA) of the ESC.

Right heart failure (RHF) following implantation of a left ventricular assist device (LVAD) is a common and potentially serious condition with a wide spectrum of clinical presentations with an unfavourable effect on patient outcomes. Clinical scores that predict the occurrence of right ventricular (RV) failure have included multiple clinical, biochemical, imaging and haemodynamic parameters. However, unless the right ventricle is overtly dysfunctional with end-organ involvement, prediction of RHF post-LVAD implantation is, in most cases, difficult and inaccurate. For these reasons optimization of RV function in every patient is a reasonable practice aiming at preparing the right ventricle for a new and challenging haemodynamic environment after LVAD implantation. To this end, the institution of diuretics, inotropes and even temporary mechanical circulatory support may improve RV function, thereby preparing it for a better adaptation post-LVAD implantation. Furthermore, meticulous management of patients during the perioperative and immediate postoperative period should facilitate identification of RV failure refractory to medication. When RHF occurs late during chronic LVAD support, this is associated with worse long-term outcomes. Careful monitoring of RV function and characterization of the origination deficit should therefore continue throughout the patient's entire follow-up. Despite the useful information provided by the echocardiogram with respect to RV function, right heart catheterization frequently offers additional support for the assessment and optimization of RV function in LVAD-supported patients. In any patient candidate for LVAD therapy, evaluation and treatment of RV function and failure should be assessed in a multidimensional and multidisciplinary manner.

New insights into the oncological risk in heart transplant recipients: could skin tumors represent a marker of increased risk for solid neoplasm?

BACKGROUND: Solid organ transplant recipients are at increased risk for skin cancers due to immune-suppressive therapies. However, little is known about the risk and the characteristics of neoplasms in heart transplant recipients (HTRs). The aim of this study is to delineate the incidence of different skin tumors in HTRs and to correlate it with the incidence of other malignancies, including solid tumors and hematological neoplasms. METHODS: Patients who underwent to HTRs between January 1991 and November 2021 were retrieved. Clinical data on immunosuppressive therapies, skin tumors, solid and hematological neoplasms were obtained. HTRs with skin tumors were included in group A, while patients with no evidence of skin tumors during the follow-up were included in group B. RESULTS: One hundred and eight patients were retrieved. A significant increase in solid tumors was observed in group A, while no significant difference in hematological neoplasms was detected between the two groups. CONCLUSIONS: HTRs with skin tumors showed a significantly higher incidence of solid neoplasms. In most of the cases the skin tumor preceded the onset of the solid neoplasm, suggesting that the skin tumor could represent a 'marker' of immunosuppression eventually leading to the development of an internal malignancy.

Effect of a Fourth Dose of mRNA Vaccine and of Immunosuppression in Preventing SARS-CoV-2 Breakthrough Infections in Heart Transplant Patients.

Patients with heart transplantation (HT) have an increased risk of COVID-19 disease and the efficacy of vaccines on antibody induction is lower, even after three or four doses. The aim of our study was to assess the efficacy of four doses on infections and their interplay with immunosuppression. We included in this retrospective study all adult HT patients (12/21-11/22) without prior infection receiving a third or fourth dose of mRNA vaccine. The endpoints were infections and the combined incidence of ICU hospitalizations/death after the last dose (6-month survival rate). Among 268 patients, 62 had an infection, and 27.3% received four doses. Following multivariate analysis, three vs. four doses, mycophenolate (MMF) therapy, and HT < 5 years were associated with an increased risk of infection. MMF ≥ 2000 mg/day independently predicted infection, together with the other variables, and was associated with ICU hospitalization/death. Patients on MMF had lower levels of anti-RBD antibodies, and a positive antibody response after the third dose was associated with a lower probability of infection. In HT patients, a fourth dose of vaccine against SARS-CoV-2 reduces the risk of infection at six months. Mycophenolate, particularly at high doses, reduces the clinical effectiveness of the fourth dose and the antibody response to the vaccine.

Inotropic therapy in patients with advanced heart failure. A clinical consensus statement from the Heart Failure Association of the European Society of Cardiology.

This clinical consensus statement reviews the use of inotropic support in patients with advanced heart failure. The current guidelines only support use of inotropes in the setting of acute decompensated heart failure with evidence of organ malperfusion or shock. However, inotropic support may be reasonable in other patients with advanced heart failure without acute severe decompensation. The clinical evidence supporting use of inotropes in these situations is reviewed. Particularly, patients with persistent congestion, systemic hypoperfusion, or advanced heart failure with need for palliation, and specific situations relevant to implantation of left ventricular assist devices or heart transplantation are discussed. Traditional and novel drugs with inotropic effects are discussed and use of guideline-directed therapy during inotropic support is reviewed. Finally, home inotropic therapy is described, and palliative care and end-of-life aspects are reviewed in relation to management of ongoing inotropic support (including guidance for maintenance and weaning of chronic inotropic therapy support).

Donor heart selection: Evidence-based guidelines for providers.

The proposed donor heart selection guidelines provide evidence-based and expert-consensus recommendations for the selection of donor hearts following brain death. These recommendations were compiled by an international panel of experts based on an extensive literature review.

Slurry wall containment performance: monitoring and modeling of unsaturated and saturated flow.

A specific 2-year program to monitor and test both the vadose zone and the saturated zone, coupled with a numerical analysis, was performed to evaluate the overall performance of slurry wall systems for containment of contaminated areas. Despite local physical confinement (slurry walls keyed into an average 2-m-thick aquitard), for at least two decades, high concentrations of chlorinated solvents (up to 110 mg l(-1)) have been observed in aquifers that supply drinking water close to the city of Milan (Italy). Results of monitoring and in situ tests have been used to perform an unsaturated-saturated numerical model. These results yielded the necessary quantitative information to be used both for the determination of the hydraulic properties of the different media in the area and for the calibration and validation of the numerical model. Backfill material in the shallower part of the investigated aquifer dramatically affects the natural recharge of the encapsulated area. A transient simulation from wet to drought periods highlights a change in the ratio between leakages from lateral barriers that support a specific scenario of water loss through the containment system. The combination of monitoring and modelling allows a reliable estimate of the overall performance of the physical confinement to be made without using any invasive techniques on slurry wall.

Role of Quantitative Flow Ratio in Predicting Future Cardiac Allograft Vasculopathy in Heart Transplant Recipients.

BACKGROUND: Coronary angiography is the gold standard for cardiac allograft vasculopathy (CAV) diagnosis, but it usually detects the disease at an advanced stage. We investigated the role of quantitative flow ratio (QFR), a noninvasive tool to identify potentially flow-limiting lesions, in predicting CAV development in heart transplant recipients. METHODS: Consecutive heart transplant recipients with no evidence of angiographic CAV at baseline coronary angiography were retrospectively included between January 2010 and December 2015, and QFR computation was performed. The relationship between vessel QFR and the occurrence of angiographic vessel-related CAV (≥50% stenosis) was assessed. RESULTS: One hundred forty-three patients were included and QFR computation was feasible in 241 vessels. The median value of QFR at baseline coronary angiography was 0.98 (interquartile range, 0.94-1.00). During a median follow-up of 6.0 years (interquartile range, 4.6-7.8 years), vessel-related CAV occurred in 25 (10.4%) vessels. Receiver-operating characteristic curve analysis identified a QFR best cutoff of ≤0.95 (area under the curve, 0.81 [95% CI, 0.71-0.90]; P<0.001). QFR≤0.95 was associated with an increased risk of vessel-related CAV (adjusted hazard ratio, 20.87 [95% CI, 5.35-81.43]; P<0.001). In an exploratory analysis, QFR≤0.95 in at least 2 vessels was associated with higher incidence of cardiovascular death or late graft dysfunction (71.4% in recipients with 2-3 vessels affected versus 5.1% in recipients with 0-1 vessels affected, P<0.001). CONCLUSIONS: In a cohort of heart transplant recipients, QFR computation at baseline coronary angiography may be a safe and reliable tool to predict vessel-related CAV and clinical outcomes at long-term follow-up.

Indications, Complications, and Outcomes of Cardiac Surgery After Heart Transplantation: Results From the Cash Study.

Background: Allograft pathologies, such as valvular, coronary artery, or aortic disease, may occur early and late after cardiac transplantation. Cardiac surgery after heart transplantation (CASH) may be an option to improve quality of life and allograft function and prolong survival. Experience with CASH, however, has been limited to single-center reports. Methods: We performed a retrospective, multicenter study of heart transplant recipients with CASH between January 1984 and December 2020. In this study, 60 high-volume cardiac transplant centers were invited to participate. Results: Data were available from 19 centers in North America (n = 7), South America (n = 1), and Europe (n = 11), with a total of 110 patients. A median of 3 (IQR 2-8.5) operations was reported by each center; five centers included ≥ 10 patients. Indications for CASH were valvular disease (n = 62), coronary artery disease (CAD) (n = 16), constrictive pericarditis (n = 17), aortic pathology (n = 13), and myxoma (n = 2). The median age at CASH was 57.7 (47.8-63.1) years, with a median time from transplant to CASH of 4.4 (1-9.6) years. Reoperation within the first year after transplantation was performed in 24.5%. In-hospital mortality was 9.1% (n = 10). 1-year survival was 86.2% and median follow-up was 8.2 (3.8-14.6) years. The most frequent perioperative complications were acute kidney injury and bleeding revision in 18 and 9.1%, respectively. Conclusion: Cardiac surgery after heart transplantation has low in-hospital mortality and postoperative complications in carefully selected patients. The incidence and type of CASH vary between international centers. Risk factors for the worse outcome are higher European System for Cardiac Operative Risk Evaluation (EuroSCORE II) and postoperative renal failure.