Results of a Gene Panel Approach in a Cohort of Patients with Incomplete Distal Renal Tubular Acidosis and Nephrolithiasis.

Background: Distal renal tubular acidosis (dRTA) is characterized by an impairment of urinary acidification resulting in metabolic acidosis, hypokalemia, and inappropriately elevated urine pH. If not treated, this chronic condition eventually leads to nephrocalcinosis, nephrolithiasis, impaired renal function, and bone demineralization. dRTA is a well-defined entity that can be diagnosed by genetic testing of 5 genes known to be disease-causative. Incomplete dRTA (idRTA) is defined as impaired urinary acidification that does not lead to overt metabolic acidosis and therefore can be diagnosed if patients fail to adequately acidify urine after an ammonium chloride (NH4Cl) challenge or furosemide and fludrocortisone test. It is still uncertain whether idRTA represents a distinct entity or is part of the dRTA spectrum and whether it is caused by mutations in the same genes of overt dRTA. Methods: In this cross-sectional study, we investigated a group of 22 stone formers whose clinical features were suspicious of idRTA. They underwent an NH4Cl challenge and were found to have impaired urinary acidification ability. These patients were then analyzed by genetic testing with sequencing of 5 genes: SLC4A1, ATP6V1B1, ATP6V0A4, FOXI1, and WDR72. Results: Two unrelated individuals were found to have two different variants in SLC4A1 that had never been described before. Conclusions: Our results suggest the involvement of other genes or nongenetic tubular dysfunction in the pathogenesis of idRTA in stone formers. However, genetic testing may represent a cost-effective tool to recognize, treat, and prevent complications in these patients

Interaction between VA-ECMO and the right ventricle.

The response of the right ventricle (RV) to the hemodynamic effects of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is currently unpredictable. We hypothesized that the presence of uni- or bi-ventricular failure before implantation and the cannulation strategy may influence this interaction. We sought to assess the RV performance during VA-ECMO support and identify RV-related predictors of successful weaning. Changes in RV size and function during VA-ECMO support by echocardiography were retrospectively analyzed in 87 consecutive adult patients between February 2008 and June 2017. Predictors of successful weaning due to myocardial recovery were evaluated by multivariable logistic regression. RV echocardiographic parameters did not vary significantly during VA-ECMO support and neither after stratification by the type of cannulation or the presence of isolated or biventricular failure. Successful weaning was conditioned by the absence of RV dysfunction before implantation (OR, 14.7; 95% CI, 13.3-140.3; p = 0.025) or in the last day of support (OR, 9.5; 95% CI, 1.6-54; p = 0.011) and was favored by a total or partial recovery of RV function during the assistance (OR, 6.2; 95%CI, 1.7-22.4; p = 0.005). RV improvement was more often observed in patients with acute RV failure and longer support, while VA-ECMO configuration, additional mechanical support, or pharmacological therapy had no effect. Preservation or improvement of RV function during VA-ECMO is essential for successful weaning. RV echocardiographic performance does not change significantly during VA-ECMO support and is not influenced by cannulation type or the presence of uni- or bi-ventricular failure before implantation.This work was supported by the Alfonso Martin Escudero Foundation.S

Clinical outcomes of transcatheter aortic valve implantation: from learning curve to proficiency

Objective: The use of transcatheter aortic valve implantation (TAVI) is growing rapidly in countries with a predominantly elderly population, posing a huge challenge to healthcare systems worldwide. The increment of human and economic resource consumption imposes a careful monitoring of clinical outcomes and cost-benefit balance, and this article is aimed at analysing clinical outcomes related to the TAVI learning curve.Methods: Outcomes of 177 consecutive transfemoral TAVI procedures performed in 5 years by a single team were analysed by the Cumulative Sum of failures method (CUSUM) according to the clinical events comprised in the Valve Academic Research Consortium (VARC-2) safety end point and the VARC-2 definition of device success. Margins for events acceptance were extrapolated from landmark trials that tested both balloon or self-expandable percutaneous valves.Results: 30-day and 1-year survival rates were 97.2% and 89.9%, respectively. Achievement of the primary end point (number of cases needed to provide the acceptable margin of the composite end point of any death, stroke, myocardial infarction, life-threatening bleeding, major vascular complications, stage 2-3 acute kidney injury and valve-related dysfunction requiring a repeat procedure) required the performance of 54 cases, while the learning curve to achieve 'device success' identified 32 cases to reach the expected proficiency. In this experience, the baseline clinical risk as assessed by the Society of Thoracic Surgeons (STS) score determined the long-term survival rather than the adverse events related to the learning curve.Conclusions: A relatively large number of cases are required to achieve clinical outcomes comparable to those reported in high-volume centres and controlled trials. According to our national workload standards, this represents more than 2 years of continuous activity

Aspetti epidemiologici della calcolosi di calcio in Italia: distribuzione dei fenotipi intermedi nella popolazione italiana

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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Strain and conventional echocardiographic parameters as predictors of successful VA ECMO weaning

Introduzione: Venoarterial extracorporeal membrane oxygenation (VA ECMO) è un tipo di supporto di circolo e respiratorio temporaneo usato in caso di gravi insufficienze cardiovascolari e respiratorie. La popolazione di pazienti (pz) supportati da VA ECMO ha un alto tasso di mortalità. Non esiste un protocollo di svezzamento da VA ECMO validato internazionalmente. La decisione di svezzare un pz da VA ECMO è complessa perché è necessario sia capire se il pz è in grado di sopravvivere senza VA ECMO, sia evitare qualsiasi ritardo nello svezzamento per ridurre il rischio di complicanze. Obiettivi: lo scopo di questo studio pilota era quello di valutare se lo strain ottenuto tramite speckle tracking fosse in grado di fornire delle informazioni aggiuntive ai parametri ecocardiografici convenzionali ed emodinamici nell’identificazione di pz che svilupperanno eventi avversi entro 3 (± 1) mesi dalla rimozione del VA ECMO. Metodi: studio pilota osservazionale prospettico condotto presso Royal Brompton and Harefield NHS Foundation Trust e l’Azienda Ospedaliera Universitaria Integrata Verona nell’arco di 3 anni. I pz supportati da VA ECMO sono stati screenati e quelli sottoposti a rimozione di VA ECMO (non per palliazione) dopo una prova di svezzamento sono stati reclutati nello studio e seguiti nel tempo. I valori dei parametri ecocardiografici convenzionali, emodinamici e speckle tracking (strain) dei pazienti che hanno sviluppato un outcome clinico composito (ClO+) entro 3 (± 1) mesi dalla rimozione di VA ECMO sono stati confrontati con quelli dei pz che non hanno sviluppato outcome (ClO–). Sono stati inoltre eseguite una sub-analisi sullo sviluppo di eventi cardiaci (CaO) e una analisi ROC. Risultati: nell’arco di 3 anni sono stati screenati 92 pz supportati da VA ECMO. 21 pz sono stati reclutati e, di questi, 19 analizzati. 5 pz sono risultati ClO+ (3 CaO+, 2 shock settici). Al più basso flusso di VA ECMO, la mediana della frazione di eiezione (EF) del gruppo di pz ClO+ era 23.9% (IQR 15.4), invece era pari al 45.8% (IQR 18.7) nei pz ClO– (p = 0.06). Considerando invece la funzione del ventricolo destro (RV), lo strain e i parametri emodinamici, non sono state riscontrate differenze significative tra i 2 gruppi di pz. Il volume telediastolico indicizzato (iEDV) era significativamente più basso nei pz ClO– rispetto ai pz ClO+ (44.7 ml m-2 IQR 17.9; 70.4 ml m-2 IQR 43.0, p < 0.01). Analizzando i pz reclutati sulla base dello sviluppo di CaO, la mediana dell’iEDV è significativamente più alta nel gruppo di pz CaO+ (112.5 ml min-1m-2 IQR 47.1; p = 0.01). Il valore mediano dello strain circonferenziale (circ.) era -5.6% (IQR 1.0) e quello della EF 23.0% (IQR 4.2) per i pz CaO+. Mentre, il valore mediano dello strain circ. era -15.5% (IQR 6.5) e quello della EF era 45.8% (IQR 15.6) per i pz CaO–. Organizzando graficamente i risultati è stato possibile osservare che, rispetto ai pz liberi da eventi, il valore assoluto della EF e dello strain circ. è minore nei pz CaO+, mentre è minore lo strain longitudinale della parete libera (long. FW) del RV nei pz ClO+. All’analisi ROC, i migliori cut point per discriminare i pz ClO+ da quelli ClO– erano per l’EF 26.32% (AUC 0.79), per l’integrale velocità tempo al tratto di efflusso del ventricolo sinistro 14.36cm, (AUC 0.78), per l’indice cardiaco 2.5ml min-1 m-2 (AUC 0.71) e per lo strain long. FW del RV -12.0%. (AUC 0.75). Conclusioni: la decisione di svezzare un pz da VA ECMO è complessa e richiede una valutazione multiparametrica. Sulla base del nostro studio, elevati valori di iEDV e basse EF predispongono allo sviluppo di outcome clinici, tuttavia anche valori bassi di strain circ. e di strain long. FW del RV possono essere indicativi di sviluppo di CaO e ClO rispettivamente. E’ fondamentale distinguere le ragioni per cui un VA ECMO viene impiantato e le cause di fallimento dello svezzamento per identificare correttamente, in uno studio futuro, i predittori di successo per lo svezzamento da VA ECMO.Introduction: Venoarterial extracorporeal membrane oxygenation (VA ECMO) is a type of temporary mechanical circulatory support and gas exchange device for acute cardiovascular and respiratory failure. The population of VA ECMO patients has high mortality rates. No protocol for VA ECMO weaning has been validated worldwide. The decision to wean a patient from VA ECMO is particularly challenging because it is necessary to understand whether the patient can survive without VA ECMO support, but it is also important to avoid any delays to reduce the risk of complications. Objectives: the aim of this pilot study was to assess whether strain obtained through speckle tracking could give additional information to hemodynamic, and conventional echocardiographic parameters in identifying patients who will develop adverse outcomes within 3 (± 1) months from VA ECMO removal. Methods: observational prospective pilot study delivered over 3 years at Royal Brompton and Harefield NHS Foundation Trust and Azienda Ospedaliera Universitaria Integrata Verona. The VA ECMO patients who underwent VA ECMO removal (not for palliation) after a VA ECMO weaning trial have been recruited and followed up. Conventional echocardiographic, haemodynamic and speckle tracking (strain) parameters of patients developing a composite clinical outcome (ClO+) within 3 (± 1) months post VA ECMO removal have been compared with those of patients free from clinical outcomes (ClO–). Furthermore, a sub-analysis on composite cardiac outcome (CaO) development and exploratory ROC analysis have been performed. Results: Over 3 years of recruitment, 92 VA ECMO patients have been screened. 21 patients met the eligibility criteria for the study. Of these, 19 patients could be analysed. 5 patients experienced the composite clinical outcome (3 had CaO, 2 were complicated by septic shock). At the lowest flow of VA ECMO support, the median ejection fraction (EF) of the ClO+ patients was 23.9% (IQR 15.4), conversely it was 45.8% (IQR 18.7) in ClO– patients (p = 0.06). Considering right ventricular (RV) function, strain and haemodynamic parameters, no significant differences were found between ClO+ and ClO– patients. The indexed end diastolic volume (iEDV) was significantly lower for ClO– patients compared to the others (respectively 44.7 ml m-2 IQR 17.9; 70.4 ml m-2 IQR 43.0, p < 0.01). Analysing the recruited patients on the basis of CaO development, the median iEDV remained significantly higher in CaO+ patients (112.5 ml min-1m-2 IQR 47.1; p = 0.01). Furthermore, the median circumferential strain was -5.6% (IQR 1.0) and the EF 23.0% (IQR 4.2) in CaO+ patients. Conversely, circumferential strain was -15.5% (IQR 6.5) and EF was 45.8% (IQR 15.6) in CaO– patients. Graphically organising the echocardiographic findings, it was possible to observe that compared to outcome free patients, the absolute values of EF and circumferential strain were lower in CaO+ , while RV free wall longitudinal strain was lower in ClO+ patients. At the ROC analysis, the best cut point to discriminate ClO+ patients and ClO– patients at the lowest flow of VA ECMO support was for EF 26.32% (AUC 0.79), for left ventricle outflow track velocity time integral 14.36cm, (AUC 0.78), for cardiac index 2.5ml min-1 m-2 (AUC 0.71) and for RV free wall longitudinal strain -12.0%. (AUC 0.75). Conclusions: the decision to wean a patient from VA ECMO is complex and require the assessment of multiple variables (echocardiographic, haemodynamic and respiratory). According to our analysis, large iEDV and low EF predispose to the ClO development. Furthermore, low values of circumferential strain and RV free wall longitudinal strain may be indicative of development of cardiac and clinical outcomes respectively. It is also important to discriminate the reasons for VA ECMO implantation and the causes of VA ECMO weaning failure to properly identify, in a future study, the predictors of VA ECMO weaning success

RAS inhibitors and renal and general mortality in patients with heart failure supported by left ventricular assist devices: a registry study

Background The aim of our study was to analyze the association between renin-angiotensin system inhibitor (RASi) therapy and renal outcomes and mortality in patients with heart failure (HF) supported by left ventricular assist device (LVAD) using a large, nationwide prospective cohort. To date, no studies have comprehensively analyzed the association between RASi and renal outcomes and mortality in patients with HF supported by LVAD. Methods We performed a retrospective observational study on LVAD patients in the Interagency Registry for Mechanically Assisted Circulatory Support. The main outcome was a composite of renal event and all-cause mortality. Secondary outcomes were the individual components of the composite outcome. A renal event was defined as a composite of doubling serum creatinine, eGFR decrease >= 40%, or need for dialysis. The exposure of interest was RASi therapy, updated during follow-up. Cox regression models adjusted for potential confounders were used to estimate the association between time-updated RASi therapy and the outcomes of interest. Results The analysis included 6448 patients. During a median follow-up of 12.7 months (IQR 19.8 months), 1632 patients developed the composite outcome. RASi therapy was associated with a lower risk of developing the composite outcome (HR 0.61, 95% CI 0.55, 0.68, P < 0.001). A significant association was confirmed between RASi therapy and renal outcomes (HR 0.74, 95% CI 0.61, 0.89, P = 0.002) and all-cause mortality (HR 0.56, 95% CI 0.50, 0.63, P < 0.001). Conclusions Our data suggest a beneficial role of RASi therapy on renal function and all-cause mortality in patients with HF supported by LVAD.[Graphics

A Tachycardia in Disguise

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Preventive left main and right coronary artery stenting to avoid coronary ostia occlusion in high-risk stentless valve-in-valve transcatheter aortic valve implantation

Transcatheter aortic valve implantation is becoming an attractive and promising alternative to redo surgery for aortic bioprosthetic valves degeneration, especially in high-risk patients. However, valve-in-valve transcatheter aortic valve implantation itself carries some procedural risks and potential challenges that interventionists must be aware of. An accurate preprocedural planning is fundamental for the prevention of potentially fatal complications. This case describes a novel strategy of simultaneous right and left coronary artery stenting preventing bilateral coronary obstruction in a patient with a stentless surgical aortic valve and extremely low origin of the 2 coronary arteries

Impact of early glomerular filtration rate decline in response to antihypertensive treatment on risk of end-stage kidney disease and cardiovascular outcomes: a systematic review and meta-analysis

Blood pressure control, which can induce a slight decrease in the glomerular filtration rate (GFR), plays a nephron- and cardioprotective role. However, the more important early decline in GFR associated with antihypertensive therapy and strict blood pressure targets is still of concern. Since few data are available from trials and observational studies, and the phenomenon is relatively rare, we performed a meta-analysis of available studies. We conclude that major reductions in the glomerular filtration rate occurring soon after starting angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and/or under intensive blood pressure control predict end-stage kidney disease