CaV1 and CaV2 calcium channels mediate the release of distinct pools of synaptic vesicles.

Activation of voltage-gated calcium channels at presynaptic terminals leads to local increases in calcium and the fusion of synaptic vesicles containing neurotransmitter. Presynaptic output is a function of the density of calcium channels, the dynamic properties of the channel, the distance to docked vesicles, and the release probability at the docking site. We demonstrate that at Caenorhabditis elegans neuromuscular junctions two different classes of voltage-gated calcium channels, CaV2 and CaV1, mediate the release of distinct pools of synaptic vesicles. CaV2 channels are concentrated in densely packed clusters ~250 nm in diameter with the active zone proteins Neurexin, α-Liprin, SYDE, ELKS/CAST, RIM-BP, α-Catulin, and MAGI1. CaV2 channels are colocalized with the priming protein UNC-13L and mediate the fusion of vesicles docked within 33 nm of the dense projection. CaV2 activity is amplified by ryanodine receptor release of calcium from internal stores, triggering fusion up to 165 nm from the dense projection. By contrast, CaV1 channels are dispersed in the synaptic varicosity, and are colocalized with UNC-13S. CaV1 and ryanodine receptors are separated by just 40 nm, and vesicle fusion mediated by CaV1 is completely dependent on the ryanodine receptor. Distinct synaptic vesicle pools, released by different calcium channels, could be used to tune the speed, voltage-dependence, and quantal content of neurotransmitter release.

Chronic use of renin-angiotensin-aldosterone inhibitors in hypertensive COVID-19 patients: Results from a Spanish registry and meta-analysis.

Background: Hypertension is a prevalent condition among SARS-CoV-2 infected patients. Whether renin-angiotensin-aldosterone system (RAAS) inhibitors are beneficial or harmful is controversial. Methods: We have performed a national retrospective, nonexperimental comparative study from two tertiary hospitals to evaluate the impact of chronic use of RAAS inhibitors in hypertensive COVID-19 patients. A meta-analysis was performed to strengthen our findings. Results: Of 849 patients, 422 (49.7%) patients were hypertensive and 310 (73.5%) were taking RAAS inhibitors at baseline. Hypertensive patients were older, had more comorbidities, and a greater incidence of respiratory failure (-0.151 [95% CI -0.218, -0.084]). Overall mortality in hypertensive patients was 28.4%, but smaller among those with prescribed RAAS inhibitors before (-0.167 [95% CI -0.220, -0.114]) and during hospitalization (0.090 [-0.008,0.188]). Similar findings were observed after two propensity score matches that evaluated the benefit of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers among hypertensive patients. Multivariate logistic regression analysis of hypertensive patients found that age, diabetes mellitus, C-reactive protein, and renal failure were independently associated with all-cause mortality. On the contrary, ACEIs decreased the risk of death (OR 0.444 [95% CI 0.224-0.881]). Meta-analysis suggested a protective benefit of RAAS inhibitors (OR 0.6 [95% CI 0.42-0.8]) among hypertensive COVID-19. Conclusion: Our data suggest that RAAS inhibitors may play a protective role in hypertensive COVID-19 patients. This finding was supported by a meta-analysis of the current evidence. Maintaining these medications during hospital stay may not negatively affect COVID-19 outcomes.

Introducción: La hipertensión es una condición prevalente entre los pacientes infectados por el SARS-CoV-2. Es controvertido si los inhibidores del sistema renina-angiotensina-aldosterona (SRAA) son beneficiosos o perjudiciales. Métodos: Hemos desarrollado un estudio comparativo nacional retrospectivo y no experimental en 2 hospitales terciarios para evaluar el impacto del uso crónico de inhibidores del SRAA en pacientes hipertensos con COVID-19. Se realizó un metaanálisis para reforzar los hallazgos. Resultados: De 849 pacientes, 422 (49,7%) eran hipertensos y 310 (73,5%) tomaban inhibidores del SRAA al inicio del estudio. Los pacientes hipertensos eran mayores, tenían más comorbilidades y una mayor incidencia de insuficiencia respiratoria (−0,151; IC 95%: [−0,218; −0,084]). La mortalidad global en los pacientes hipertensos fue del 28,4%, pero fue menor entre los que tenían prescritos inhibidores del SRAA antes (−0,167; IC 95%: [−0,220; −0,114]) y durante la hospitalización (0,090; [−0,008; 0,188]). Se observaron hallazgos similares tras 2 emparejamientos de puntuación de propensión que evaluaron el beneficio de los inhibidores de la enzima convertidora de angiotensina y los bloqueadores de los receptores de angiotensina entre los pacientes hipertensos. El análisis de regresión logística multivariante de los pacientes hipertensos reveló que la edad, la diabetes mellitus, la proteína C reactiva y la insuficiencia renal se asociaban de forma independiente con la mortalidad por todas las causas. Por el contrario, los inhibidores de la enzima convertidora de angiotensina disminuyeron el riesgo de muerte (OR 0,444; IC 95%: 0,224-0,881). El metaanálisis indicó un beneficio protector de los inhibidores del SRAA (OR 0,6; IC 95%: 0,42-0,8) entre los hipertensos con COVID-19. Conclusión: Nuestros datos indican que los inhibidores del SRAA pueden desempeñar un papel protector en los pacientes hipertensos con COVID-19. Este hallazgo fue apoyado por un metaanálisis de la evidencia actual. Su mantenimiento durante la estancia hospitalaria puede no afectar negativamente a los resultados de la COVID-19.

Chronic use of renin-angiotensin-aldosterone inhibitors in hypertensive COVID-19 patients: Results from a Spanish registry and meta-analysis.

BACKGROUND: Hypertension is a prevalent condition among SARS-CoV-2 infected patients. Whether renin-angiotensin-aldosterone system (RAAS) inhibitors are beneficial or harmful is controversial. METHODS: We have performed a national retrospective, nonexperimental comparative study from two tertiary hospitals to evaluate the impact of chronic use of RAAS inhibitors in hypertensive COVID-19 patients. A meta-analysis was performed to strengthen our findings. RESULTS: Of 849 patients, 422 (49.7%) patients were hypertensive and 310 (73.5%) were taking RAAS inhibitors at baseline. Hypertensive patients were older, had more comorbidities, and a greater incidence of respiratory failure (-0.151 [95% CI -0.218, -0.084]). Overall mortality in hypertensive patients was 28.4%, but smaller among those with prescribed RAAS inhibitors before (-0.167 [95% CI -0.220, -0.114]) and during hospitalization (0.090 [-0.008,0.188]). Similar findings were observed after two propensity score matches that evaluated the benefit of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers among hypertensive patients. Multivariate logistic regression analysis of hypertensive patients found that age, diabetes mellitus, C-reactive protein, and renal failure were independently associated with all-cause mortality. On the contrary, ACEIs decreased the risk of death (OR 0.444 [95% CI 0.224-0.881]). Meta-analysis suggested a protective benefit of RAAS inhibitors (OR 0.6 [95% CI 0.42-0.8]) among hypertensive COVID-19. CONCLUSION: Our data suggest that RAAS inhibitors may play a protective role in hypertensive COVID-19 patients. This finding was supported by a meta-analysis of the current evidence. Maintaining these medications during hospital stay may not negatively affect COVID-19 outcomes.

Exercise Ventilatory Inefficiency in Post-COVID-19 Syndrome: Insights from a Prospective Evaluation.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is a systemic disease characterized by a disproportionate inflammatory response in the acute phase. This study sought to identify clinical sequelae and their potential mechanism. METHODS: We conducted a prospective single-center study (NCT04689490) of previously hospitalized COVID-19 patients with and without dyspnea during mid-term follow-up. An outpatient group was also evaluated. They underwent serial testing with a cardiopulmonary exercise test (CPET), transthoracic echocardiogram, pulmonary lung test, six-minute walking test, serum biomarker analysis, and quality of life questionaries. RESULTS: Patients with dyspnea (n = 41, 58.6%), compared with asymptomatic patients (n = 29, 41.4%), had a higher proportion of females (73.2 vs. 51.7%; p = 0.065) with comparable age and prevalence of cardiovascular risk factors. There were no significant differences in the transthoracic echocardiogram and pulmonary function test. Patients who complained of persistent dyspnea had a significant decline in predicted peak VO2 consumption (77.8 (64-92.5) vs. 99 (88-105); p < 0.00; p < 0.001), total distance in the six-minute walking test (535 (467-600) vs. 611 (550-650) meters; p = 0.001), and quality of life (KCCQ-23 60.1 ± 18.6 vs. 82.8 ± 11.3; p < 0.001). Additionally, abnormalities in CPET were suggestive of an impaired ventilatory efficiency (VE/VCO2 slope 32 (28.1-37.4) vs. 29.4 (26.9-31.4); p = 0.022) and high PETCO2 (34.5 (32-39) vs. 38 (36-40); p = 0.025). INTERPRETATION: In this study, >50% of COVID-19 survivors present a symptomatic functional impairment irrespective of age or prior hospitalization. Our findings suggest a potential ventilation/perfusion mismatch or hyperventilation syndrome.

Atrial fibrillation in patients with SARS-CoV-2 infection.

INTRODUCTION AND OBJECTIVE: the SARS-CoV-2 infection ranges from asymptomatic to critical forms and several prognostic factors have been described. Atrial fibrillation (AF) is common in acute situations where it is linked with more complications and mortality. We aimed to evaluate the prognostic information of AF in this population. METHODS: retrospective analysis of a cohort of 517 patients consecutively admitted in a tertiary hospital due to SARS-CoV-2 infection. We divided the patients in two groups according the development of AF and compared the main features of both groups. An univariable and multivariable analysis of mortality were also performed. RESULTS: among 517 patients with SARS-CoV-2 infection admitted in a tertiary center, 54 (10.4%) developed AF. These patients are older (81.6 vs 66.5 years old, p < 0.001) and present more hypertension (74% vs 47%, p < 0.001), cardiomyopathy (9% vs 1%, p = 0.002), previous heart failure admission (9% vs 0.4%, p < 0.001), previous episodes of AF (83% vs 1%, p < 0.001) and bigger left atrium (47.8 vs 39.9 mm, p < 0.001). AF COVID-19 patients present more acute respiratory failure (72% vs 40%, p < 0.001) and higher in-hospital mortality (50% vs 22%, p < 0.001). Predictors of AF development are age and previous AF. AF is not an independent predictor of in-hospital mortality. Predictors are age, creatinine > 1.5 mg/dL at admission, LDH > 250 UI/L at admission and acute respiratory failure. CONCLUSION: Atrial fibrillation appears in 10% of hospitalized patients with SARS-CoV-2 infection. These patients present more comorbidities and two-fold increase in hospital mortality. Atrial fibrillation is not an independent prognostic factor.

INTRODUCCIÓN Y OBJETIVO: La infección por SARS-CoV-2 presenta un amplio espectro clínico, y varios factores pronósticos han sido descritos. La fibrilación auricular (FA) es frecuente en situaciones agudas, donde se ha relacionado con aumento de complicaciones y mortalidad. Nuestro objetivo ha sido evaluar el impacto pronóstico de la FA en esta población. MÉTODOS: Análisis retrospectivo de una cohorte de 517 pacientes con infección SARS-CoV-2 consecutivamente ingresados en un hospital terciario. Dividimos a los pacientes en dos grupos de acuerdo al desarrollo de FA durante el ingreso y comparamos las características de los grupos. Realizamos análisis univariado y multivariado de mortalidad. RESULTADOS: De los 517 pacientes, 54 (10,4%) desarrollaron FA. Estos pacientes son mayores (81,6 vs. 66,5 años, p < 0,001) y presentan más hipertensión (74% vs. 47%, p < 0,001), miocardiopatía (9% vs. 1%, p = 0,002), ingreso previo por insuficiencia cardiaca (9% vs. 0,4%, p < 0,001), historia de FA (83% vs. 1%, p < 0,001) y mayor aurícula izquierda (47,8 vs. 39,9 mm, p < 0,001). Los pacientes con FA presentan más fallo respiratorio agudo (72% vs. 40%, p < 0,001) y mayor mortalidad hospitalaria (50% vs. 22%, p < 0,001). Los predictores de FA son la edad y la historia de FA previa. La FA no es un predictor independiente de mortalidad hospitalaria. Los predictores son: edad, creatinina > 1,5 mg/dL al ingreso, LDH > 250 U/L al ingreso y el fallo respiratorio agudo. CONCLUSIÓN: La FA aparece en el 10% de los pacientes hospitalizados por SARS-CoV-2. Estos presentan mayor comorbilidad y el doble de mortalidad hospitalaria, pero la FA no es un factor pronóstico independiente.

The COVID-19 lab score: an accurate dynamic tool to predict in-hospital outcomes in COVID-19 patients.

Deterioration is sometimes unexpected in SARS-CoV2 infection. The aim of our study is to establish laboratory predictors of mortality in COVID-19 disease which can help to identify high risk patients. All patients admitted to hospital due to Covid-19 disease were included. Laboratory biomarkers that contributed with significant predictive value for predicting mortality to the clinical model were included. Cut-off points were established, and finally a risk score was built. 893 patients were included. Median age was 68.2 ± 15.2 years. 87(9.7%) were admitted to Intensive Care Unit (ICU) and 72(8.1%) needed mechanical ventilation support. 171(19.1%) patients died. A Covid-19 Lab score ranging from 0 to 30 points was calculated on the basis of a multivariate logistic regression model in order to predict mortality with a weighted score that included haemoglobin, erythrocytes, leukocytes, neutrophils, lymphocytes, creatinine, C-reactive protein, interleukin-6, procalcitonin, lactate dehydrogenase (LDH), and D-dimer. Three groups were established. Low mortality risk group under 12 points, 12 to 18 were included as moderate risk, and high risk group were those with 19 or more points. Low risk group as reference, moderate and high patients showed mortality OR 4.75(CI95% 2.60-8.68) and 23.86(CI 95% 13.61-41.84), respectively. C-statistic was 0-85(0.82-0.88) and Hosmer-Lemeshow p-value 0.63. Covid-19 Lab score can very easily predict mortality in patients at any moment during admission secondary to SARS-CoV2 infection. It is a simple and dynamic score, and it can be very easily replicated. It could help physicians to identify high risk patients to foresee clinical deterioration.

Impact of the presence of heart disease, cardiovascular medications and cardiac events on outcome in COVID-19.

BACKGROUND: Cardiovascular risk factors and usage of cardiovascular medication are prevalent among coronavirus disease 2019 (COVID-19) patients. Little is known about the cardiovascular implications of COVID-19. The goal herein, was to evaluate the prognostic impact of having heart disease (HD) and taking cardiovascular medications in a population diagnosed of COVID-19 who required hospitalization. Also, we studied the development of cardiovascular events during hospitalization. METHODS: Consecutive patients with definitive diagnosis of COVID-19 made by a positive real time- -polymerase chain reaction of nasopharyngeal swabs who were admitted to the hospital from March 15 to April 14 were included in a retrospective registry. The association of HD with mortality and with mortality or respiratory failure were the primary and secondary objectives, respectively. RESULTS: A total of 859 patients were included in the present analysis. Cardiovascular risk factors were related to death, particularly diabetes mellitus (hazard ratio in the multivariate analysis: 1.810 [1.159- -2.827], p = 0.009). A total of 113 (13.1%) patients had HD. The presence of HD identified a group of patients with higher mortality (35.4% vs. 18.2%, p < 0.001) but HD was not independently related to prognosis; renin-angiotensin-aldosterone system inhibitors, calcium channel blockers, diuretics and beta-blockers did not worsen prognosis. Statins were independently associated with decreased mortality (0.551 [0.329-0.921], p = 0.023). Cardiovascular events during hospitalization identified a group of patients with poor outcome (mortality 31.8% vs. 19.3% without cardiovascular events, p = 0.007). CONCLUSIONS: The presence of HD is related to higher mortality. Cardiovascular medications taken before admission are not harmful, statins being protective. The development of cardiovascular events during the course of the disease is related to poor outcome.

Atrial fibrillation in patients with SARS-CoV-2 infection.

INTRODUCTION AND OBJECTIVE: the SARS-CoV-2 infection ranges from asymptomatic to critical forms and several prognostic factors have been described. Atrial fibrillation (AF) is common in acute situations where it is linked with more complications and mortality. We aimed to evaluate the prognostic information of AF in this population. METHODS: retrospective analysis of a cohort of 517 patients consecutively admitted in a tertiary hospital due to SARS-CoV-2 infection. We divided the patients in two groups according the development of AF and compared the main features of both groups. An univariable and multivariable analysis of mortality were also performed. RESULTS: among 517 patients with SARS-CoV-2 infection admitted in a tertiary center, 54 (10.4%) developed AF. These patients are older (81.6 vs 66.5 years old, p<0.001) and present more hypertension (74% vs 47%, p<0.001), cardiomyopathy (9% vs 1%, p=0.002), previous heart failure admission (9% vs 0.4%, p<0.001), previous episodes of AF (83% vs 1%, p<0.001) and bigger left atrium (47.8 vs 39.9mm, p<0.001). AF COVID-19 patients present more acute respiratory failure (72% vs 40%, p<0.001) and higher in-hospital mortality (50% vs 22%, p<0.001). Predictors of AF development are age and previous AF. AF is not an independent predictor of in-hospital mortality. Predictors are age, creatinine>1.5mg/dL at admission, LDH>250UI/L at admission and acute respiratory failure. CONCLUSION: Atrial fibrillation appears in 10% of hospitalized patients with SARS-CoV-2 infection. These patients present more comorbidities and two-fold increase in hospital mortality. Atrial fibrillation is not an independent prognostic factor.

Impact of renin-angiotensin system inhibitors on outcomes after surgical or transcatheter aortic valve replacement. A meta-analysis.

INTRODUCTION AND OBJECTIVES: To determine whether renin-angiotensin system inhibitor (RASi) prescription is associated with better outcomes after transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR). METHODS: All comparative studies of RASi vs no RASi prescription in patients undergoing TAVI/SAVR were gathered from PubMed, Web of Science, and Google Scholar through August, 2019. We extracted hazard ratios (HRs) with their confidence intervals (CIs) for mortality from each study and combined study-specific estimates using inverse variance-weighted averages of logarithmic HRs in the random effects model. RESULTS: We identified 6 eligible studies with a total of 21 390 patients (TAVI: 17 846; SAVR: 3544) and included them in the present meta-analysis. The 6 studies were observational comparative studies (including 3 propensity score matched and 3 cohort studies) of RASi vs no RASi prescription. The analysis demonstrated that RASi prescription was associated with significantly lower mortality in the whole group of patients undergoing aortic valve intervention (HR, 0.64; 95%CI, 0.47-0.88; P <.001). However, subgroup analysis suggested differences according to the selected therapy, with TAVI showing better mortality rates in the RASi group (HR, 0.67; 95%CI, 0.49-0.93) but not in the SAVR group (HR, 0.61; 95%CI, 0.29-1.30). No funnel plot asymmetry was identified, suggesting minimum publication bias. Sensitivity analyses sequentially eliminating dissimilar studies did not substantially alter the primary result favoring RASI prescription. CONCLUSIONS: These findings suggest a mortality benefit of RASi in patients with AS treated with aortic valve replacement that might be particularly relevant following TAVI. Future randomized studies are warranted to confirm this relevant finding.

Self-expandable transcatheter heart valves for aortic stenosis. Short-term outcome and matched hemodynamic performance.

INTRODUCTION AND OBJECTIVES: Aortic self-expandable (SE) transcatheter aortic valve implantation (TAVI) devices are particularly useful for patients with aortic stenosis and small/tortuous vessels, small aortic annuli, or low coronary ostia. However, it is unclear whether the growing range of SE devices shows comparable hemodynamic and clinical outcomes. We aimed to determine the differential hemodynamic (residual valve area and regurgitation) and clinical outcomes of these devices in comparable scenarios. METHODS: All patients were enrolled from 4 institutions and were managed with 4 different SE TAVI devices. Baseline and follow-up clinical data were collected and echocardiographic tests blindly and centrally analyzed. Patients were compared according to valve type and a 1:1 matched comparison was performed according to degree of calcification, aortic annulus dimensions, left ventricular ejection fraction, and body surface area. RESULTS: In total, 514 patients were included (Evolut R/PRO, 217; ACURATE neo, 107; ALLEGRA, 102; Portico, 88). Surgical risk scores were comparable in the unmatched population. No differences were observed in the post-TAVI regurgitation rate and in in-hospital mortality (2.7%). The rate of pacemaker implantation at discharge was significantly different among devices (P=.049), with Portico showing the highest rate (23%) and ACURATE neo the lowest (9.5%); Evolut R/PRO and ALLEGRA had rates of 15.9% and 21.2%, respectively. The adjusted comparison showed worse residual TAVI gradients and aortic valve area with ACURATE neo vs ALLEGRA (P=.001) but the latter had higher risk of valve embolization and a tendency for more cerebrovascular events. CONCLUSIONS: A matched comparison of 4 SE TAVI devices showed no differences regarding residual aortic regurgitation and in-hospital mortality.

Ramipril in High-Risk Patients With COVID-19.

BACKGROUND: Coronavirus disease-2019 (COVID-19) is caused by severe acute respiratory-syndrome coronavirus-2 that interfaces with the renin-angiotensin-aldosterone system (RAAS) through angiotensin-converting enzyme 2. This interaction has been proposed as a potential risk factor in patients treated with RAAS inhibitors. OBJECTIVES: This study analyzed whether RAAS inhibitors modify the risk for COVID-19. METHODS: The RASTAVI (Renin-Angiotensin System Blockade Benefits in Clinical Evolution and Ventricular Remodeling After Transcatheter Aortic Valve Implantation) trial is an ongoing randomized clinical trial randomly allocating subjects to ramipril or control groups after successful transcatheter aortic valve replacement at 14 centers in Spain. A non-pre-specified interim analysis was performed to evaluate ramipril's impact on COVID-19 risk in this vulnerable population. RESULTS: As of April 1, 2020, 102 patients (50 in the ramipril group and 52 in the control group) were included in the trial. Mean age was 82.3 ± 6.1 years, 56.9% of the participants were male. Median time of ramipril treatment was 6 months (interquartile range: 2.9 to 11.4 months). Eleven patients (10.8%) have been diagnosed with COVID-19 (6 in control group and 5 receiving ramipril; hazard ratio: 1.150; 95% confidence interval: 0.351 to 3.768). The risk of COVID-19 was increased in older patients (p = 0.019) and those with atrial fibrillation (p = 0.066), lower hematocrit (p = 0.084), and more comorbidities according to Society of Thoracic Surgeons score (p = 0.065). Admission and oxygen supply was required in 4.9% of patients (2 in the ramipril group and 3 in the control group), and 4 of them died (2 in each randomized group). A higher body mass index was the only factor increasing the mortality rate (p = 0.039). CONCLUSIONS: In a high-risk population of older patients with cardiovascular disease, randomization to ramipril had no impact on the incidence or severity of COVID-19. This analysis supports the maintenance of RAAS inhibitor treatment during the COVID-19 crisis. (Renin-Angiotensin System Blockade Benefits in Clinical Evolution and Ventricular Remodeling After Transcatheter Aortic Valve Implantation [RASTAVI]; NCT03201185).

Renin-Angiotensin System Inhibition Following Transcatheter Aortic Valve Replacement.

BACKGROUND: Several studies have demonstrated the benefits of transcatheter aortic valve replacement (TAVR) in patients with aortic stenosis, but the presence of persistent fibrosis and myocardial hypertrophy has been related to worse prognosis. OBJECTIVES: The aim of this study was to explore the potential benefits of renin-angiotensin system (RAS) inhibitors on left ventricular remodeling and major clinical outcomes following successful transcatheter aortic valve replacement (TAVR). METHODS: Patients from 10 institutions with severe aortic stenosis who underwent TAVR between August 2007 and August 2017 were included. All baseline data were prospectively recorded, and pre-specified follow-up was performed. Doses and types of RAS inhibitors at discharge were recorded, and matched comparison according to their prescription at discharge was performed. RESULTS: A total of 2,785 patients were included. Patients treated with RAS inhibitors (n = 1,622) presented similar surgical risk scores but a higher rate of all cardiovascular risk factors, coronary disease, and myocardial infarction. After adjustment for these baseline differences, reduction of left ventricular volumes and hypertrophy was greater and cardiovascular mortality at 3-year follow-up was lower (odds ratio: 0.59; 95% confidence interval: 0.41 to 0.87; p = 0.007) in patients treated with RAS inhibitors. Moreover, RAS inhibitors demonstrated a global cardiovascular protective effect with significantly lower rates of new-onset atrial fibrillation, cerebrovascular events, and readmissions. CONCLUSIONS: Post-TAVR RAS inhibitors are associated with lower cardiac mortality at 3-year follow-up and offer a global cardiovascular protective effect that might be partially explained by a positive left ventricular remodeling. An ongoing randomized trial will help confirm these hypothesis-generating findings. (Renin-Angiotensin System Blockade Benefits in Clinical Evolution and Ventricular Remodeling After Transcatheter Aortic Valve Implantation [RASTAVI]; NCT03201185).

Impact of renin-angiotensin system inhibitors on clinical outcomes and ventricular remodelling after transcatheter aortic valve implantation: rationale and design of the RASTAVI randomised multicentre study.

INTRODUCTION: Transcatheter aortic valve implantation (TAVI) as a treatment in severe aortic stenosis (AS) is an excellent alternative to conventional surgical replacement. However, long-term outcomes are not benign. Renin-angiotensin system (RAS) blockade has shown benefit in terms of adverse remodelling in severe AS and after surgical replacement. METHODS AND ANALYSIS: The RAS blockade after TAVI (RASTAVI) trial aims to detect if there is a benefit in clinical outcomes and ventricular remodelling with this therapeutic strategy following the TAVI procedure. The study has been designed as a randomised 1:1 open-label study that will be undertaken in 8 centres including 336 TAVI recipients. All patients will receive the standard treatment. The active treatment group will receive ramipril as well. Randomisation will be done before discharge, after signing informed consent. All patients will be followed up for 3 years. A cardiac magnetic resonance will be performed initially and at 1 year to assess ventricular remodelling, defined as ventricular dimensions, ejection fraction, ventricular mass and fibrosis. Recorded events will include cardiac death, admission due to heart failure and stroke. The RASTAVI Study will improve the management of patients after TAVI and may help to increase their quality of life, reduce readmissions and improve long-term survival in this scenario. ETHICS AND DISSEMINATION: All authors and local ethics committees have approved the study design. All patients will provide informed consent. Results will be published irrespective of whether the findings are positive or negative. TRIAL REGISTRATION NUMBER: NCT03201185.

Transubclavian approach: A competitive access for transcatheter aortic valve implantation as compared to transfemoral.

AIMS: Empirically, transfemoral (TF) approach is the first choice for transcatheter aortic valve implantation (TAVI). We aimed to investigate whether transubclavian (TSc) and TF approaches present comparable major outcomes according to current evidence. METHODS: We systematically searched PubMed, EMBASE, and Cochrane database for studies with symptomatic aortic stenosis patients who underwent TAVI through TF or TSc/axillary access from January/2006 to January/2017. Searched terms were: ("aortic stenosis" OR "transcatheter aortic" OR "TAVI" OR "TAVR") and ("transfemoral" OR "transaxillary" OR "transubclavian"). Major outcomes according to Valve Academic Research Consortium-2 criteria were gathered. The odds ratio (OR) was used as a summary statistic. A random-effects model was used. A fully percutaneous TSc TAVI case from our institution illustrates minimalist approach. RESULTS: Final analysis was made with six studies including 4,504 patients (3,886 TF and 618 TSc). Baseline characteristics of compared groups in individual studies were similar, with the exception of a higher logistic EuroSCORE in the TSc group (23.7 ± 1.92 vs. 21.17 ± 3.51, P = 0.04) and higher prevalence of coronary and peripheral artery disease with OR = 0.67 [95% CI: 0.54-0.83] (P = 0.0003) and OR = 0.08 [95% CI: 0.05-0.12] (P < 0.00001), respectively. TSc group presented comparable 30-day mortality (OR = 1.37; [95%CI: 0.85-2.21]; P = 0.20). There were no differences for procedural success, 30-day stroke rate, need for new pacemaker implantation, major vascular complications, and acute kidney injury requiring dialysis. Also, no differences were found concerning 1-year mortality. CONCLUSIONS: Our study suggests that TSc approach may be, not only an alternative route to TF approach for TAVI, but even a competitive one in certain patients with increased risk of femoral injury.