Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS: In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. CONCLUSIONS: Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.

Repetitive ambulatory levosimendan as a bridge to heart transplantation.

INTRODUCTION AND OBJECTIVES: Repetitive ambulatory doses of levosimendan are an option as a bridge to heart transplantation (HT), but evidence regarding the safety and efficacy of this treatment is scarce. The objective of the LEVO-T Registry is to describe the profile of patients on the HT list receiving levosimendan, prescription patterns, and clinical outcomes compared with patients not on levosimendan. METHODS: We retrospectively reviewed all patients listed for elective HT from 2015 to 2020 from 14 centers in Spain. RESULTS: A total of 1015 consecutive patients were included, of whom 238 patients (23.4%) received levosimendan. Patients treated with levosimendan had more heart failure (HF) admissions in the previous year and a worse clinical profile. The most frequent prescription pattern were fixed doses triggered by the patients' clinical needs. Nonfatal ventricular arrhythmias occurred in 2 patients (0.8%). No differences in HF hospitalizations were found between patients who started levosimendan in the first 30 days after listing and those who did not (33.6% vs 34.5%; P=.848). Among those who did not, 102 patients (32.9%) crossed over to levosimendan after an HF admission. These patients had a rate of 0.57 HF admissions per month before starting levosimendan and 0.21 afterwards. Propensity score matching analysis showed no differences in survival at 1 year after listing between patients receiving levosimendan and those who did not (HR, 1.03; 95%CI, 0.36-2.97; P=.958) or in survival after HT (HR, 0.97; 95%CI, 0.60-1.56; P=.958). CONCLUSIONS: Repetitive levosimendan in an ambulatory setting as a bridge to heart transplantation is commonly used, is safe, and may reduce HF hospitalizations.

Heart failure risk scores in advanced heart failure patients: insights from the LEVO-D registry.

AIMS: The prevalence of advanced heart failure (HF) is increasing due to the growing number of patients with HF and their better treatment and survival. There is a scarcity of data on the accuracy of HF web-based risk scores in this selected population. This study aimed to assess mortality prediction performance of the Meta-Analysis Global Group in Chronic HF (MAGGIC-HF) risk score and the model of the Barcelona Bio-HF Risk Calculator (BCN-Bio-HF) containing N terminal pro brain natriuretic peptide in HF patients receiving intermittent inotropic support with levosimendan as destination therapy. METHODS AND RESULTS: Four hundred and three advanced HF patients from 23 tertiary hospitals in Spain receiving intermittent inotropic support with levosimendan as destination therapy were included. Discrimination for all-cause mortality was compared by area under the curve (AUC) and Harrell's C-statistic at 1 year. Calibration was assessed by calibration plots comparing observed versus expected events based on estimated risk by each calculator. The included patients were predominantly men, aged 71.5 [interquartile range 64-78] years, with reduced left ventricular ejection fraction (27.5 ± 9.4%); ischaemic heart disease was the most prevalent aetiology (52.5%). Death rate at 1 year was 26.8%, while the predicted 1-year mortality by BCN-Bio-HF and MAGGIC-HF was 17.0% and 22.1%, respectively. BCN-Bio-HF AUC was 0.66 (Harrell's C-statistic 0.64), and MAGGIC-HF AUC was 0.62 (Harrell's C-statistic 0.61). CONCLUSIONS: The two evaluated risk scores showed suboptimal discrimination and calibration with an underestimation of risk in advanced HF patients receiving levosimendan as destination therapy. There is a need for specific scores for advanced HF.

Left Ventricular Assist Device as a Destination Therapy: Current Situation and the Importance of Patient Selection.

Advanced heart failure is a growing problem for which the best treatment is cardiac transplantation. However, the shortage of donors' hearts made left ventricular assist devices as destination therapy (DT-LVAD) a highly recommended alternative: they improved mid-term prognosis as well as patients' quality of life. Current intracorporeal pumps with a centrifugal continuous flow evolved in the last few years. Since 2003, when first LVAD was approved for long-term support, smaller device sizes with better survival and hemocompatibility profile were reached. The most important difficulty lies in the moment of the implant. Recent indications range from INTERMACS class 2 to 4, with close monitoring in intermediate cases. Moreover, a large multiparametric study is needed for considering the candidacy: basal situation, with a special interest in frailty, comorbidities, including renal and hepatic dysfunction, and medical background, considering every prior cardiac condition, must be evaluated. In addition, some clinical risk scores can be helpful to measure the possibility of right heart failure or morbi-mortality. With this review, we sought to summarize all the device improvements, with their updated clinical results, as well as to focus on all the patient selection criteria.

Transcatheter Tricuspid Valve Replacement With a Dedicated Device in a Patient With 2 Endocardial Leads.

A 79-year-old woman with a history of dilated cardiomyopathy who required a permanent peacemaker, recently upgraded to implantable cardioverter-defibrillator cardiac resynchronization therapy, was admitted for right heart failure. On echocardiography, torrential tricuspid regurgitation was noted, with 2 leads across the valve. After multidisciplinary evaluation, a dedicated transcatheter valve replacement was successfully implanted. (Level of Difficulty: Intermediate.).

Hypotension at heart failure discharge: Should it be a limiting factor for drug titration?

BACKGROUND: Medical treatment in Heart Failure (HF) with reduced ejection fraction (HFrEF; LVEF ≤40%) has shifted towards quadruple therapy. Maximum tolerated dose is the goal, yet no hypotension's cut-off point has been specified. In this work, we analyze the impact of intensive drug titration in clinical events, focusing on low blood pressure (BP) patients at hospital discharge. METHODS AND RESULTS: Retrospective analysis of 713 patients with HFrEF discharged after an acute HF event (mean LVEF 30 ± 5%). Mean SBP was 112.4 ± 16.5 mmHg and 50.6% were discharged on triple therapy. We considered hypotension as a Systolic blood pressure (SBP) <100 mmHg (21.7% of patients, mean SBP was 112.4 ± 16.5 mmHg) and codified the intensity of drug therapy in 5 stages from untreated to very high therapy intensity. The impact of the intensity of treatment was analysed with a propensity score and increasing the intensity was associated in the whole cohort with a reduction of the composite outcome of all-cause mortality and HF readmission, (HR 0.69; CI95% 0.57-0.85, p < 0.001) and benefit in mortality was maintained for SBP < 100 mmHg (HR 0.42; CI95% 0.22-0.82; p = 0.011). Moreover, therapy intensity was clearly associated with lower risk of HF-hospitalization and death after the additional regression, considering SBP as a covariate, in the whole cohort (HR 0.70; CI95% 0.57-0.85; p < 0.001). CONCLUSIONS: In this retrospective cohort analysis, patients with HFrEF and an acute-HF admission, intensive drug dose titration was related to better outcomes, even in patients with low blood pressure at hospital discharge. Therefore, hypotension is not a contraindication for NHB uptitration.

Impact of dapagliflozin on cardiac remodelling in patients with chronic heart failure: The DAPA-MODA study.

AIMS: Dapagliflozin improves the prognosis of patients with heart failure (HF), regardless of left ventricular ejection fraction (LVEF). However, its effect on cardiac remodelling parameters, specifically left atrial (LA) remodelling, is not well established. METHODS AND RESULTS: The DAPA-MODA trial (NCT04707352) is a multicentre, single-arm, open-label, prospective and interventional study that aimed to evaluate the effect of dapagliflozin on cardiac remodelling parameters over 6 months. Patients with stable chronic HF receiving optimized guideline-directed therapy, except for any sodium-glucose cotransporter 2 inhibitor, were included. Echocardiography was performed at baseline, 30 and 180 days, and analysed by a central core-lab in a blinded manner to both patient and time. The primary endpoint was the change in maximal LA volume index (LAVI). A total of 162 patients (64.2% men, 70.5 ± 10.6 years, 52% LVEF >40%) were included in the study. At baseline, LA dilatation was observed (LAVI 48.1 ± 22.6 ml/m2 ) and LA parameters were similar between LVEF-based phenotypes (≤40% vs. >40%). LAVI showed a significant reduction at 180 days (-6.6% [95% confidence interval -11.1, -1.8], p = 0.008), primarily due to a decrease in reservoir volume (-13.8% [95% confidence interval -22.5, -4], p = 0.007). Left ventricular geometry improved with significant reductions in left ventricular mass index (-13.9% [95% confidence interval -18.7, -8.7], p < 0.001), end-diastolic volume (-8.0% [95% confidence interval -11.6, -4.2], p < 0.001) and end-systolic volume (-11.9% [95% confidence interval -16.7, -6.8], p < 0.001) at 180 days. N-terminal pro-B-type natriuretic peptide (NT-proBNP) showed a significant reduction at 180 days (-18.2% [95% confidence interval -27.1, -8.2], p < 0.001), without changes in filling Doppler measures. CONCLUSION: Dapagliflozin administration in stable out-setting patients with chronic HF and optimized therapy results in global reverse remodelling of cardiac structure, including reductions in LA volumes and improvement in left ventricular geometry and NT-proBNP concentrations.

Intermittent inotropic support with levosimendan in advanced heart failure as destination therapy: The LEVO-D registry.

AIM: Patients with advanced heart failure (AHF) who are not candidates to advanced therapies have poor prognosis. Some trials have shown that intermittent levosimendan can reduce HF hospitalizations in AHF in the short term. In this real-life registry, we describe the patterns of use, safety and factors related to the response to intermittent levosimendan infusions in AHF patients not candidates to advanced therapies. METHODS AND RESULTS: Multicentre retrospective study of patients diagnosed with advanced heart failure, not HT or LVAD candidates. Patients needed to be on the optimal medical therapy according to their treating physician. Patients with de novo heart failure or who underwent any procedure that could improve prognosis were not included in the registry. Four hundred three patients were included; 77.9% needed at least one admission the year before levosimendan was first administered because of heart failure. Death rate at 1 year was 26.8% and median survival was 24.7 [95% CI: 20.4-26.9] months, and 43.7% of patients fulfilled the criteria for being considered a responder lo levosimendan (no death, heart failure admission or unplanned HF visit at 1 year after first levosimendan administration). Compared with the year before there was a significant reduction in HF admissions (38.7% vs. 77.9%; P < 0.0001), unplanned HF visits (22.7% vs. 43.7%; P < 0.0001) or the combined event including deaths (56.3% vs. 81.4%; P < 0.0001) during the year after. We created a score that helps predicting the responder status at 1 year after levosimendan, resulting in a score summatory of five variables: TEER (+2), treatment with beta-blockers (+1.5), Haemoglobin >12 g/dL (+1.5), amiodarone use (-1.5) HF visit 1 year before levosimendan (-1.5) and heart rate >70 b.p.m. (-2). Patients with a score less than -1 had a very low probability of response (21.5% free of death or HF event at 1 year) meanwhile those with a score over 1.5 had the better chance of response (68.4% free of death or HF event at 1 year). LEVO-D score performed well in the ROC analysis. CONCLUSION: In this large real-life series of AHF patients treated with levosimendan as destination therapy, we show a significant decrease of heart failure events during the year after the first administration. The simple LEVO-D Score could be of help when deciding about futile therapy in this population.

[Transcatheter aortic valve implantation: results of a new therapeutic option for high surgical risk aortic stenosis]. / Implantação percutânea de próteses valvulares aórticas: resultados de uma nova opção terapêutica na estenose aórtica com alto risco cirúrgico.

INTRODUCTION: Transcatheter aortic valve implantation (TAVI) is an alternative to surgical aortic valve replacement in patients with severe aortic stenosis (AS) and unacceptably high surgical risk. METHODS: We present our first two years' experience with TAVI. A total of 76 AS patients were evaluated for TAVI and 23 of them underwent a TAVI procedure. These patients had a mean EuroSCORE of 22.4% and a mean age of 81.5 years, and were prospectively followed for a mean of 12.9 ± 11 months. RESULTS: The percutaneous aortic valve was successfully implanted in 100% of the patients. Mortality at 30 days was 4%. The most common complications were access site-related bleeding and transfusion (22%), followed by new permanent pacemaker implantation (9%). After a mean follow-up of 12.9 months, survival was 87%. In a maximum follow-up of 30 months there were no cases of prosthesis dysfunction or cardiovascular death. CONCLUSIONS: Two years after the introduction of a TAVI program in our center, the procedure has established itself as a safe and effective alternative for patients with severe AS and unacceptably high surgical risk.

3D Transesophageal echocardiographic guidance and monitoring of percutaneous aortic valve replacement.

We describe a preliminary clinical experience with 3D transesophageal echocardiography (3D TEE) in an 84-year-old man with severe aortic stenosis and multiple comorbidity, who underwent percutaneous aortic valve implantation. Although 3D TEE monitoring is not a standard procedure during aortic valve replacement procedure (PAVR), when used in combination with conventional 2D-TEE contributes to improving adequate patient selection and provides more accurate information to the interventional cardiologist during positioning, deployment, and early function of the prosthesis.

Exercise right heart catheterization predicts outcome in asymptomatic degenerative aortic stenosis.

INTRODUCTION AND OBJECTIVES: Degenerative aortic stenosis (DAS) is the most frequent valvular heart disease. It remains unclear how to identify asymptomatic DAS patients with normal left ventricular ejection fraction who have a high probability of event occurrence and would thus benefit from early intervention. Here, we describe a protocol for exercise hemodynamics in true asymptomatic patients with moderate or severe DAS and assess the prognostic value of the data obtained in this population. METHODS: This study involved a prospective single-centre registry of consecutive asymptomatic patients with moderate or severe DAS. Patients underwent cardiopulmonary exercise testing to confirm symptom absence during exercise and then right heart catheterization (RHC) at rest and during exercise. Events were defined as death, surgical aortic valve replacement, or transcatheter aortic valve implantation according to clinical guidelines. RESULTS: Thirty-three patients underwent baseline and exercise RHC. The mean aortic valve area was 1.08 cm2 and the aortic gradient was 39mmHg. The mean pulmonary artery pressure was 21mmHg with a pulmonary artery occlusion pressure of 14mmHg and cardiac output of 5.6 L/min. The mean pulmonary artery pressure at peak exercise was 34mmHg. After a mean follow-up of 27 months, 8 patients experienced an event (24%). There were no differences in baseline variables, aortic valve area, or cardiopulmonary exercise testing parameters between the event and event-free groups. Patients with an event did not have higher pulmonary or filling pressures after peak exercise but had lower pulmonary artery oxygen saturation on effort (median, 48% vs 57%, P=.03). CONCLUSIONS: Exercise RHC is feasible and safe in this population. Peak pulmonary artery oxygen saturation might identify patients with increased risk of serious adverse events.

[Implantation of aortic valvular prosthesis via transfemoral catheter. Evaluation of candidates undergoing the procedure]. / Implantación de prótesis valvulares aórticas por vía transfemoral. Evaluación de pacientes candidatos al procedimiento.

BACKGROUND AND OBJECTIVE: In recent years, techniques for implantation of aortic prosthesis via catheter have been developed as a therapeutic alternative in patients with severe aortic stenosis rejected for surgery. The correct selection of candidates is one of the more complex aspects of this treatment. We analyzed the acceptance rate in our environment for transcatheter aortic valve implantation in patients referred to our hospital for evaluation as possible candidates, describing the exclusion reasons. PATIENTS AND METHOD: 30 patients with severe aortic stenosis and rejected for surgical aortic valve replacement were referred to our hospital to evaluate transcatheter aortic valve implantation. The patients first underwent clinical evaluation and were studied with echocardiography, angiography and computed tomography. RESULTS: Of the 30 patients, 18 were rejected for the procedure (60%): 4 patients with non-severe aortic stenosis, 2 asymptomatic patients, 2 patients who finally underwent surgery because of a low-surgical-risk, 5 patients with contraindications for the procedure, 2 patients who finally did not want to undergo the procedure and 3 patients were further rejected because the vascular access was inappropriate. Of the remaining 12 patients initially accepted, 3 died before the procedure was performed. Finally, only 9 patients (30%) underwent transcatheter aortic valve implantation. CONCLUSIONS: Of the patients referred for transcatheter aortic valve implantation, only 40% were accepted. The mortality rate during the evaluation process of this procedure is high, showing that these patients are terminally ill.

Long-term prognostic value of endothelial dysfunction in patients with chest pain and angiographically normal coronary arteries.

OBJECTIVE: To evaluate the prognostic impact of endothelial function in patients with angina and angiographically normal coronary arteries. METHODS: In 147 consecutive patients with angina and normal coronary arteries on coronary angiography, we studied endothelial function by incremental intracoronary bolus of acetylcholine (ACh). Patients were divided in two groups according to their vasomotor response to ACh: 1) ACh+ group (n = 95), those with diffuse vasoconstriction during ACh administration; and 2) ACh- group (n = 52): those showing normal endothelial function. Cardiovascular events, including hospital admissions for unstable angina, myocardial infarction, coronary revascularization, stroke and cardiac death, were studied during a mean follow-up of 7 years. RESULTS: A total of 33 patients (22%) had cardiac events, 29 in the ACh+ group and 4 in the ACh- group (p = 0.002). ACh+ group patients had less time free of cardiovascular events (p = 0.001). Cox proportional regression analysis after controlling for conventional risk factors demonstrated that endothelial dysfunction was an independent predictor of cardiovascular events. If hospital admissions for unstable angina were excluded from the analysis, only 6 patients had major cardiac events, 5 patients in the ACh+ group vs. 1 patient in the ACh- group (p = 0.2). CONCLUSION: A simple endothelial function test performed in patients with angina and normal coronary angiograms may identify a subgroup of patients with high probability of cardiovascular events on long-term follow-up, mainly hospital readmissions for worsening angina.

Impact of aortic valve closure on adverse events and outcomes with the HeartWare ventricular assist device.

BACKGROUND: This study examined whether aortic valve opening (AVO) and other echocardiographic parameters influence outcomes in patients on left ventricular (LV) assist device (LVAD) support. Pump thrombosis (PT) and ischemic stroke (IS) are known complications of LVAD, but mechanisms that could influence them are not completely understood. METHODS: This was a retrospective analysis of 147 patients who received a HeartWare Ventricular Assist Device ( HeartWare International) as a bridge to transplant or to candidacy between July 2009 and August 2015, of whom 126 had at least 30 days of follow-up before the first event (30-days-out cohort). Outcomes included survival, PT, IS, and PT+IS (combined thrombotic event; CTE). RESULTS: Median time on support was 518 days. Of the 30-days-out cohort, 29% had a first PT and 19% a first IS. AVO was associated with longer survival on device (1,081 vs 723 days; p = 0.01) in the entire cohort. In the 30-days-out cohort, the aortic valve was more frequently closed in patients with lower ejection fractions on support (14% ± 6% vs 18% ± 9%; p = 0.009), more dilated pre-event echocardiogram (LV end-diastolic diameter, 66 ± 12 mm vs 62 ± 10 mm; p = 0.04), and pre-implant LV end-diastolic diameter (70 ± 10 mm vs 66 ± 9 mm; p = 0.06). CTE-free survival on the device was lower with a closed aortic valve (897 vs 1,314 days; p = 0.003) as was PT-free survival on the device (1,070 vs 1,457 days; p = 0.02). Cox regression analysis showed that AVO was an independent predictor of CTE (p = 0.03) CONCLUSIONS: Thrombotic events are relatively frequent in patients on long-term LVAD support. A closed aortic valve was associated with decreased overall survival, thrombosis-free survival, and poorer LV function on support. These are high-risk patients, so whether they require more intense anti-coagulation or prioritizing for transplantation requires further research.

Optical coherence tomography evaluation of pulmonary arterial vasculopathy in Systemic Sclerosis.

Our current understanding of the pathophysiology of pulmonary vascular disease is incomplete, since information about alterations of the pulmonary vasculature in pulmonary arterial hypertension (PAH) is primarily provided by autopsy or tissue specimens. The aim of this study was to compare the distal pulmonary vasculature of <2 mm in diameter in Systemic Sclerosis (SSc) patients with (n = 17) and without (n = 5) associated PAH using Optical Coherence Tomography during Right Heart catheterization. SSc-PAH patients showed significant thickening of Intima Media Thickening Area compared to patients without PAH (27 +/- 5.8% vs. 21 +/- 1.4%, p = 0.024). A good haemodynamic response to previous targeted PAH treatment was associated with a significantly greater number of small pulmonary artery side branches <300 µm per cm vessel (3.8 +/- 1.1 vs. 1.8 +/- 1.1; p = 0.010) and not associated with Intima Media thickening Area (26 +/- 5.4% vs. 28 +/- 6.7%; p = 0.6). Unexpected evidence of pulmonary artery thrombus formation was found in 19% of SSc-PAH patients. This is the first in-vivo study demonstrating a direct link between a structural abnormality of pulmonary arteries and a response to targeted treatment in PAH. Intravascular imaging may identify subgroups that may benefit from anticoagulation.