The safety of sodium-glucose co-transporter 2 inhibitors in patients with left ventricular assist device - a single center experience.

AIMS: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are used increasingly for patients with heart failure or chronic kidney disease to improve cardiac and renal outcomes. The use of these medications in patients with left ventricular assist devices (LVAD) is still limited and lacks evidence regarding the safety profile. In this study, we aimed to report our experience in treating 20 patients, supported by LVAD, with SGLT2 inhibitors. METHODS: We studied the safety profile of SGLT2 inhibitors (dapagliflozin and empagliflozin) in 20 patients (mean age 64.7 ±â€Š12.2 years, 75% male) supported by LVAD as destination therapy. All patients have diabetes mellitus and were prescribed SGLT2 inhibitors for glycemic control. RESULTS: SGLT2 inhibitors were well tolerated with no major adverse events. Few suction events were reported in three patients without the need for pump speed adjustment. There was no change in mean arterial pressure (71.1 ±â€Š5.6 vs. 70.1 ±â€Š4.8 mmHg, P  = 0.063). Modest decline in renal function was observed in six patients within the first weeks after drug initiation. There were no events of diabetic ketoacidosis or limb amputation. CONCLUSION: SGLT2 inhibitors are safe in patients with LVAD and may potentially improve cardiovascular and renal outcomes in this special population.

Cancer Incidence and Survival Among Patients Following an Acute Coronary Syndrome.

To examine the role of acute coronary syndrome (ACS) in subsequent cancer incidence and survival, 2 cohorts of patients hospitalized with ACS were matched 1:1 by gender and age (±3 years) to cardiovascular disease (CVD)-free patients from 2 cycles of the Israeli National Health and Nutrition Surveys. Data on all-cause mortality were retrieved from national registries. Cancer incidence with death treated as a competing event, overall survival, and mortality risk associated with incident cancer as a time-dependent variable were compared between the groups. Our cohort included 2,040 cancer-free matched pairs (mean age of 60±14 years, 42.5% women). Despite higher rates of smokers and patients with hypertension and diabetes mellitus, 10-year cumulative cancer incidence was significantly lower in the ACS group compared with CVD-free group (8.0% vs 11.4%, p = 0.02). This decreased risk was more pronounced in women than men (pinteraction = 0.05). Although being free of CVD meant a significant (p <0.001) survival advantage in the general cohort, this advantage faded once a cancer diagnosis was made (p = 0.80). After adjustment for sociodemographic and clinical covariates, the hazard ratios for mortality associated with a cancer diagnosis were 2.96 (95% confidence interval: 2.36 to 3.71) in the ACS group versus 6.41 (95% confidence interval: 4.96 to 8.28) in the CVD-free group (Pinteraction<0.001). In conclusion, in this matched cohort, ACS was associated with a lower risk of cancer and mitigated the excess risk of mortality associated with cancer incidence.

Arterial Thromboembolism in Patients With AF and CHA2DS2-VASc Score 0-2 With and Without Cancer.

Background: It is unclear whether newly diagnosed cancer adds to the risk of arterial thromboembolism (ATE) in patients with atrial fibrillation/flutter (AF). This is especially relevant for AF patients with low to intermediate CHA2DS2-VASc scores in whom the risk-benefit ratios between ATE and bleeding are delicately balanced. Objectives: The objectives were to evaluate the ATE risk in AF patients with a CHA2DS2-VASc score of 0 to 2 with and without cancer. Methods: A population-based retrospective cohort study was performed. Patients with a CHA2DS2-VASc score of 0 to 2 not receiving anticoagulation at cancer diagnosis (or the matched index date) were included. Patients with embolic ATE or cancer before study index were excluded. AF patients were categorized into AF and cancer and AF and no cancer cohorts. Cohorts were matched for multinomial distribution of age, sex, index year, AF duration, CHA2DS2-VASc score, and low/high/undefined ATE risk cancer. Patients were followed from study index until the primary outcome or death. The primary outcome was acute ATE (ischemic stroke, transient ischemic attack, or systemic ATE) at 12 months using International Classification of Diseases-Ninth Revision codes from hospitalization. The Fine-Gray competing risk model was used to estimate the HR for ATE with death as a competing risk. Results: The 12-month cumulative incidence of ATE was 2.13% (95% CI: 1.47-2.99) in 1,411 AF patients with cancer and 0.8% (95% CI: 0.56-1.10) in 4,233 AF patients without cancer (HR: 2.70; 95% CI: 1.65-4.41). The risk was highest in men with CHA2DS2-VASc = 1 and women with CHA2DS2-VASc = 2 (HR: 6.07; 95% CI: 2.45-15.01). Conclusions: In AF patients with CHA2DS2-VASc scores of 0 to 2, newly diagnosed cancer is associated with an increased incidence of stroke, transient ischemic attack, or systemic ATE compared with matched controls without cancer.

Self-care behaviours of patients with left ventricular assist devices in Israel: changes during the COVID-19 pandemic.

AIMS: Left ventricular assist devices (LVADs) support the hearts of patients with advanced heart failure. Following LVAD implantation, patients face a complex regimen of self-care behaviours including self-care maintenance, self-care monitoring and self-care management. However, during the COVID-19 pandemic, symptoms of anxiety and depression may have interfered with their self-care. Currently, little is known on how specific self-care behaviours of LVAD-implanted patients changed during the COVID-19 pandemic. We aim to describe the changes in self-care behaviours among patients with an implanted LVAD in Israel during the COVID-19 pandemic and explore the factors related to self-care behaviour change. METHODS: A prospective observational cross-sectional study design. A convenience sample of 27 Israeli LVAD-implanted patients (mean age 62.4 ± 9, 86% male, 78.6% living with a partner) completed the LVAD Self-Care Behaviour Scale (1 = never to 5 = always) and Hospital Anxiety and Depression Scale (0 = not at all to 3 = most of the time). Data were collected before and after the onset of the COVID-19 pandemic in Israel. Statistical analyses included paired t-tests, Pearson's correlations, and one-way repeated measures ANOVAs. RESULTS: During the COVID-19 pandemic, a significant decrease was found in patients' adherence to checking and recording their LVAD speed, flow, power and PI (Pulsatility Index) (P = 0.05), checking their INR (P = 0.01), and daily weighing (P < 0.01). The prevalence of some behaviours (e.g. regularly exercising) increased in some patients and decreased in others. Patients living without a partner worsened their adherence to some of the self-care behaviours (e.g. taking medicines as prescribed), compared with those living with a partner (Mb  = 5.0 ± 0 and Md  = 5.0 ± 0, delta = 0 vs. Mb  = 5.0 ± 0 and Md  = 4.6 ± 0.9, delta = -0.4, respectively; F = 4.9, P = 0.04). Women, and not men, tended to improve their adherence to the self-care behaviour such as avoiding kinking, pulling, or moving the LVAD driveline at the exit site (Mb  = 4.0 ± 1.0 and Md  = 5.0 ± 0, delta = 1.0 vs. Mb  = 4.5 ± 0.9 and Md  = 4.4 ± 1.2, delta = -0.1, F = 4.7, P = 0.04, respectively). In total, 41% (11) patients reported neither anxiety nor depression, 11% (3) reported anxiety, 15% (4) reported depression, and 44% (12) reported both anxiety and depression. No associations between anxiety and/or depression and self-care behaviours were found. CONCLUSIONS: Priorities in self-care behaviours among patients with implanted LVAD changed after the onset of the COVID-19 pandemic. Factors that assisted with adherence to self-care behaviours included living with a partner and being female. The current results may guide further research on identifying behaviours that are at risk of not being maintained during a time of emergency.

The short and long-term characteristics and outcomes of patients with grade 1 myocardial uptake on cardiac scintigraphy.

AIMS: This study aimed to characterize the final diagnosis and prognosis of patients with grade 1 myocardial scintigraphy uptake, which is an unequivocal result for the diagnosis of transthyretin cardiac amyloidosis (ATTR-CA) requiring further invasive investigation with tissue biopsy. METHODS AND RESULTS: We retrospectively compared the clinical and imaging parameters of patients suspected for ATTR-CA (based on clinical and echocardiographic parameters) with grade 1 vs. grades 2/3 technetium pyrophosphate uptake on cardiac scintigraphy. Prospectively, grade 1 patients underwent re-evaluation for ATTR-CA at long term. Of the 132 ATTR-CA suspected patients, 89 (67%) were diagnosed as grade 1 and 43 (33%) as grades 2/3 uptake. Grade 1 vs. grades 2/3 patients were younger and female predominant with lower biomarker levels and left ventricular mass. Based on available imaging and pathology findings, only 6 out of the 89 patients with grade 1 uptake (7%) were finally diagnosed with light-chain cardiac amyloidosis, whereas no patient was diagnosed with ATTR-CA. At 2 [interquartile range (IQR) 0.75, 3.25] years of follow-up, the survival of patients with grade 1 vs. grades 2/3 uptake was significantly better [hazard ratio 0.271 (95% confidence interval 0.130 to 0.563, P = 0.0005)]. Prospectively, 30 patients with grade 1 uptake were re-evaluated at a median follow-up of 3.2 (IQR 2.2, 3.9) years. Their New York Heart Association class, biomarker levels, and echocardiography findings remained stable. No patient (0/25) demonstrated grades 2/3 uptake at repeated long-term scintigraphy. CONCLUSIONS: Patients with suspected ATTR-CA and a grade 1 scintigraphy uptake demonstrate a stable clinical, laboratory, imaging, and scintigraphy phenotype along with a benign survival profile at long-term follow-up. Larger studies should define the optimal evaluation strategy in this population.

Implantable Cardioverter Defibrillator for the Primary Prevention of Sudden Cardiac Death among Patients With Cancer.

Data are limited regarding the characteristics and outcomes of patients with cancer who are found eligible for primary defibrillator therapy. We performed a single-center retrospective analysis of patients with preexisting cancer diagnoses who become eligible for a primary prevention implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) defibrillator. Multicenter Automatic Defibrillator Implantation Trial-ICD (MADIT-ICD) benefit scores were calculated. The study included 75 cancer patients at a median age of 73 (interquartile range 64, 81) years at heart failure diagnosis. Active cancer was present in 51%. Overall, 55% of the cohort had coronary artery disease and 37% were CRT eligible. We found that 48%, 49%, and 3% of cohorts had low, intermediate, and high MADIT-ICD Benefit scores, respectively. Only 27% of patients underwent primary defibrillator implantation. Using multivariate analysis, indication for CRT and intermediate/high MADIT-ICD Benefit categories were found as independent predictors for implantation (odds ratio 8.42 p <0.001 and odds ratio 3.74 p = 0.040, respectively). During a median follow-up of 5.3 (interquartile range 4.5, 7.2) years, one patient (5%) with a defibrillator had appropriate shock therapy and 2 patients (10%) had bacteremia. Of 13 patients with CRT defibrillator-implants, one patient was admitted for heart failure exacerbation (8%). Using a time-varying covariate model, we did not observe statistically significant differences in the survival of patients with cancer implanted versus those not implanted with primary defibrillators (hazard ratio 0.521, p = 0.127). In conclusion, although primary defibrillator therapy is underutilized in patients with cancer, its relative benefit is limited because of competing risk of nonarrhythmic mortality. These findings highlight the need for personalized cardiologic and oncologic coevaluation.

18-Month effect of tafamidis on the progression of cardiac amyloidosis evaluated according to a multiparametric expert consensus tool.

BACKGROUND: A recently published expert consensus document recommended a multiparametric tool to monitor cardiac disease progression in patients with transthyretin cardiac amyloidosis (ATTR-CA). We aimed to evaluate the effect of the transthyretin stabiliser drug, tafamidis, by applying this integrative tool. METHODS: We retrospectively applied a multiparametric tool in a group of ATTR-CA patients who were given tafamidis between the years 2019-2021 and were followed in a dedicated clinic. We used three pre-specified follow-up timepoints: at 6, 12 and 18 months. RESULTS: We included 16 ATTR-CA patients (wild-type (n = 14) and mutant (n = 2)). The median age at the initiation of tafamidis was 76 (IQR 70, 84) years and 75% of study patients were classified as NYHA functional class 2 or 3. All patients had elevated levels of high-sensitive troponin T (median 92 (IQR 63, 115) ng/L) and NT-proBNP (median 3784 (2290, 8773) pg/mL). At the end of 18-month follow-up, two patients have suffered from high-grade atrioventricular block and required permanent pacing, and one patient had heart-failure-related admission. Twenty-five percent and 50% of patients were classified as NYHA Class 1 at the initiation of tafamidis and at 18-months treatment, respectively. No patient was defined with disease progression at 6- or 12-month follow up; however, one patient (14%) was defined with a deteriorated disease status at 18-month follow-up. CONCLUSIONS: Based on a multiparametric tool, the use of tafamidis promoted disease stabilisation in the majority of patients at 18-month follow-up. Further study should focus on monitoring disease improvement in patients with ATTR-CA.

Severe vs Nonsevere Immune Checkpoint Inhibitor-Induced Myocarditis: Contemporary 1-Year Outcomes.

Background: The long-term contemporary outcomes of patients with immune checkpoint inhibitor (ICI) myocarditis, spanning the spectrum of clinical severity, are undetermined. Objectives: We sought to investigate the characteristics and cardiovascular outcomes of patients with severe and nonsevere ICI myocarditis. Methods: This was a retrospective cohort study of patients with suspected ICI myocarditis at Massachusetts General Brigham Health System conducted between 2015 and 2022. Cases were classified as severe, nonsevere, and negative based on the International Cardio-Oncology Society criteria. One-year cardiovascular mortality, all-cause mortality, and cardiovascular readmissions were evaluated. We also evaluated 1-year ICI resumption and left ventricular ejection fraction over a median follow-up of 18 (Q1-Q3: 8-67) weeks. Results: The study included 160 patients: 28 severe, 96 nonsevere, and 36 negative cases. Patients with severe myocarditis had an increased risk of 1-year cardiovascular mortality, particularly in the early post-myocarditis period (29% vs 5%; HR: 6.52; 95% CI: 2.2-19.6; P < 0.001). Patients with nonsevere myocarditis had a cardiovascular mortality rate similar to negative cases (HR: 0.61; 95% CI: 0.14-2.54). One-year all-cause mortality did not differ between severe, nonsevere, and negative cases (P = 0.74). Rates of 1-year cardiovascular readmissions and long-term left ventricular ejection fraction were also similar among the 3 groups. ICI resumption was low, even in negative cases. Conclusions: In a contemporary analysis of patients with suspected ICI myocarditis, severe ICI myocarditis was associated with increased 1-year cardiovascular mortality, which was lower than previously reported. Patients with nonsevere ICI myocarditis had outcomes similar to negative cases. The optimal management strategies for nonsevere ICI myocarditis need to be re-evaluated.

Anti-immunoglobulin-like transcript 3 induced acute myocarditis-A case report.

To the best of our knowledge, this is the first published report of anti-immunoglobulin-like transcript 3 (ILT3)-induced myocarditis. A 48-year old female patient with refractory acute myeloid leukemia who was given a single dose of anti-ILT3 monotherapy presented with fever, hypotension, chest pain, and elevated cardiac biomarkers. Systolic bi-ventricular function was in normal limits. The patient was promptly treated with pulse dose steroids with a rapid hemodynamic and clinical improvement and declining levels of cardiac biomarkers. The diagnosis of acute myocarditis was confirmed using cardiac magnetic resonance imaging applying the revised Lake Lewis criteria. While larger-scale data are needed in order to assess the incidence, management and prognosis of anti-ILT-3 induced myocarditis, we believe a high level of suspicion for adverse non-target cardiac effects is required in patients receiving this novel class of drugs.

Cancer-associated non-bacterial thrombotic endocarditis.

This paper reviews the current evidence on the pathogenesis, clinical manifestations, diagnosis and management of cancer-associated non-bacterial thrombotic endocarditis (NBTE). NBTE is an underdiagnosed condition characterized by sterile valvular vegetations composed of platelets and fibrin which are susceptible to systemic embolization. Cancer is a leading cause of NBTE and should be excluded in NBTE cases without a clear etiology. Malignancies most frequently associated with NBTE are mucin-releasing adenocarcinomas of the lung, ovary, biliary system, pancreas, breast and stomach. NBTE carries a high risk of arterial thromboembolism, while cardiac valvular dysfunction is much less frequent. NBTE appears to be an important underdiagnosed cause of cancer-associated embolic stroke of undetermined source. Characteristics associated with cancer-associated NBTE include elevated D-dimer, visceral infarcts, cerebral infarcts in multiple vascular territories, transcranial doppler microembolic signals, disseminated cancer and adenocarcinoma histology. Transesophageal echocardiography is the diagnostic test of choice, and all suspected cases should be evaluated for the presence of elevated D-dimers and disseminated intravascular coagulation. Long-term anticoagulation with low molecular weight heparin should be strongly considered, and surgical intervention is usually not needed. Underlying cancer must be diagnosed swiftly (if previously undiagnosed) and anti-cancer treatment should be initiated as soon as possible. The paucity of data regarding all aspects of NBTE, and the severe clinical consequences of untreated NBTE, are an urgent call for future research.

Coronary artery disease and revascularization associated with immune checkpoint blocker myocarditis: Report from an international registry.

PURPOSE: Immune checkpoint blocker (ICB) associated myocarditis (ICB-myocarditis) may present similarly and/or overlap with other cardiac pathology including acute coronary syndrome presenting a challenge for prompt clinical diagnosis. METHODS: An international registry was used to retrospectively identify cases of ICB-myocarditis. Presence of coronary artery disease (CAD) was defined as coronary artery stenosis >70% in patients undergoing coronary angiogram. RESULTS: Among 261 patients with clinically suspected ICB-myocarditis who underwent a coronary angiography, CAD was present in 59/261 patients (22.6%). Coronary revascularization was performed during the index hospitalisation in 19/59 (32.2%) patients. Patients undergoing coronary revascularization less frequently received steroids administration within 24 h of admission compared to the other groups (p = 0.029). Myocarditis-related 90-day mortality was 9/17 (52.7%) in the revascularised cohort, compared to 5/31 (16.1%) in those not revascularized and 25/156 (16.0%) in those without CAD (p = 0.001). Immune-related adverse event-related 90-day mortality was 9/17 (52.7%) in the revascularized cohort, compared to 6/31 (19.4%) in those not revascularized and 31/156 (19.9%) in no CAD groups (p = 0.007). All-cause 90-day mortality was 11/17 (64.7%) in the revascularized cohort, compared to 13/31 (41.9%) in no revascularization and 60/158 (38.0%) in no CAD groups (p = 0.10). After adjustment of age and sex, coronary revascularization remained associated with ICB-myocarditis-related death at 90 days (hazard ratio [HR] = 4.03, 95% confidence interval [CI] 1.84-8.84, p < 0.001) and was marginally associated with all-cause death (HR = 1.88, 95% CI, 0.98-3.61, p = 0.057). CONCLUSION: CAD may exist concomitantly with ICB-myocarditis and may portend a poorer outcome when revascularization is performed. This is potentially mediated through delayed diagnosis and treatment or more severe presentation of ICB-myocarditis.

Improved immunogenicity following the third dose of BNT162b2 mRNA vaccine in heart transplant recipients.

OBJECTIVES: The immunogenicity of two-dose severe acute respiratory syndrome coronavirus 2 vaccine is lower among heart transplant (HTx) recipients, compared with the general population. Our aim was to assess the immunogenicity of a third-dose vaccine in HTx recipients. METHODS: This is a prospective cohort study of HTx recipients who received a third dose of the BNT162b2 vaccine. Immunogenicity was assessed by serum levels of anti-spike immunoglobulin G (S-IgG), taken at baseline and 14-28 days after the third dose. Titres above 50 U/ml were interpreted positive. RESULTS: We Included 42 HTx recipients at a median age of 65 years [interquartile range (IQR) 58-70]. At baseline, the median of 27 days (IQR 13-42) before the third dose and the median titre of the whole group was 18 U/ml (IQR 4-130). Only 14 patients (33%) were S-IgG seropositive. After the third dose, the proportion of seropositive patients increased significantly to 57% (P = 0.05) and the median titre increased significantly to 633 U/ml (IQR 7-6104, P < 0.0001). Younger age at HTx (OR per 1-year decrease 1.07, P = 0.05), low tacrolimus serum level (OR per 1-unit decrease 2.28, P = 0.02), mammalian target of rapamycin use (OR 13.3, P = 0.003), lack of oral steroids use (OR 4.17, P = 0.04) and lack of calcineurin inhibitor use (71% of responders vs 100% non-responders received calcineurin inhibitors, P = 0.01) were predictors of seropositive result after the third dose. However, no significant association was detected following adjustment for baseline S-IgG titre. CONCLUSIONS: Third-dose booster of BNT162b2 vaccine significantly increased immunogenicity among HTx recipients who previously received a two-dose vaccine.

The Potential Cardiotoxicity of Immune Checkpoint Inhibitors.

The use of immune checkpoint inhibitors (ICIs) as a mono- or adjuvant oncologic treatment is rapidly expanding to most fields of cancer. Alongside their efficacy, ICIs carry the risk of immune-related adverse events (irAEs) arising from misguided immune-mediated response to normal tissues. In the cardiovascular system, the cardiac toxicity of ICIs has been primarily related to the development of an acute, immune-mediated myocarditis; beyond this potentially fatal complication, evidence of an increased risk of cardiovascular events and accelerated atherosclerosis is emerging, as well as reports of other cardiovascular adverse events such as arrythmias, Takotsubo-like syndrome and vascular events. The absence of identified risk factors for cardiotoxic complications, specific monitoring strategies or diagnostic tests, pose challenges to the timely recognition and optimal management of such events. The rising numbers of patients being treated with ICIs make this potential cardiotoxic effect one of paramount importance for further investigation and understanding. This review will discuss the most recent data on different cardiotoxic effects of ICIs treatment.

Six-months immunogenicity of BNT162b2 mRNA vaccine in heart transplanted and ventricle assist device-supported patients.

AIMS: To assess the 6 months immunogenicity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine in a population of heart transplanted (HTx) recipients and left ventricular assist device (LVAD)-supported patients. METHODS AND RESULTS: A prospective single-centre cohort study of HTx recipients and LVAD-supported patients who received a two-dose SARSCoV-2 mRNA vaccine (BNT162b2, Pfizer-BioNTech). Whole blood for anti-spike IgG (S-IgG) antibodies were drawn at 6 months after the first vaccine dose. S-IgG data at 6 weeks were available for a subgroup of HTx recipients. S-IgG ≥ 50 AU/mL were interpreted positive. The cohort included 53 HTx recipients and 18 LVAD-supported patients. The median time from HTx or LVAD implantation to the 1st vaccine dose was 90 (IQR 30, 172) months and 22 (IQR 6, 78) months, respectively. The seropositivity rates of S-IgG antibodies and their titre levels in HTx recipients and LVAD-supported patients were 45% and 83% respectively, (P = 0.006), and 35 (IQR 7, 306) AU/mL and 311 (IQR 86, 774) AU/mL, respectively, (P = 0.006). Reduced SARSCoV-2 vaccine immunogenicity in HTx recipients was associated with older age [odds ratio (OR) 0.917 confidence interval (CI 0.871, 0.966), P = 0.011] and with the use of anti-metabolites-based immunosuppressive regimens [OR 0.224 (CI 0.065, 0.777), P = 0.018]. mTOR inhibitors were associated with higher immunogenicity [OR 3.1 (CI 1.01, 9.65), P = 0.048]. Out of 13 HTx recipients who were S-IgG seropositive at 6 weeks after the first vaccine dose, 85% remained S-IgG seropositive at 6 month follow-up. CONCLUSIONS: At 6 months post-vaccination, S-IgG immunogenicity in HTx recipients is low, particularly in older HTx recipients and in those treated with anti-metabolites drugs.

The Effect of Tafamidis on Circulating Endothelial Progenitor Cells in Patients with Transthyretin Cardiac Amyloidosis.

AIMS: Endothelial microvascular dysfunction is a known mechanism of vascular pathology in cardiac amyloidosis (CA). Scientific evidence regarding the possible protective role of the amyloid transthyretin (ATTR) stabilizer, tafamidis, is lacking. Circulating endothelial progenitor cells (cEPCs) have an important role in the process of vascular repair. We aimed to examine the effect of tafamidis on cEPCs. METHODS AND RESULTS: Study population included patients with ATTR-CA. cEPCs were assessed using flow cytometry by the expression of CD34(+)/CD133(+) and vascular endothelial growth factor receptor (VEGFR)-2(+) and by the formation of colony-forming units (CFUs) and production of VEGF. Tests were repeated at pre-specified time-points up to 12 months following the initiation of tafamidis. Included were 18 ATTR-CA patients at a median age of 77 (IQR 71, 85) years and male predominance (n = 15, 83%). Following the initiation of tafamidis and during 12 months of drug treatment, there was a gradual increase in the levels of CD34(+)/VEGFR-2(+) (0.43 to 2.42% (IQR 1.53, 2.91)%, p = 0.002) and CD133(+)/VEGFR-2(+) (0.49 to 1.64% (IQR 0.97, 2.90)%, p = 0.004). Functionally, increase in EPCs-CFUs was microscopically evident following treatment with tafamidis (from 0.5 CFUs (IQR 0.0, 1.0) to 3.0 (IQR 1.3, 3.8) p < 0.001) with a concomitant increase in EPC's viability as demonstrated by an MTT assay (from 0.12 (IQR 0.03, 0.16) to 0.30 (IQR 0.18, 0.33), p < 0.001). VEGF levels increased following treatment (from 54 (IQR 52, 72) to 107 (IQR 62, 129) pg/ml, p = 0.039). CONCLUSIONS: Tafamidis induced the activation of the cEPCs pathway, possibly promoting endothelial repair in ATTR-CA.

The Effect of Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors on Circulating Endothelial Progenitor Cells in Patients with Cardiovascular Disease.

PURPOSE: Circulating endothelial progenitor cells (cEPCs) are vital to vascular repair by re-endothelialization. We aimed to explore the effect of proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) on cEPCs hypothesizing a possible pleiotropic effect. METHODS: Patients with cardiovascular disease (CVD) were sampled for cEPCs at baseline and following the initiation of PCSK9i. cEPCs were assessed using flow cytometry by the expression of CD34(+)/CD133(+) and vascular endothelial growth factor receptor (VEGFR)-2(+), and by the formation of colony-forming units (CFUs) and production of VEGF. RESULTS: Our cohort included 26 patients (median age 68 (IQR 63, 73) years; 69% male). Following 3 months of treatment with PCSK9i and a decline in low-density lipoprotein cholesterol levels (153 (IQR 116, 176) to 56 (IQR 28, 72) mg/dl), p < 0.001), there was an increase in CD34(+)/CD133(+) and VEGFR-2(+) cell levels (0.98% (IQR 0.37, 1.55) to 1.43% (IQR 0.90, 4.51), p = 0.002 and 0.66% (IQR 0.22, 0.99) to 1.53% (IQR 0.73, 2.70), p = 0.05, respectively). Functionally, increase in EPCs-CFUs was microscopically evident following treatment with PCSK9i (1 CFUs (IQR 0.0, 1.0) to 2.5 (IQR 1.5, 3), p < 0.001) with a concomitant increase in EPC's viability as demonstrated by an MTT assay (0.15 (IQR 0.11, 0.19) to 0.21 (IQR 0.18, 0.23), p < 0.001). VEGF levels increased following PCSK9i treatment (57 (IQR 18, 24) to 105 (IQR 43, 245), p = 0.006). CONCLUSIONS: Patients with CVD treated with PCSK9i demonstrate higher levels of active cEPCs, reflecting the promotion of endothelial repair. These findings may represent a novel mechanism of action of PCSK9i.