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Resting myocardial blood flow (MBF) and myocardial flow reserve (MFR) are reduced in heart failure (HF) patients supported by pulsatile left ventricular assist devices (LVADs). The effect of continuous-flow (CF) physiology on these parameters is underexplored in CF-LVAD patients. We investigated the impact of CF-LVADs on resting MBF and MFR under two left ventricular (LV) loading conditions. Nine HeartMate II patients (42 ± 12 years, 100% male) on support for 370 ± 281 days were enrolled. Results were compared with 9 HF patients (58 ± 13 years, 67% male, LV ejection fraction 27 ± 9%) and 10 healthy volunteers (56 ± 10 years, 20% male). CF-LVAD patients underwent transthoracic echocardiography with ramp study. MBF and MFR were measured utilizing positron emission/computed tomography imaging under two LV loading conditions: "high-speed" (HS), promoting aortic valve (AV) closure and LV unloading; "low-speed" (LS), promoting AV opening and LV loading. Global resting MBF was similar in HS, LS, HF, and healthy: 0.8 ± 0.3, 0.7 ± 0.3, 0.7 ± 0.1, 0.9 ± 0.2 ml/min/g, respectively; p = NS. HS global MFR was reduced compared with LS and HF: 1.6 ± 0.6 versus 1.9 ± 0.5, p = 0.004; 1.6 ± 0.6 versus 2.4 ± 0.5, p = 0.01, respectively. HS regional MFR was reduced compared with LS in the left anterior descending (1.7 ± 0.7 vs. 2.0 ± 0.6, p = 0.027) and left circumflex (1.8 ± 0.7 vs. 2.2 ± 0.9, p = 0.008), but not in right coronary artery (1.7 ± 0.7 vs. 1.7 ± 0.6, p = 0.76). Resting MBF is preserved among CF-LVAD patients and is similar to HF and healthy. Promoting LV ventricular unloading with higher speed was associated with lower global and regional left coronary MFR, while right coronary MFR did not change.

Kinesins are motor proteins involved in microtubule (MT)-mediated intracellular transport. They contribute to key cellular processes, including intracellular trafficking, organelle dynamics and cell division. Pathogenic variants in kinesin-encoding genes underlie several human diseases characterized by an extremely variable clinical phenotype, ranging from isolated neurodevelopmental/neurodegenerative disorders to syndromic phenotypes belonging to a family of conditions collectively termed as ‘ciliopathies.’ Among kinesins, kinesin-1 is the most abundant MT motor for transport of cargoes towards the plus end of MTs. Three kinesin-1 heavy chain isoforms exist in mammals. Different from KIF5A and KIF5C, which are specifically expressed in neurons and established to cause neurological diseases when mutated, KIF5B is an ubiquitous protein. Three de novo missense KIF5B variants were recently described in four subjects with a syndromic skeletal disorder characterized by kyphomelic dysplasia, hypotonia and DD/ID. Here, we report three dominantly acting KIF5B variants (p.Asn255del, p.Leu498Pro and p.Leu537Pro) resulting in a clinically wide phenotypic spectrum, ranging from dilated cardiomyopathy with adult-onset ophthalmoplegia and progressive skeletal myopathy to a neurodevelopmental condition characterized by severe hypotonia with or without seizures. In vitro and in vivo analyses provide evidence that the identified disease-associated KIF5B variants disrupt lysosomal, autophagosome and mitochondrial organization, and impact cilium biogenesis. All variants, and one of the previously reported missense changes, were shown to affect multiple developmental processes in zebrafish. These findings document pleiotropic consequences of aberrant KIF5B function on development and cell homeostasis, and expand the phenotypic spectrum resulting from altered kinesin-mediated processes.

Limited data exist on the circadian blood pressure (BP) and heart rate (HR) variations that occur in heart failure (HF) patients on left ventricular assist device (LVAD) support.We prospectively recorded clinic and 24-hour ambulatory BP and HR data in patients on HeartMate II LVAD support. Results were compared to HF patients with ejection fraction ≤30% and controls with no history of cardiovascular disease. Physiologic nocturnal BP and HR dipping was defined as a ≥10% decline compared to daytime values.Twenty-nine LVAD patients (age 59 ± 15 years, 76% male, 38% ischemic etiology), 25 HF patients (age 64 ± 13 years, 84% male, 32% ischemic etiology) and 26 controls (age 56 ± 9 years, 62% male) were studied. Normal nocturnal BP dipping was less frequent in LVAD patients (10%) than in HF patients (28%) and controls (62%) and reversed BP dipping (BP increase at night) was more common in LVAD patients (24%), compared to HF (16%) and controls (8%), (p0.001, for all comparisons). Physiologic HR reduction was less frequent in LVAD patients (14%), compared to HF (16%) and controls (59%) (p0.001, for all comparisons). Among LVAD patients, 36% exhibited sustained hypertension over the 24-hours and 25% had white-coat hypertension.Treatment of advanced HF with an LVAD does not restore physiologic circadian variability of BP and HR; additionally, BP was not adequately controlled in more than a third of LVAD patients, and a quarter of them exhibited white-coat hypertension. Future studies are warranted to confirm these findings and investigate prognostic and management implications in this population.

Driveline infection (DLI) is common after left ventricular assist device (LVAD). Limited data exist on DLI prevention and management. We investigated the impact of standardized driveline care initiatives, specific pathogens, and chronic antibiotic suppression (CAS) on DLI outcomes. 591 LVAD patients were retrospectively categorized based on driveline care initiatives implemented at our institution (2009-2019). Era (E)1: nonstandardized care; E2: standardized driveline care protocol; E3: addition of marking driveline exit site; E4: addition of "no shower" policy. 87(15%) patients developed DLI at a median (IQR) of 403(520) days. S. aureus and P. aeruginosa were the most common pathogens. 31 (36%) of DLI patients required incision and drainage (ID) and 5 (5.7%) device exchange. P. aeruginosa significantly increased risk for initial ID (HR 2.7, 95% CI, 1.1-6.3) and recurrent ID or death (HR 4.2, 95% CI, 1.4-12.5). Initial ID was associated with a significant increased risk of death (HR 2.92 (1.33-6.44); P = 0.008) when compared to patients who did not develop DLI. Implementation of standardized driveline care protocol (E2) was associated with increased 2-year freedom from DLI compared to nonstandardized care (HR 0.36, 95% CI, 0.2-0.6, P0.01). Additional preventive strategies (E3E4) showed no further reduction in DLI rates. 57(65%) DLI patients received CAS, 44% of them required escalation to intravenous antibiotics and/or ID. Presence of P. aeruginosa DLI markedly increased risk for ID or death. Conditional survival of patients progressing to ID is diminished. Standardized driveline care protocol was associated with a significant reduction in DLI, while additional preventive strategies require further testing.

The use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) following acute myocardial infarction with cardiogenic shock (AMI-CS) is increasing, but the ability to predict favorable outcomes with support remains limited. We retrospectively reviewed all patients with AMI-CS supported with VA-ECMO between December 2008 and June 2018. One hundred twenty-six patients received VA-ECMO for AMI-CS during the study period; of these, 39 (31.0%) experienced ventricular recovery and were discharged while 87 (69.0%) did not recover, with 71 (56.3%) dying in the hospital and 16 (12.7%) surviving to discharge with either left ventricular assist device or heart transplant. TIMI 3 flow in culprit artery (OR, 4.01; 95% CI, 1.25-12.77; p = 0.02), serum lactate (OR, 0.89; 95% CI, 0.80-0.99; p = 0.04), and prompt revascularization (OR, 3.39; 95% CI, 1.18-9.81; p = 0.02) were independent predictors of ventricular recovery. Four variables emerged as independent predictors of in-hospital mortality and were used to create the AMI-ECMO Risk Score: age70 years, creatinine1.5 mg/dL, serum lactate4.0 mmol/L, and lack of TIMI 3 flow in culprit artery. In patients supported with VA-ECMO for AMI-CS, prompt, successful revascularization, and lower serum lactate were associated with ventricular recovery while younger age, lower serum lactate, and creatinine, and successful revascularization were associated with survival to discharge. The AMI-ECMO risk score is a simple tool that can help risk stratify patients with AMI-CS being considered for VA-ECMO support.

Background There is a paucity of data on depression, anxiety and post-traumatic stress disorder after left ventricular assist device (LVAD) implantation. We designed an observational study to integrate these with functional capacity and health-related quality of life (HR-QOL) in surviving LVAD patients. Methods and Results Consenting patients between 1 month and 9 years after LVAD implantation (n = 121) were screened for functional capacity (World Health Organization Disability Assessment Schedule 2.0 [WHODAS 2.0)]); HR-QOL (European Quality of Life [EQ-5D] and Visual Assessment Scales [EQ-VAS]), depression (Patient Health Questionnaire [PHQ-9], anxiety (Generalized Anxiety Disorder Scale [GAD-7]) and post-traumatic stress disorder (Impact of Event Scale Revised [IES-R]). Of the 94% of patients who consented, 34.7% reported impaired functional capacity (WHODAS 2.0 score of ≥25%), 23.1%–34.7% HR-QOL problems (domain EQ-5D of ≥3), 10.7% “poor health” (EQ-VAS of ≤40), 14.9% depression (PHQ-9 of >14), 11.7% suicidal ideation and 17.5% anxiety (GAD-7 of >10). Among these patients, 23.5% had a positive screen for post-traumatic stress disorder (IES-R of ≥24). An EQ-VAS of 80 or greater predicted good functional capacity (P Conclusions One-third of discharged LVAD patients reported impaired function, HR-QOL, and psychological issues. A standardized evaluation before and after LVAD implantation could facilitate psychologic prehabilitation, inform decision-making, and identify indications for mental health intervention.

Objectives This analysis sought to investigate the waitlist and post-transplant outcomes of individuals bridged to transplantation by using temporary percutaneous endovascular mechanical circulatory support (tMCS) through a status 2 designation (cardiogenic shock and exception). Background The 2018 donor heart allocation policy change granted a status 2 designation to patients supported with tMCS. Methods Adult patients in the United Network for Organ Sharing registry after October 18, 2018 who received a status 2 designation for tMCS were included and grouped by their status 2 criteria: cardiogenic shock with hemodynamic criteria (CS-HD), cardiogenic shock without hemodynamic criteria before tMCS (CS-woHD), and exception. Baseline characteristics, waitlist events (death and delisting), and post-transplant outcomes were compared. Results A total of 2,279 patients met inclusion criteria: 68.6% (n = 1,564) with CS-HD, 3.2% (n = 73) with CS-woHD, and 28.2% (n = 642) with exceptions. A total of 64.2% of patients underwent heart transplantation within 14 days of status 2 listing or upgrade, and 1.9% died or were delisted for worsening clinical condition. Among the 35.8% who did not undergo transplantation following 14 days, only 2.8% went on to receive a left ventricular assist device (LVAD). The 30-day transplantation likelihood was similar among groups: 80.1% for the CS-HD group vs 79.7% for the exception group vs 73.3% for the CS-woHD group; P = 0.31. However, patients who met criteria for CS-woHD had 2.3-fold greater risk of death or delisting (95% CI: 1.10-4.75; P = 0.03) compared with CS-HD patients after multivariable adjustment. Pre-tMCS hemodynamics were not associated with adverse waitlist events. Conclusions The use of tMCS is an efficient, safe, and effective strategy as a bridge to transplantation; however, patients with CS-woHD may represent a high-risk cohort. Transition to a durable LVAD was a rare event in this group.

Introduction: The present study sought to characterize taxonomic and functional characteristics of the saliva microbiome and their cross-sectional association with cardiometabolic biomarkers. Hypothesis: Features of the saliva microbiome will be associated with cardiometabolic risk. Methods: Saliva microbiome composition from 265 ORIGINS participants was defined with 16S rRNA sequencing (Illumina, DADA2). Functional composition (KEGG orthologs; KOs) was inferred with PICRUSt2. Alpha Diversity was computed with the Shannon Index. Blood pressure was defined as normal (SBP Results: Participants were 71% female, 22% Black, 40% Hispanic, and 18% white, with mean age of 33±10 years. Prevalence of hypertension was 36%, prediabetes was 17%, high CRP was 23%, and high HOMA-IR was 25%. Estimated ORs for the association between microbiome metrics and cardiometabolic outcomes are summarized in Figure 1. Conclusion: Microbiome scores based on specific taxa or KOs are associated with hypertension, prediabetes, and increased inflammation and insulin resistance.

Background: Periodontitis (a bacterially-driven, inflammatory disease) is a plausible risk factor for prediabetes and diabetes. We studied the association between clinical attachment loss (CAL – a cumulative measure of tooth-supporting tissues lost due to periodontitis), prediabetes, and glucose levels among non-diabetic younger adults. Hypothesis: We hypothesize that greater CAL is associated with higher levels of biomarkers of cardiometabolic risk cross-sectionally. Methods: We included n=1071 non-diabetic participants from the Oral Infections, Glucose Intolerance and Insulin Resistance Study (ORIGINS) who underwent full-mouth periodontal examinations and provided fasting blood at baseline. Baseline enrollment occurred in two waves: Wave 1 (2011-2013; n=293) and Wave 2 (2016-2020; n=778). HbA1c and glucose were measured during clinical exams. Prediabetes was defined as fasting glucose between 100-125 mg/dL or HbA1c between 5.7-6.4% per American Diabetes Association guidelines. We computed prevalence ratios and 95% confidence intervals of prediabetes among 2 nd and 3 rd CAL tertiles (vs. 1 st tertile) via multivariable Poisson regression with robust variance estimation. Multivariable linear regression was used to assess the association between CAL tertiles (independent variable) and estimates of glucose and HbA1c. We adjusted for demographics, health variables, and study wave. Results: The mean age(SD) of participants was 32.3(9.6) years and 28% were male. Prediabetes prevalence was 8.7%. Multivariable adjusted prevalence ratios (95%CIs) for prediabetes in tertiles 2 and 3 (vs. 1) were 1.45(0.79,2.67) and 1.91(0.99,3.67), respectively, consistent with p for trend = 0.05 and stronger associations with continuous glucose and HbA1c (see Table ). Conclusion: CAL, a cumulative measure of periodontitis, was cross-sectionally associated with increased prediabetes prevalence, glucose and HbA1c.

Introduction: Infections are associated with worse clinical outcomes among patients with heart failure (HF). However, little is known about the influence of infection-related hospitalizations on development of incident HF and its subtype. Hypothesis: We hypothesize that those with an infection-related hospitalization (hereafter ‘infection’) compared to those without infection, will experience an increased rate of incident HF events (any HF, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF)). Methods: We examined 14,398 participants enrolled in the Atherosclerosis Risk in Communities Study who were HF free at visit 1 (1987-1989). Hospitalized infections and HF were identified via participant self-report and active surveillance of hospitalizations. Among the hospitalized, infection was further defined using ICD-9/10 codes in the first five positions of hospital records. A subset of HF events was further classified as HFpEF or HFrEF via chart abstraction and adjudication by centrally trained and certified physicians. Infection was treated as a time-varying exposure and the co-occurrence of infection and HF in the same hospital visit were excluded. Multivariable-adjusted Cox proportional hazards models assessed the association between infection and incident HF, HFrEF, and HFpEF. Results: The overall baseline sample was 54% (7,835 of 14,398) female, 26% (3,688 of 14,398) Black and had a mean(SD) age of 54(5.8). Mean(SD) time to infection was 16.1(8.7) years, and 2.3(7.5) years from infection to incident HF. Average follow-up among the full sample was 23.0(8.5). Overall, 46% (6,603 of 14,398) had an infection and 3,561 developed any HF. Among participants with subtype adjudication, 470 had HFpEF and 450 had HFrEF. Infection-related hospitalization was associated with an increased risk for both HFpEF and HFrEF (Table). Conclusion: Infection-related hospitalization was associated with both incident HFpEF and HFrEF. A stronger effect is seen among those with HFpEF.

Background Heart failure predisposes to intracardiac thrombus (ICT) formation. There are limited data on the prevalence and impact of preexisting ICT on postoperative outcomes in left ventricular assist device patients. We examined the risk for stroke and death in this patient population. Methods and Results We retrospectively studied patients who were implanted with HeartMate (HM) II or HM3 between February 2009 and March 2019. Preoperative transthoracic echocardiograms, intraoperative transesophageal echocardiograms and operative reports were reviewed to identify ICT. There were 525 patients with a left ventricular assist device (median age 60.6 years, 81.8% male, 372 HMII and 151 HM3) included in this analysis. An ICT was identified in 44 patients (8.4%). During the follow-up, 43 patients experienced a stroke and 55 died. After multivariable adjustment, presence of ICT increased the risk for the composite of stroke or death at 6-month (hazard ratio [HR] 1.82, 95% confidence interval [CI] 1.00–3.33, P = .049). Patients with ICT were also at higher risk for stroke (HR 2.45, 95% CI 1.14–5.28, P = .021) and death (HR 2.36, 95% CI 1.17–4.79 P = .016) at 6 months of follow-up. Conclusions The presence of ICT is an independent predictor of stroke and death at 6 months after left ventricular assist device implantation. Additional studies are needed to help risk stratify and optimize the perioperative management of this patient population.

OBJECTIVES Left atrial appendage occlusion (LAAO) at the time of implantation may reduce thromboembolic events (TEs) during continuous-flow left ventricular assist device support. The HeartMate 3 (HM3) reduces TEs overall, but the efficacy of LAAO in HM3 is unknown. METHODS Adults receiving first HM3 implantation from November 2014 through December 2019 at a single, large medical centre were retrospectively reviewed. TEs included device thrombosis and ischaemic stroke. Patients were classified by whether they received LAAO or not. Incidence of TEs was compared between groups using cumulative incidence curves with competing risks (death and heart transplant) and risk factors for TEs were assessed with Fine and Gray competing risk regression. RESULTS A total of 182 patients received HM3, of whom 99 (54%) received LAAO versus 83 (46%) who did not. There were 14 TEs, including 13 strokes (7%) and 1 pump thrombosis (0.5%). No significant difference in the incidence of TEs in each group was found (Gray’s test: P = 0.35). LAAO was not associated with TEs in multivariable Fine–Gray analysis (P = 0.10) and no significant risk factors for TEs were found. There were zero disabling strokes in those who received LAAO compared to 6 (7%) in those who did not receive LAAO (P = 0.008). CONCLUSIONS A low number of TEs was observed in HM3 recipients. LAAO did not further reduce the overall rate of TEs in this patient population, though its use may be beneficial in preventing disabling ischaemic strokes after HM3 implantation.

Background Primary graft dysfunction (PGD) is the leading cause of early mortality after heart transplant . Pre-transplant predictors of PGD remain elusive and its etiology remains unclear. Methods Microvesicles were isolated from 88 pre-transplant serum samples and underwent proteomic evaluation using TMT mass spectrometry. Monte Carlo cross validation (MCCV) was used to predict the occurrence of severe PGD after transplant using recipient pre-transplant clinical characteristics and serum microvesicle proteomic data. Putative biological functions and pathways were assessed using gene set enrichment analysis (GSEA) within the MCCV prediction methodology. Results Using our MCCV prediction methodology, decreased levels of plasma kallikrein (KLKB1), a critical regulator of the kinin-kallikrein system, was the most predictive factor identified for PGD (AUROC 0.6444 [0.6293, 0.6655]; odds 0.1959 [0.0592, 0.3663]. Furthermore, a predictive panel combining KLKB1 with inotrope therapy achieved peak performance (AUROC 0.7181 [0.7020, 0.7372]) across and within (AUROCs of 0.66–0.78) each cohort. A classifier utilizing KLKB1 and inotrope therapy outperforms existing composite scores by more than 50 percent. The diagnostic utility of the classifier was validated on 65 consecutive transplant patients, resulting in an AUROC of 0.71 and a negative predictive value of 0.92–0.96. Differential expression analysis revealed a enrichment in inflammatory and immune pathways prior to PGD. Conclusions Pre-transplant level of KLKB1 is a robust predictor of post-transplant PGD. The combination with pre-transplant inotrope therapy enhances the prediction of PGD compared to pre-transplant KLKB1 levels alone and the resulting classifier equation validates within a prospective validation cohort. Inflammation and immune pathway enrichment characterize the pre-transplant proteomic signature predictive of PGD.

Objective The objective of this study was to describe the profiles and outcomes of a cohort of advanced heart failure patients on ambulatory inotropic therapy (AIT). Background With the growing burden of patients with end-stage heart failure, AIT is an increasingly common short or long-term option, for use as bridge to heart transplant (BTT), bridge to ventricular assist device (BTVAD), bridge to decision regarding advanced therapies (BTD) or as palliative care. AIT may be preferred by some patients and physicians to facilitate hospital discharge. However, counseling patients on risks and benefits is critically important in the modern era of defibrillators, durable mechanical support and palliative care. Methods We retrospectively studied a cohort of 241 patients on AIT. End points included transplant, VAD implantation, weaning of inotropes, or death. The primary outcomes were survival on AIT and ability to reach intended goal if planned as BTT or BTVAD. We also evaluated recurrent heart failure hospitalizations, incidence of ventricular arrhythmias (VT/VF) and indwelling line infections. Unintended consequences of AIT, such reaching unintended end point (e.g. VAD implantation in BTT patient) or worse than expected outcome after LVAD or HT, were recorded. Results Mean age of the cohort was 60.7 ± 13.2 years, 71% male, with Class III-IV heart failure (56% non-ischemic). Average ejection fraction was 19.4 ± 10.2%, pre-AIT cardiac index was 1.5 ± 0.4 L/min/m2 and 24% had prior ventricular arrhythmias. Overall on-AIT 1-year survival was 83%. Hospitalizations occurred in 51.9% (125) of patients a total of 174 times for worsening heart failure, line complication or ventricular arrhythmia. In the BTT cohort, only 42% were transplanted by the end of follow-up, with a 14.8% risk of death or delisting for clinical deterioration. For the patients who were transplanted, 1-year post HT survival was 96.7%. In the BTVAD cohort, 1-year survival after LVAD was 90%, but with 61.7% of patients undergoing LVAD as INTERMACS 1-2. In the palliative care cohort, only 24.5% of patients had a formal palliative care consult prior to AIT. Conclusions AIT is a strategy to discharge advanced heart failure patients from the hospital. It may be useful as bridge to transplant or ventricular assist device, but may be limited by complications such as hospitalizations, infections, and ventricular arrhythmias. Of particular note, it appears more challenging to bridge to transplant on AIT in the new allocation system. It is important to clarify the goals of AIT therapy upfront and continue to counsel patients on risks and benefits of the therapy itself and potential unintended consequences. Formalized, multi-disciplinary care planning is essential to clearly define individualized patient, as well as programmatic goals of AIT.

While rates of stroke have declined with the HeartMate3 (HM3) continuous- flow (CF) left ventricular assist device (LVAD), the impact of non-pulsatile flow and artificial pulse physiology on cerebrovascular function is not known. We hypothesized that improved hemodynamics and artificial pulse physiology of HM3 patients would augment cerebrovascular metabolic reactivity (CVR) compared with HeartMate II (HMII) CF-LVAD and heart failure (HF) patients.Mean, peak systolic and diastolic flow velocities (MFV, PSV, MinFV, respectively) and cerebral pulsatility index were determined in the middle cerebral artery (MCA) before and after a 30 sec breath-hold challenge in 90 participants: 24 healthy controls; 30 HF, 15 HMII, and 21 HM3 patients.In HM3 patients, breath-holding increased MFV (Δ8 ± 10 cm/sec, p.0001 vs baseline) to levels similar to HF patients (Δ9 ± 8 cm/sec, p.05), higher than HMII patients (Δ2 ± 8 cm/sec, p.01) but lower than healthy controls (Δ13 ± 7 cm/sec, p.05). CF-LVAD altered the proportion of systolic and diastolic flow responses as reflected by a differential cerebral pulsatility index (p = .03). Baseline MFV was not related to CVR (rCompared with HMII, HM3 patients have a significantly improved CVR. However, CVR remains lower in HM3 and HF patients than in healthy controls, therefore suggesting that changes in cerebral hemodynamics are not reversed by CF-LVAD therapy. Further research on the mechanisms and the long-term impact of altered cerebral hemodynamics in this unique patient population are warranted.

Despite significant advances in therapies, heart failure (HF) remains a progressive disease that, once advanced, is associated with significant death and disability. Cardiac replacement therapies with left ventricular assist device (LVAD) and heart transplantation (HT) are the only treatment options for advanced HF, while lifesaving they can also be lifespan limiting due to the associated complications. Systemic inflammation is mechanistically important in HF pathophysiology and progression. However, directly targeting inflammation in HF has not been beneficial thus far. These failed attempts at therapeutics might be related to our limited understanding of the factors that cause inflammation in HF, and, therefore, to our inability to investigate these triggers in interventional studies. Observational studies have consistently demonstrated associations between alterations in the digestive (gut and oral) microbiome, inflammation and HF risk and progression. Additionally, recent data indicate that these microbial perturbations persist following LVAD and HT, along with residual inflammation and oxidative stress. Furthermore, there is rising recognition of the critical contribution of the microbiome to the metabolism of immunosuppressive drugs after HT. Cumulatively, these findings might posit a mechanistic link between microbiome alterations, systemic inflammation, and adverse outcomes in HF patients before and after cardiac replacement therapies. This review (1) provides an update on available data linking changes in digestive tract microbiota, inflammation, and oxidative stress, to HF pathogenesis and progression; (2) describes evolution of these relationships following LVAD and HT; and (3) outlines present and future intervention strategies that can manipulate the microbiome and possibly modify HF disease trajectory.

Among left ventricular assist device patients, the most commonly infected component is the drive line, which can be managed with antibiotics and local debridement. Infection of intrathoracic device components is less common but more difficult to manage. Herein we describe the incidence of deep device infection (DDI) at our center as well as management and outcomes.We retrospectively reviewed 658 patients who underwent implantable left ventricular assist device insertion with HeartMate 2 (Abbott) or HeartMate 3 (Abbott) devices between January 2004 and June 2021. DDI was defined according to radiographic and clinical criteria. Cumulative incidence was calculated using a Fine-Gray subdistribution model; survival analysis was performed using the method of Kaplan and Meier.There were 32 (4.8%) DDIs during this study period. Drive line infection and re-exploration for bleeding were associated with development of DDI. Cumulative incidence of DDI increased over time, affecting 11% (7%-18%) at 5 years. The dominant microbes involved in DDI were Pseudomonas aeruginosa (19%) and methicillin-resistant Staphylococcus aureus (13%). Nineteen patients (59%) with device infection underwent device exchange, 6 (19%) underwent initial transplant, and 7 (22%) were treated solely with debridement and antibiotics. Of those who underwent device exchange, 12 (63%) developed reinfection of their new device and 6 underwent subsequent heart transplant. Patients who underwent transplantation for management of device infection had improved 5-year survival (80% vs 11%; P = .01) but 3 patients (25%) developed deep sternal wound infection after transplant.DDI is a rare but challenging complication in this destination era. Heart transplantation is the preferred management strategy for eligible patients but infectious complication is common.

Mycophenolate mofetil (MMF) is the gold-standard immunosuppressive agent in heart transplantation (HT), but dose-dependent toxicities (e.g., neutropenia) are frequent. Gut bacteria β-d-glucuronidases (GUS) modulate MMF bioavailability, and changes in the intestinal flora may influence the pharmacokinetics of MMF. The objective of this study was to evaluate the safety and efficacy of MMF 1.5 g every 12 h (q12) [high-dose, HD] versus 1 g q12 [low-dose, LD] and explore the association between neutropenia and GUS.We compared the incidence of acute cellular rejection (ACR) and neutropenia during the first 6 months post-HT. The association between neutropenia and GUS was investigated in an exploratory analysis on a subset of patients with prospectively collected stool data. Stool samples were analyzed using 16S rRNA sequencing.A total of 168 patients (120 MMF-HD, 48 MMF-LD; mean age 55.7 years, 79% male) were studied. Neutropenia occurred in 38.6% of patients at a median of 106 [64-143] days. Freedom from neutropenia was lower in MMF-HD compared with MMF-LD (57% vs. 73%, p = 0.03). ACR (≥1R/1B) occurred in 37.5% of patients at a median of 20 [10-96] days, while high-grade ACR (≥2R/3A) occurred in 11.3% at a median of 14 [9-89] days. Freedom from ACR was similar between groups. MMF-LD was associated with more high-grade ACR (hazard ratio [HR] 3.47, 95% confidence interval [CI] 1.09-11.08, p = 0.03) during the first month, but less neutropenia (HR 0.54, 95% CI 0.29-1.00, p = 0.05) between 1 and 6 months. GUS-producing bacteria were more abundant in neutropenic patients.MMF-LD was associated with higher rates of early high-grade ACR and lower rates of later neutropenia. Further studies are warranted to test whether temporal MMF dose adjustments and gut microbial composition could improve clinical outcomes post-HT.

In the general population, increased aortic stiffness is associated with an increased risk of cardiovascular events. Previous studies have demonstrated an increase in aortic stiffness in patients with a continuous flow left ventricular assist device (CF-LVAD). However, the association between aortic stiffness and common adverse events is unknown.Forty patients with a HeartMate II (HMII) (51 $ 11 years; 20% female; 25% ischemic) implanted between January 2011 and September 2017 were included. Two-dimensional transthoracic echocardiograms of the ascending aorta, obtained before HMII placement and early after heart transplant, were analyzed to calculate the aortic stiffness index (AO-SI). The study cohort was divided into patients who had an increased vs decreased AO-SI after LVAD support. A composite outcome of gastrointestinal bleeding, stroke, and pump thrombosis was defined as the primary end point and compared between the groups. While median AO-SI increased significantly after HMII support (AO-SI 4.4-6.5, P = .012), 16 patients had a lower AO-SI. Patients with increased (n = 24) AO-SI had a significantly higher rate of the composite end point (58% vs 12%, odds ratio 9.8, P.01). Similarly, those with increased AO-SI tended to be on LVAD support for a longer duration, had higher LVAD speed and reduced use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.Increased aortic stiffness in patients with a HMII is associated with a significantly higher rates of adverse events. Further studies are warranted to determine the causality between aortic stiffness and adverse events, as well as the effect of neurohormonal modulation on the conduit vasculature in patients with a CF-LVAD.

AIMS Infections are common following left ventricular assist device (LVAD) implantation and predict adverse events. Infections are frequent prior to LVAD implantation although their impact on postoperative outcomes remains unknown. Gut and nasal microbial imbalance may predispose to mucosal colonization with pathogens. Herein, we investigated the predictive role of pre-LVAD infections, and explored the association of nasal Staphylococcus aureus (SA) colonization and gut microbiota, on postoperative outcomes. METHODS AND RESULTS Overall, 254 LVAD patients were retrospectively categorized based on pre-LVAD infection status: Group 1, bacterial/fungal bloodstream infection (BSI); Group 2, other bacterial/fungal; Group 3, viral; and Group 4, no infection. In a subset of patients, nasal SA colonization (n = 140) and pre-LVAD stool (n = 25) were analysed using 16S rRNA sequencing. A total of 75 (29%) patients had a pre-LVAD infection [Group 1: 22 (29%); Group 2: 41 (55%); Group 3: 12 (16%)]. Pre-LVAD BSIs were independent predictors of 1-year postoperative mortality and infections [Group 1 vs. 4: hazard ratio (HR) 2.70, P = 0.036 vs. HR 1.8, P = 0.046]. In an unadjusted analysis, pre-LVAD infections other than BSIs, INTERMACS profile ≤2, higher serum creatinine, lower serum albumin and nasal SA colonization were also significantly associated with postoperative infections. Patients with early post-LVAD infections exhibited decreased microbial diversity (P

There are limited safety data on reduced anti-thrombotic therapy (RT) in patients with HeartMate 3 (HM3) left ventricular assist device (LVAD). We conducted a single-center, retrospective study of patients with HM3 managed with RT from November 2014 through January 2020. We analyzed baseline characteristics, RT indications, and bleeding and thrombotic complications. We found that 50 of 161 patients with HM3 (31.1%) received RT starting at a median time of 90.5 days after LVAD implantation. Patients on RT were older and more likely to have ischemic heart failure than patients on standard anti-thrombotic therapy (ST). The most common indication for RT was gastrointestinal bleeding (29 patients [58.0%]). At 1-year follow-up, 5.0% of patients on RT developed a thrombotic event. Switching patients from ST to RT reduced the occurrence of major bleeding from 1.252 to 0.324 events per patient-year (p = 0.006). In our population of patients with HM3 LVAD, RT reduces bleeding without increasing the incidence of thrombosis. Our retrospective study suggests that an upfront RT strategy in patients with HM3 may be beneficial and should be prospectively studied.

Background Vasoplegia is a frequent complication of left ventricular assist device (LVAD) implantation. We investigated the effectiveness of methylene blue (MB) for vasoplegia in LVAD recipients. Methods Twenty-seven patients received MB for vasoplegia after LVAD implantation and met study criteria between March 2015 and May 2018. Propensity score inverse probability weighting identified 41 controls who did not receive MB for post-LVAD vasoplegia. Clinical outcomes were compared between control and MB groups and between patients who received doses during (n = 15) and after surgery (n = 12). Hemodynamics and vasopressor requirements were analyzed using analysis of covariance. Results Median total MB dose was 1.9 mg/kg (interquartile range, 1.2-2.2 mg/kg). Methylene blue recipients experienced a transient initial decline in norepinephrine requirement from 141 ng/kg per min (95% confidence interval [CI], 81-201 ng/kg per min) to 117 ng/kg per min (95% CI, 58-176 ng/kg per min; P = .022) and a delayed decline in vasopressin from 4.8 U/h (95% CI, 3.8-5.8 U/h) to 4.0 U/h (95% CI, 2.8-5.1 U/h) (P = .004). In-hospital mortality, postoperative complications, and end-organ dysfunction did not differ from those of controls. There were no observed differences in mean arterial pressure, vasopressor requirements, or outcomes between patients who received doses during or after surgery. Weighted overall mortality in the entire study cohort was 8.8%. Conclusions Although MB may affect vasopressor requirements, clinical outcomes in vasoplegia after LVAD implantation did not improve and were not affected by the timing of administration.

Left ventricular assist devices (LVADs) are associated with major vascular complications including stroke and gastrointestinal bleeding (GIB). These adverse vascular events may be the result of widespread vascular dysfunction resulting from pre-LVAD abnormalities or continuous flow during LVAD therapy. We hypothesized that pre-existing large artery atherosclerosis and/or abnormal blood flow as measured in carotid arteries using ultrasonography are associated with a post-implantation composite adverse outcome including stroke, GIB, or death. We retrospectively studied 141 adult HeartMate II patients who had carotid ultrasound duplex exams performed before and/or after LVAD surgery. Structural parameters examined included plaque burden and stenosis. Hemodynamic parameters included peak-systolic, end-diastolic, and mean velocity as well as pulsatility index. We examined the association of these measures with the composite outcome as well as individual subcomponents such as stroke. After adjusting for established risk factors, the composite adverse outcome was associated with pre-operative moderate-to-severe carotid plaque (OR 5.08, 95% CI 1.67-15.52) as well as pre-operative internal carotid artery stenosis (OR 9.02, 95% CI 1.06-76.56). In contrast, altered hemodynamics during LVAD support were not associated with the composite outcome. Our findings suggest that pre-existing atherosclerosis possibly in combination with LVAD hemodynamics may be an important contributor to adverse vascular events during mechanical support. This encourages greater awareness of carotid morphology pre-operatively and further study of the interaction between hemodynamics, pulsatility, and structural arterial disease during LVAD support.

Acute myocardial infarction with refractory cardiogenic shock (AMI-RCS) is associated with poor outcomes. Several percutaneous mechanical circulatory support devices exist; however, limitations exist regarding long-term use. Herein, we describe our experience with the temporary surgical CentriMag VAD. We reviewed 74 patients with AMI-RCS who underwent CentriMag VAD insertion as bridge-to-decision device from 2007 to 2020. Patients were divided into groups based on introduction of the “shock team” model: Era 1 (2007–2014, n = 51) and Era 2 (2015–2020, n = 23). Era 2 had higher proportion of patients with INTERMACS Profile I. The use of percutaneous MCS as bridge to VAD and the use of minimally invasive VAD were higher in Era 2. There were fewer postoperative bleeding events in Era 2 (80% vs 61%, p = .07). Thirty-day mortality was 23% and 1-year survival was 55%, which were no differences between eras. Destinations after CentriMag VAD included myocardial recovery (39%), durable LVAD (27%), and transplantation (5%). CentriMag VAD device represents a viable bridge-to-decision device with acceptable short- and long-term outcomes for patients with AMI-RCS. Stable outcomes in a progressively sicker population may be related to changes in practice patterns as well as introduction of the “shock team” concept.

Coronary allograft vasculopathy (CAV) continues to afflict a high number of heart transplant (HT) recipients, and elevated LDL is a key risk factor. Many patients cannot tolerate statin medications after HT; however, data for alternative agents remains scarce. To address this key evidence gap, we evaluated the safety and efficacy of the PCSK9i after HT through systematic review and meta-analysis. We searched Medline, Cochrane Central, and Scopus from the earliest date through July 15th, 2021. Citations were included if they were a report of PCSK9i use in adults after HT and reported an outcome of interest. Outcomes included change in LDL cholesterol from baseline, incidence of adverse events, and evidence of CAV. Changes from baseline and outcome incidences were pooled using contemporary random-effects model methodologies. A total of six studies including 97 patients were included. Over a mean follow-up of 13 months (range 3-21), PCSK9i use lowered LDL by 82.61 mg/dL (95% CI - 119.15 to - 46.07; I