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Background: The ICU environment is disruptive to a patient's biological rhythms where sleep-wake cycles are often desynchronized from the environmental day-night changes. This puts patients at increased risk to develop delirium with consequent fiscal pressure for the health care system. An underappreciated dimension is how time-specific patient phenotypes in the critical care environment relate to clinical outcomes. We set out to analyze how rhythmic components (or the lack thereof) in physiological data streams sampled at high resolution in the ICU were associated with the future incidence of delirium and death. To offer cues for further interrogation into mechanism and risk prognosis, we examined differences in 24-hour fluctuations of clinical labs in ICU patient populations at risk., Methods: Rhythmic components using dipping ratios and JTK_CYCLE statistics were derived from 24-hour blood pressure and heart rate measurements available from ICU patient admissions recorded in the MIMIC IV database. Logistic adjusted regression models assessed the association between disrupted vital sign rhythms and the future incidence of delirium during the same hospital admission and death. Aggregation of numeric clinical lab measurements across the first 24 hours from all patient admissions allowed modelling of rhythmic patterns and subsequent association studies to link potential biochemical mechanisms to perturbed vital sign rhythms and adverse ICU outcomes., Results: Patients with reverse blood pressure dipping were at a 40% higher risk to have a diagnosis of delirium (Odds Ratio: 1.40, 95% CI: 1.14-1.72) and a 13% increased risk of death (Odds Ratio: 1.13, 95% CI: 1.02-1.26). Compared to the patient population with nocturnal blood pressure dip, reverse dippers showed 24-hour biochemistry profiles suggestive of altered circadian programs specifically in clinical parameters of renal, metabolic, and hemostatic function., Conclusions: Reverse blood pressure dipping can be an early sign for the future development of delirium in the ICU and is accompanied by disrupted biorhythms across multiple organ systems. Dampened and reversed heart rate and blood pressure rhythms are associated with a higher risk for death in ICU patients. Considering the inclusion of these risk factors in preventive care may improve patient outcomes and reduce burden on the health care system., Competing Interests: Competing Interests CS is the Robert L. McNeil Jr. Fellow in Translational Medicine and Therapeutics. GAF is the McNeil Professor of Translational Medicine and Therapeutics. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Aims: Right ventricular (RV) failure (RVF) after left ventricular assist device (LVAD) implant is an important cause of morbidity and mortality. Modern, data-driven approaches for defining and predicting RVF have been under-utilized., Methods: Two hundred thirty-two patients were identified with a mean age of 55 years; 40 (17%) were women, 132 were (59%) Caucasian and 74 (32%) were Black. Patients were split between Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Classes 1, 2 and 3 (25%, 38% and 34%, respectively). Within this group, 'provisional RVF' patients were identified, along with 'no RVF' patients. 'No RVF' patients were defined as patients who never demonstrated more than moderate RV dysfunction on a post-LVAD transthoracic echocardiogram (TTE) (ordinal RV function <3), never required an RV assist device (RVAD), were not discharged on sildenafil and were not on a pulmonary vasodilator or inotropic medication at 3 months after LVAD implant. In total, n = 67 patients were defined as 'no RVF'. The remaining patients represented the 'provisional RVF' population (n = 165). Extensive electronic health records queries yielded >1200 data points per patient. Using <1 and >1 month post-LVAD time windows motivated by established, expert-consensus definitions of 'early' and 'late' post-implant RVF, unbiased clustering analysis was performed to identify hidden patient 'phenogroups' within these two established RVF populations. Clusters were compared on post-implant clinical metrics and 1 year outcomes. Lastly, pre-implant metrics were used to generate models for predicting post-implant RVF phenogroup., Results: Within the 'early RVF' time window, distinct 'well' and 'sick' patient phenogroup clusters were identified. These clusters had similar RV function and pulmonary vasodilator usage during the first month after LVAD but differed significantly in heart failure therapy tolerance, renal (P < 0.001) and hepatic (P = 0.013) function, RVAD usage (P = 0.001) and 1 year mortality (P = 0.047). Distinct 'well' and 'sick' phenogroups were also identified in the 'late RVF' time window. These clusters had similar RV function (P = 0.111) and RVAD proportions (P = 0.757) but differed significantly in heart failure medication tolerance, pulmonary vasodilator usage (P = 0.001) and 1 year mortality (P < 0.001). Prediction of phenogroup clusters from the 'early RVF' population achieved an area under the receiver operating characteristic curve (AUROC) of 0.84, with top predictors including renal function, liver function, heart rate and pre-LVAD RV function., Conclusions: Distinct, potentially predictable phenogroups of patients who have significantly different long-term outcomes exist within consensus-defined post-LVAD RVF populations., (© 2025 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The efficacy of extracorporeal membrane oxygenation (ECMO) as a bridge to left ventricular assist device (LVAD) remains unclear, and recipients of the more contemporary HeartMate 3 (HM3) LVAD are not well represented in previous studies. We therefore undertook a multicenter, retrospective study of this population., Methods and Results: INTERMACS 1 LVAD recipients from five U.S. centers were included. In-hospital and one-year outcomes were recorded. The primary outcome was the overall mortality hazard comparing ECMO versus non-ECMO patients by propensity-weighted survival analysis. Secondary outcomes included survival by LVAD type, as well as postoperative and one-year outcomes. One hundred and twenty-seven patients were included; 24 received ECMO as a bridge to LVAD. Mortality was higher in patients bridged with ECMO in the primary analysis (HR 3.22 [95%CI 1.06-9.77], p = 0.039). Right ventricular assist device was more common in the ECMO group (ECMO: 54.2% vs non-ECMO: 11.7%, p < 0.001). Ischemic stroke was higher at one year in the ECMO group (ECMO: 25.0% vs non-ECMO: 4.9%, p = 0.006). Among the study cohort, one-year mortality was lower in HM3 than in HeartMate II (HMII) or HeartWare HVAD (10.5% vs 46.9% vs 31.6%, respectively; p < 0.001) recipients. Pump thrombosis at one year was lower in HM3 than in HMII or HVAD (1.8% vs 16.1% vs 16.2%, respectively; p = 0.026) recipients., Conclusions: Higher mortality was observed with ECMO as a bridge to LVAD, likely due to higher acuity illness, yet acceptable one-year survival was seen compared with historical rates. The receipt of the HM3 was associated with improved survival compared with older generation devices., (© 2024 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Background: The Heartmate 3 (HM3) risk score (HM3RS) was derived and validated internally from within the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trial population and provides 1- and 2-year mortality risk prediction for patients in those before HM3 left ventricular assist device (LVAD) implantation. We aimed to evaluate the HM3RS in nontrial unselected patients, including those not meeting inclusion criteria for MOMENTUM 3 trial enrollment., Methods: Patients who underwent HM3 LVAD implant at 1 of 7 US centers between 2017 and 2021, with at least 1-year follow-up, were included in this analysis. Patients were retrospectively assessed for their eligibility for the MOMENTUM 3 trial based on study inclusion and exclusion criteria. HM3RS risk discrimination was evaluated using time-dependent receiver operating characteristic curve analysis for 1-year mortality for all patients and further stratified by MOMENTUM 3 trial eligibility. Kaplan-Meier curves were constructed using the HM3RS-based risk categories., Results: Of 521 patients included in the analysis, 266 (51.1%) would have met enrollment criteria for MOMENTUM 3. The 1- and 2-year survival for the total cohort was 85% and 81%, respectively. There was no statistically significant difference in survival between those who met and did not meet enrollment criteria at 1 (87% vs 83%; p = 0.21) and 2 years postimplant (80% vs 78%; p = 0.39). For the total cohort, HM3RS predicted 1-year survival with an area under the curve (AUC) of 0.63 (95% confidence interval [CI]: 0.57-0.69, p < 0.001). HM3RS performed better in the subset of patients meeting enrollment criteria: AUC 0.69 (95% CI:0.61-0.77, p < 0.001) compared to the subset that did not: AUC 0.58 (95% CI: 0.49-0.66, p = 0.078)., Conclusions: In this real-world evidence, multicenter cohort, 1- and 2-year survival after commercial HM3 LVAD implant was excellent, regardless of trial eligibility. The HM3RS provided adequate risk discrimination in "trial-like" patients, but predictive value was reduced in patients who did not meet trial criteria., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Study Objectives: While heart failure with preserved ejection fraction (HFpEF) is associated with the presence of obstructive sleep apnea (OSA), few studies have examined the association between scoring systems used to predict HFpEF risk, such as the H 2 FPEF and HFA-PEFF scores, and OSA prevalence and severity., Methods: We performed chart review on all patients who underwent both an echocardiogram and sleep study at the University of Pennsylvania between July 1, 2020, and June 30, 2022. There were 277 patients in the final cohort after excluding patients with relevant comorbidities. Associations between echocardiographic parameters and OSA severity, as well as between H 2 FPEF score and OSA severity, were examined using linear tests of trend. The association between H 2 FPEF score and prevalent OSA was examined with logistic regression., Results: OSA severity was associated with echocardiographic markers, including left atrial volume index ( P = .03) and left ventricular relative thickness ( P = .008). Patients with high H 2 FPEF risk scores had over 17-fold higher odds of prevalent OSA compared with those with low-risk scores (17.7; 95% CI 4.3, 120.7; P < .001). Higher H 2 FPEF scores were strongly correlated with OSA severity ( P < .001). After controlling for body mass index, H 2 FPEF scores were not associated with prevalence or severity of OSA., Conclusions: In an ambulatory population referred for sleep study and echocardiogram, markers of diastolic dysfunction were associated with OSA severity. OSA prevalence and severity were associated with increased H 2 FPEF scores, although these associations were largely explained by obesity. Clinicians should have low thresholds for referring patients with OSA for cardiac workup and patients with HFpEF for sleep study., Citation: Connolly JE, Genuardi MV, Mora JI, Prenner SB. Heart failure with preserved ejection fraction risk is associated with prevalence and severity of obstructive sleep apnea. J Clin Sleep Med . 2024;20(3):381-387., (© 2024 American Academy of Sleep Medicine.)

Competing Interests: Disclosures None.

Competing Interests: Disclosures Dr Genuardi reports consulting income from Respicardia and a research agreement with Abbott. The other authors report no conflicts.

Background: Accurate blood pressure (BP) measurement remains challenging in patients with HeartMate 3™ left ventricular assist devices (HM3 LVADs). The Finapres® NOVA is a promising non-invasive continuous BP monitor that uses the volume clamp method via a finger cuff, so here we aimed to validate the instrument in HM3 patients., Methods: In a single-center cohort, BP was monitored in 15 patients within 72 h following HM3 implantation. A radial artery catheter quantified arterial blood pressure (ABP), while the NOVA measured finger arterial pressure (fiAP) and reconstructed brachial artery pressure (reBAP). Waveforms were recorded for 10 min, and mean values were calculated in 15-s intervals., Resuts: fiAP and ABP were moderately correlated during both the first (ICC 0.61, p = 0.04) and final measurements (ICC 0.66, p = 0.03). reBAP and ABP were strongly correlated during both the first (ICC 0.81, p = 0.002) and final measurements (ICC 0.83, p = 0.001). Both NOVA-derived values may underestimate low BP values while overestimating relatively high BP values. The reBAP was within 5 mm Hg of the ABP in 40% of patients (and within 10 mm Hg in 67%)., Conclusions: This pilot represents the first evidence in support of the Finapres® NOVA for non-invasive BP measurement in select patients with HM3 LVADs. The instrument may provide useful data during BP medication adjustments or pump titration, but despite the correlation between the non-invasive reBAP and invasive ABP, individual-level inaccuracy may be clinically meaningful. Further investigation is needed to clarify these limitations and optimize accuracy before widespread adoption in this unique patient population., (© 2023 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Subacute groin complications associated with extracorporeal membrane oxygenation (ECMO) cannulation are well recognized, yet their effects on clinical outcomes remain unknown. This single-center, retrospective study reviewed all patients receiving venoarterial ECMO from 01/2017 to 02/2020. Cohorts analyzed included transplanted patients (TPs) and non-transplanted patients (N-TPs) who did or did not develop ECMO-related subacute groin complications. Standard descriptive statistics were used for comparisons. Logistic regressions identified associated risk factors. Overall, 82/367 (22.3%) ECMO patients developed subacute groin complications, including 25/82 (30.5%) seromas/lymphoceles, 32/82 (39.0%) hematomas, 18/82 (22.0%) infections, and 7/82 (8.5%) non-specified collections. Of these, 20/82 (24.4%) underwent surgical interventions, most of which were muscle flaps (14/20, 70.0%). TPs had a higher incidence of subacute groin complications than N-TPs (14/28, 50.0% vs. 68/339, 20.1%, P = 0.001). Seromas/lymphoceles more often developed in TPs than N-TPs (10/14, 71.4% vs. 15/68, 22.1%, P = 0.001). Most patients with subacute groin complications survived to discharge (60/68, 88.2%). N-TPs who developed subacute groin complications had longer post-ECMO lengths of stay than those who did not (34 days, IQR 16-53 days vs. 17 days, IQR 8-34 days, P < 0.001). Post-ECMO length of stay was also longer among patients who underwent related surgical interventions compared to those who did not (50 days, IQR 35-67 days vs. 29 days, IQR 16-49 days, P = 0.007). Transplantation was the strongest risk factor for developing subacute groin complications (OR 3.91, CI 95% 1.52-10.04, P = 0.005). Subacute groin complications and related surgical interventions are common after ECMO cannulation and are associated with longer hospital stays. When surgical management is warranted, muscle flaps may reduce lengths of stay compared to other surgical interventions., (© 2022. The Japanese Society for Artificial Organs.)

Introduction: The contribution of chronotropic incompetence to reduced exercise tolerance after a heart transplant is well known, but its role as a prognostic marker of post-transplant mortality is unclear. The aim of this study is to examine the relationship between post-transplant heart rate response (HRR) and survival., Methods: We performed a retrospective analysis of all adult heart transplant recipients at the University of Pennsylvania between the years 2000 and 2011 who underwent a cardiopulmonary exercise test (CPET) within a year of transplant. Follow-up time and survival status were observed through October 2019, using data merged from the Penn Transplant Institute. HRR was calculated by subtracting the resting HR from the peak exercise HR. The association between HRR and mortality was analyzed using Cox proportional hazard models and Kaplan-Meier analysis. The optimal cut-off point for HRR was generated by Harrell's C statistic. Patients with submaximal exercise tests were excluded, defined by a respiratory exchange ratio (RER) cut-off of 1.05., Results: Of 277 patients with CPETs performed within a year post-transplant, 67 were excluded for submaximal exercise. In the 210 included patients, the mean follow-up time was 10.9 years (Interquartile range (IQR) 7.8-14). Resting HR and peak HR did not significantly impact mortality after adjusting for covariates. In a multivariable linear regression analysis, each 10-beat increase in heart rate response was associated with a 1.3 mL/kg/min increase in peak V O 2 and a 48 s increase in the total exercise time. Each beat/min increase in HRR was associated with a 3% reduction in the hazard of mortality (HR 0.97; 95% CI 0.96-0.99, p = 0.002). Using the optimal cut-off point generated by Harrell's C statistic, survival was significantly higher in patients with an HRR > 35 beats/min compared to those with an HRR < 35 beats/min (log rank p = 0.0012)., Conclusion: In heart transplant patients, a low HRR is associated with increased all-cause mortality and decreased exercise capacity. Additional studies are needed to validate whether targeting HRR in cardiac rehabilitation may improve outcomes.

Background: Decreased peak oxygen consumption during exercise (peak Vo 2 ) is a well-established prognostic marker for mortality in ambulatory heart failure. After heart transplantation, the utility of peak Vo 2 as a marker of post-transplant survival is not well established., Methods and Results: We performed a retrospective analysis of adult heart transplant recipients at the Hospital of the University of Pennsylvania who underwent cardiopulmonary exercise testing within a year of transplant between the years 2000 to 2011. Using time-to-event models, we analyzed the hazard of mortality over nearly two decades of follow-up as a function of post-transplant percent predicted peak Vo 2 (%Vo 2 ). A total of 235 patients met inclusion criteria. The median post-transplant %Vo 2 was 49% (IQR 42 to 60). Each standard deviation (±14%) increase in %Vo 2 was associated with a 32% decrease in mortality in adjusted models (HR 0.68, 95% CI 0.53 to 0.87, p = 0.002). A %Vo 2 below 29%, 64% and 88% predicted less than 80% survival at 5, 10, and 15 years, respectively., Conclusions: Post-transplant peak Vo 2 is a highly significant prognostic marker for long-term post-transplant survival. It remains to be seen whether decreased peak Vo 2 post-transplant is modifiable as a target to improve post-transplant longevity.

The coronavirus disease 2019 (COVID-19) pandemic continues to pose a significant threat to patients receiving advanced heart failure therapies. The current study was undertaken to better understand the relationship between obesity and outcomes of SARS-CoV-2 infection in patients with a left ventricular assist device (LVAD) or heart transplant. We performed a retrospective review of patients with a heart transplant or LVAD who presented to one of the participating 11 institutions between April 1 and November 30, 2020. Patients were grouped by body mass index (BMI) into obese (BMI ≥ 30 k/m2) and nonobese cohorts (BMI < 30 kg/m2). Multivariable logistic regression models were used to estimate effects of obesity on outcomes of interest. Across all centers, 162 heart transplant and 81 LVAD patients were identified; 54 (33%) and 38 (47%) were obese, respectively. Obese patients tended to have more symptoms at presentation. No differences in rates of hospitalization or ICU admission were noted. Obese patients with LVADs were more likely to require mechanical ventilation (39% vs. 8%, p < 0.05). No differences in renal failure or secondary infection were noted. Mortality was similar among heart transplant patients (11% [obese] vs. 16% [nonobese], p = 0.628) and LVAD patients (12% vs. 15%, p = 1.0). BMI was not associated with increased adjusted odds of mortality, ICU admission, or mechanical ventilation (all p > 0.10). In summary, acute presentations of SARS-CoV-2 among heart transplant and LVAD recipients carry a significantly higher mortality than the general population, although BMI does not appear to impact this. Further studies on the longer-term effects of COVID-19 on this population are warranted., (Copyright © ASAIO 2022.)

Background: Early right heart failure (RHF) remains a major source of morbidity and mortality after left ventricular assist device (LVAD) implantation, yet efforts to predict early RHF have proven only modestly successful. Pharmacologic unloading of the left ventricle may be a risk stratification approach allowing for assessment of right ventricular and hemodynamic reserve., Methods: We performed a multicenter, retrospective analysis of patients who had undergone continuous-flow LVAD implantation from October 2011 to April 2020. Only those who underwent vasodilator testing with nitroprusside during their preimplant right heart catheterization were included (n = 70). Multivariable logistic regression was used to determine independent predictors of early RHF as defined by Mechanical Circulatory Support-Academic Research Consortium., Results: Twenty-seven patients experienced post-LVAD early RHF (39%). Baseline clinical characteristics were similar between patients with and without RHF. Patients without RHF, however, achieved higher peak stroke volume index (SVI) (30.1 ± 8.8 vs 21.7 ± 7.4 mL/m 2 ; p < 0.001; AUC: 0.78; optimal cut-point: 22.1 mL/m 2 ) during nitroprusside administration. Multivariable analysis revealed that peak SVI was significantly associated with early RHF, demonstrating a 16% increase in risk of early RHF per 1 ml/m 2 decrease in SVI. A follow up cohort of 10 consecutive patients from July 2020 to October 2021 resulted in all patients being categorized appropriately in regards to early RHF versus no RHF according to peak SVI., Conclusion: Peak SVI with nitroprusside administration was independently associated with post-LVAD early RHF while resting hemodynamics were not. Vasodilator testing may prove to be a strong risk stratification tool when assessing LVAD candidacy though additional prospective validation is needed., Competing Interests: Financial disclosures No grants, contracts, or other financial support was received for this manuscript., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Aims: While it is common practice to use intravenous (IV) iron in patients with left ventricular assist devices (LVADs) and iron deficiency, there is insufficient evidence regarding outcomes in this patient population. We evaluated the safety and effectiveness of IV iron therapy in patients supported by LVADs with iron deficiency., Methods: We performed a retrospective analysis of iron deficient patients on continuous LVAD support at a large academic center between 2008 and 2019. Patients were divided into two cohorts based on IV iron sucrose treatment. The primary endpoint was hemoglobin at 12 weeks. Secondary endpoints were mean corpuscular volume (MCV) and New York Heart Association (NYHA) class at 12 weeks. Safety endpoints included hospitalization, infection, pump thrombosis, arrhythmia, and gastrointestinal bleed. Models were weighted by the inverse probability of receiving IV iron using a propensity score, and endpoints were adjusted for their corresponding baseline values., Results: Among 213 patients, 70 patients received IV iron and 143 patients did not. Hemoglobin at 12 weeks was significantly greater among those treated (intergroup difference: 0.6 g/dL; 95% CI, 0.1 to 1.1; p = 0.01), while MCV was similar in both groups (intergroup difference: 0.7 μm 3 ; 95% CI, -1.3 to 2.7; p = 0.50). NYHA class distribution at 12 weeks was significantly different (odds ratio for improvement: 2.84; 95% CI, 1.42 to 4.68; p = 0.003). The hazards of adverse events in each group were similar., Conclusions: In patients with LVADs and iron deficiency, treatment with IV iron sucrose was safe and associated with improvements in functional status and hemoglobin.

Survival after implant of a left ventricular assist device (LVAD) continues to improve for patients with end-stage heart failure. Meanwhile, more patients are implanted with a destination therapy, rather than bridge-to-transplant, indication, meaning the population of patients living long-term on LVADs will continue to grow. Non-LVAD healthcare providers will encounter such patients in their scope of practice, and familiarity and comfort with the physiology and operation of these devices and common problems is essential. This review article describes the history, development, and operation of the modern LVAD. Common LVAD-related complications such as bleeding, infection, stroke, and right heart failure are reviewed and an approach to the patient with an LVAD is suggested. Nominal operating parameters and device response to various physiologic conditions, including hypo- and hypervolemia, hypertension, and device failure, are reviewed.

It has been suggested that maintaining low mean arterial pressure (MAP) in left ventricular assist device (LVAD) recipients is associated with a reduced risk of stroke/death. However, the lower limit of the optimal MAP range has not been established. We aimed to identify this lower limit in a contemporary cohort of LVAD recipients with frequent longitudinal MAP measurements. We analyzed 86,651 MAP measurements in 309 patients with an LVAD (32% LVADs with full magnetic levitation of the impeller) at a tertiary medical center during a mean follow-up of 1.7 ± 1.1 years. Cox proportional hazards regression modeling was used to study the association of serial MAP measurements with stroke/death within 3 years after index discharge. Multivariate analysis identified MAP ≤75 mm Hg, compared with MAP >75 mm Hg, as the low MAP threshold associated with increased risk of death (hazard ratio [HR] 4.74, 95% confidence interval [CI] 2.85 to 7.87, p <0.001), stroke (HR 2.72;, 95% CI 1.39 to 5.33, p = 0.01), and stroke/death (HR 4.45, 95% CI 2.83 to 6.99, p <0.001). The risk associated with MAP ≤75 mm Hg was consistent in subgroups categorized by age, gender, race, device type, renal function, right-sided heart failure, and blood pressure medications. In conclusion, our findings suggest that maintaining MAP ≤75 mm Hg during long-term follow-up in LVAD recipients is associated with increased risk of stroke/death regardless of risk factors or medical management., Competing Interests: Disclosures Dr. Vidula has research support from Abbott Laboratories and the National Institutes of Health. Dr. Gosev is a consultant for Abbott Laboratories. Dr. Birati has research support from Medtronic. Dr. Farooq H. Sheikh has received consulting fees/honoraria and research support from Abbott Laboratories and honoraria from Medtronic. Dr. DeVore reports research funding through his institution from the American Heart Association, National Heart, Lung, and Blood Institute, and Patient-Centered Outcomes Research Institute. He has also received nonfinancial support from Abbott Laboratories for educational activities. The remaining authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Previous studies suggesting that OSA may be an independent risk factor for VTE have been limited by reliance on administrative data and lack of adjustment for clinical variables, including obesity., Research Question: Does OSA confer an independent risk of incident VTE among a large clinical cohort referred for sleep-disordered breathing evaluation?, Study Design and Methods: We analyzed the clinical outcomes of 31,309 patients undergoing overnight polysomnography within a large hospital system. We evaluated the association of OSA severity with incident VTE, using Cox proportional hazards modeling accounting for age, sex, BMI, and common comorbid conditions., Results: Patients were of mean age 50.4 years, and 50.1% were female. There were 1,791 VTE events identified over a mean follow-up of 5.3 years. In age- and sex-adjusted analyses, each 10-event/h increase in the apnea-hypopnea index was associated with a 4% increase in incident VTE risk (hazard ratio [HR], 1.04; 95% CI, 1.02-1.06). After adjusting for BMI, this association disappeared (HR, 1.01; 95% CI, 0.99-1.03). In contrast, nocturnal hypoxemia had an independent association with incident VTE. Patients with > 50% sleep time spent with oxyhemoglobin saturation < 90% are at 48% increased VTE risk compared with those without nocturnal hypoxemia (HR, 1.48; 95% CI, 1.16-1.69)., Interpretation: In this large cohort, we found that patients with more severe OSA as measured by the apnea-hypopnea index are more likely to have incident VTE. Adjusted analyses suggest that this association is explained on the basis of confounding by obesity. However, severe nocturnal hypoxemia may be a mechanism by which OSA heightens VTE risk., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Before the 33rd Annual International Society for Heart and Lung Transplantation conference, there was significant intercenter variability in definitions of primary graft dysfunction (PGD). The incidence, risk factors, and outcomes of consensus-defined PGD warrant further investigation. We retrospectively examined 448 adult cardiac transplant recipients at our institution from 2005 to 2017. Patient and procedural characteristics were compared between PGD cases and controls. Multivariable logistic regression was used to model PGD and immediate postoperative high-inotrope requirement for hypothesized risk factors. Patients were followed for a mean 5.3 years to determine longitudinal mortality. The incidence of PGD was 16.5%. No significant differences were found with respect to age, sex, race, body mass index, predicted heart mass mismatch, pretransplant amiodarone therapy, or pretransplant mechanical circulatory support (MCS) between recipients with PGD versus no PGD. Each 10 minute increase in ischemic time was associated with 5% greater odds of PGD (OR = 1.05 [95% CI, 1.00-1.10]; p = 0.049). Pretransplant MCS, predicted heart mass mismatch ≥30%, and pretransplant amiodarone therapy were associated with high-immediate postoperative inotropic requirement. The 30 day, 1 year, and 5 year mortality for patients with PGD were 28.4%, 38.0%, and 45.8%, respectively, compared with 1.9%, 7.1%, and 21.5% for those without PGD (log-rank, p < 0.0001). PGD heralded high 30 day, 1 year, and 5 year mortality. Pretransplant MCS, predicted heart mass mismatch, and amiodarone exposure were associated with high-inotrope requirement, while prolonged ischemic time and multiple perioperative transfusions were associated with consensus-defined PGD, which may have important clinical implications under the revised United Network for Organ Sharing allocation system., Competing Interests: Disclosure: Robert L. Kormos is an Abbott employee. Arman Kilic is on the advisory board for Medtronic. Mary Keebler is on the advisory board for Medtronic. The other authors have no funding and conflicts of interest to report., (Copyright © ASAIO 2021.)

Background: Direct oral anticoagulants (DOACs) are replacing warfarin for stroke prevention in patients with atrial fibrillation (AF)., Objective: To assess the effectiveness and safety of concomitant treatment with antiplatelet-DOAC compared to antiplatelet-warfarin in patients with acute coronary syndrome (ACS) and AF., Design: Retrospective propensity score-matched cohort study using United States-based commercial healthcare database from January 2016 to June 2019., Participants: New-users of antiplatelet-DOAC and antiplatelet-warfarin who initiated the combined therapy within 30 days following incident ACS diagnosis., Measurements: Primary study outcomes were recurrent cardiovascular diseases (CVD) (ie, a composite of stroke and myocardial infarction) and major bleeding events identified via discharge diagnoses. We controlled for potential confounders via propensity score matching (PSM). We generated marginal hazard ratios (HRs) via Cox proportional hazards regression using a robust variance estimator while adjusting for calendar time., Results: After PSM, a total of 2,472 persons were included (1,236 users of antiplatelet-DOAC and 1,236 users of antiplatelet-warfarin). The use of antiplatelet-DOAC (vs. antiplatelet-warfarin) was associated with a reduced rate of recurrent CVD (adjusted HR 0.72, 95% confidence interval [CI], 0.56-0.92) and major bleeding events (adjusted HR, 0.49, 95% CI 0.33-0.72)., Limitations: Residual confounding., Conclusions: In real-world data of AF patients with concurrent ACS, the use of antiplatelet-DOAC following ACS diagnosis was associated with a lower rate of recurrent CVD and major bleeding events compared with antiplatelet-warfarin. These findings highlight a potential promising role for DOACs in patients with ACS and AF requiring combined antiplatelet therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: COVID-19 continues to inflict significant morbidity and mortality, particularly on patients with preexisting health conditions. The clinical course, outcomes, and significance of immunosuppression regimen in heart transplant recipients with COVID-19 remains unclear., Methods: We included the first 99 heart transplant recipients at participating centers with COVID-19 and followed patients until resolution. We collected baseline information, symptoms, laboratory studies, vital signs, and outcomes for included patients. The association of immunosuppression regimens at baseline with severe disease were compared using logistic regression, adjusting for age and time since transplant., Results: The median age was 60 years, 25% were female, and 44% were white. The median time post-transplant to infection was 5.6 years. Overall, 15% died, 64% required hospital admission, and 7% remained asymptomatic. During the course of illness, only 57% of patients had a fever, and gastrointestinal symptoms were common. Tachypnea, oxygen requirement, elevated creatinine and inflammatory markers were predictive of severe course. Age ≥ 60 was associated with higher risk of death and the use of the combination of calcineurin inhibitor, antimetabolite, and prednisone was associated with more severe disease compared to the combination of calcineurin inhibitor and antimetabolite alone (adjusted OR = 7.3, 95% CI 1.8-36.2). Among hospitalized patients, 30% were treated for secondary infection, acute kidney injury was common and 17% required new renal replacement therapy., Conclusions: We present the largest study to date of heart transplant patients with COVID-19 showing common atypical presentations and a high case fatality rate of 24% among hospitalized patients and 16% among symptomatic patients., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) pandemic continues to afflict millions of people worldwide. Patients with end-stage heart failure and left ventricular assist devices (LVADs) may be at risk for severe COVID-19 given a high prevalence of complex comorbidities and functional impaired immunity. The objective of this study is to describe the clinical characteristics and outcomes of COVID-19 in patients with end-stage heart failure and durable LVADs., Methods: The Trans-CoV-VAD registry is a multi-center registry of LVAD and cardiac transplant patients in the United States with confirmed COVID-19. Patient characteristics, exposure history, presentation, laboratory data, course, and clinical outcomes were collected by participating institutions and reviewed by a central data repository. This report represents the participation of the first 9 centers to report LVAD data into the registry., Results: A total of 40 patients were included in this cohort. The median age was 56 years (interquartile range, 46-68), 14 (35%) were women, and 21 (52%) were Black. Among the most common presenting symptoms were cough (41%), fever, and fatigue (both 38%). A total of 18% were asymptomatic at diagnosis. Only 43% of the patients reported either subjective or measured fever during the entire course of illness. Over half (60%) required hospitalization, and 8 patients (20%) died, often after lengthy hospitalizations., Conclusions: We present the largest case series of LVAD patients with COVID-19 to date. Understanding these characteristics is essential in an effort to improve the outcome of this complex patient population.

Background Preoperative pulmonary hypertension (PH) is associated with excess mortality among patients with severe mitral regurgitation undergoing mitral valve surgery (MVS). However, the links between PH phenotype, pulmonary vascular remodeling, and persistent postoperative PH are not well understood. We aimed to describe the associations between components of pulmonary hemodynamics as well as postoperative residual PH with longitudinal mortality in patients with severe mitral regurgitation who received MVS. Methods and Results Patients undergoing MVS for severe mitral regurgitation from 2011 to 2016 were retrospectively identified within our health system (n=488). Mean pulmonary artery pressure and other hemodynamic variables were determined by presurgical right-heart catheterization. Postoperative pulmonary artery systolic pressure was assessed on echocardiogram 42 to 365 days post-MVS. Longitudinal survival over a mean 3.9 years of follow-up was evaluated using Cox proportional hazards modeling to compare survival after adjustment for demographics, surgical characteristics, and comorbidities. Pre-MVS prevalence of PH was high at 85%. After adjustment, each 10-mm Hg increase in preoperative mean pulmonary artery pressure was associated with a 1.38-fold increase in risk of death (95% CI, 1.13-1.68). Elevated preoperative pulmonary vascular resistance, transpulmonary gradient, and right atrial pressure were similarly associated with increased mortality. Among 231 patients with postoperative echocardiogram, evidence of PH on echocardiogram (pulmonary artery systolic pressure ≥35 mm Hg) was associated with increased risk of death (hazard ratio [HR], 2.02 [95% CI, 1.17-3.47]); however, this was no longer statistically significant after adjustment (HR, 1.55 [95% CI, 0.85-2.85]). Conclusions In patients undergoing MVS for mitral regurgitation, preoperative PH, and postoperative PH were associated with increased mortality.

Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are a relatively new class of antihyperglycemic drug with salutary effects on glucose control, body weight, and blood pressure. Emerging evidence now indicates that these drugs may have a beneficial effect on outcomes in heart failure with reduced ejection fraction (HFrEF). Post-approval cardiovascular outcomes data for three of these agents (canagliflozin, empagliflozin, and dapagliflozin) showed an unexpected improvement in cardiovascular endpoints, including heart failure hospitalization and mortality, among patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease or risk factors. These studies were followed by a placebo controlled trial of dapagliflozin in patients with HFrEF both with and without T2DM, showing a reduction in all-cause mortality comparable to current guideline-directed HFrEF medical therapies such as angiotensin-converting enzyme inhibitors and beta-blockers. In this review, we discuss the current landscape of evidence, safety and adverse effects, and proposed mechanisms of action for use of these agents for patients with HFrEF. The United States (US) and European guidelines are reviewed, as are the current US federally approved indications for each SGLT2 inhibitor. Use of these agents in clinical practice may be limited by an uncertain insurance environment, especially in patients without T2DM. Finally, we discuss practical considerations for the cardiovascular clinician, including within-class differences of the SGLT2 inhibitors currently available on the US market (217/300).

Purpose of Review: This review highlights the mechanisms of action of cardiac contractility modulation (CCM) and the clinical data which supports its use for the appropriate patient population., Recent Findings: CCM has beneficial effects on myocardial calcium handling and reverse remodeling of abnormal genetic programs. Clinical trials show sustained improvements in quality of life, exercise tolerance, and heart failure symptoms. Heart failure is a global epidemic that is expected to increase in prevalence over the coming years. Despite improvements in, and the standardization of, optimal medical therapy (OMT), morbidity and mortality remain unacceptably high, with a 5-year mortality rate of 50%. While more recent advances in device therapies, including chronic resynchronization therapy (CRT), and left ventricular assist devices (LVADs), have changed the care of advanced heart failure for a certain subset of patients, there remains a therapeutic gap in the treatment of patients with heart failure and reduced ejection fraction (HFrEF) who are not candidates for CRT. CCM is a novel device-based therapy which delivers an electrical stimulus during the absolute refractory period and has been shown to improve heart failure symptoms, exercise tolerance, and quality of life.

Background: Prior studies have found that sleep-disordered breathing (SDB) is common among those with left ventricular (LV) dysfunction and heart failure. Few epidemiological studies have examined this association, especially in US Hispanic/Latinos, who may be at elevated risk of SDB and heart failure., Methods: We examined associations between SDB and LV diastolic and systolic function using data from 1506 adults aged 18 to 64 years in the Hispanic Community Health Study/Study of Latinos ECHO-SOL Ancillary Study (2011-2014). Home sleep testing was used to measure the apnea-hypopnea index, a measure of SDB severity. Echocardiography was performed a median of 2.1 years later to quantify LV diastolic function, systolic function, and structure. Multivariable linear regression was used to model the association between apnea-hypopnea index and echocardiographic measures while accounting for the complex survey design, demographics, body mass, and time between sleep and echocardiographic measurements., Results: Each 10-unit increase in apnea-hypopnea index was associated with 0.2 (95% CI, 0.1-0.3) lower E', 0.3 (0.1-0.5) greater E/E' ratio, and 1.07-fold (1.03-1.11) higher prevalence of diastolic dysfunction as well as 1.3 (0.3-2.4) g/m 2 greater LV mass index. These associations persisted after adjustment for hypertension and diabetes mellitus. In contrast, no association was identified between SDB severity and subclinical markers of LV systolic function., Conclusions: Greater SDB severity was associated with LV hypertrophy and subclinical markers of LV diastolic dysfunction. These findings suggest SDB in Hispanic/Latino men and women may contribute to the burden of heart failure in this population.

We conducted a cross-sectional analysis using a database from commercial health plans in the United States to describe trends in the use of antidiabetic medications among patients with type 2 diabetes and heart failure (HF) from 2006 through 2017. We used loop diuretic dose as a surrogate for HF severity (mild HF 0-40 mg/day, moderate-severe HF >40 mg/day). We assessed antidiabetic medication dispensing in the 90 days following HF diagnosis. Over the 12-year period, we identified an increase in the use of metformin (39.2% vs. 62.6%), dipeptidyl peptidase-4 inhibitors (DPP-4i) (0.5% vs. 17.1%) and sodium-glucose co-transporter-2 inhibitors (SGLT-2i) (0.0% vs. 9.0%), but a decrease in the use of sulphonylureas (47.8% vs. 27.8%) and thiazolidinediones (TZDs) (31.7% vs. 5.3%). In 2017, patients with moderate-severe HF more commonly used insulin (43.1%); a majority of mild HF patients used metformin (62.8%). A proportion of patients with moderate-severe HF used TZDs (4.4%). Among patients with diabetes and HF, the use of metformin and DPP-4i rapidly increased, but a proportion of patients with moderate-severe HF continued to use TZDs. Despite their promising cardiovascular safety profile, SGLT-2i use remains limited., (© 2020 John Wiley & Sons Ltd.)

Background: Non-vitamin K oral anticoagulants (NOACs) have emerged as alternatives to vitamin K antagonists in select situations. For left atrial (LA) appendage thrombus in nonvalvular atrial fibrillation (AF) or flutter, guidelines recommend oral anticoagulation (OAC) for at least 3 weeks prior to reassessment. Data comparing NOACs to warfarin in this scenario are scarce., Methods: A retrospective study identified subjects with nonvalvular AF or flutter who were: a) noted to have LA thrombus detected on transesophageal echocardiography (TEE), b) previously not receiving long-term OAC; and c) evaluated for resolution of LA thrombus by follow-up TEE between 3 weeks to less than 1 year of the initial TEE., Results: The study included 45 subjects with mean age 63.2 years, 69% male, 78% white race/ethnicity, 42% paroxysmal, and mean CHA 2 DS 2 -VASc score 3.4 ± 1.7. All LA thrombi were confined to the appendage. OAC received included apixaban (3), dabigatran (13), rivaroxaban (6), and warfarin (23), The median follow-up time to repeat TEE was 67 (interquartile range, 49-96) days. LA appendage thrombus resolution rates were 76% for the entire cohort, 77% for NOACs, and 74% for warfarin. In univariable logistic regression analysis, LA appendage thrombus resolution was similar for NOACs when compared to warfarin (odds ratio, 1.20; 95% confidence interval, 0.31-4.69; P = .79)., Conclusions: In patients nonvalvular AF or flutter who were OAC naïve at the time of diagnosis with LA appendage thrombus, complete resolution was similar between NOACs and warfarin., (© 2019 Wiley Periodicals, Inc.)

Background: Short sleep may be a risk factor for atrial fibrillation. However, previous investigations have been limited by lack of objective sleep measurement and small sample size. We sought to determine the association between objectively measured sleep duration and atrial fibrillation., Methods: All 31,079 adult patients undergoing diagnostic polysomnography from 1999 to 2015 at multiple sites within a large hospital network were identified from electronic medical records. Prevalent atrial fibrillation was identified by continuous ECG during polysomnography. Incident atrial fibrillation was identified by diagnostic codes and 12-lead ECGs. Logistic regression and Cox proportional hazards modeling were used to examine the association of sleep duration and atrial fibrillation prevalence and incidence, respectively, adjusting for age, sex, BMI, hypertension, coronary artery disease, cerebrovascular disease, peripheral vascular disease, heart failure, and sleep apnea severity., Results: We identified 404 cases of prevalent atrial fibrillation among 30,061 individuals (mean age ± SD, 51.0 ± 14.5 years; 51.6% women) undergoing polysomnography. After adjustment, each 1-h reduction in sleep duration was associated with a 1.17-fold (95% CI, 1.11-1.30) increased risk of prevalent atrial fibrillation. Among 27,589 patients without atrial fibrillation at baseline, we identified 1,820 cases of incident atrial fibrillation over 4.6 years median follow-up. After adjustment, each 1-h reduction in sleep duration was associated with a 1.09-fold (95% CI, 1.05-1.13) increased risk for incident atrial fibrillation., Conclusions: Short sleep duration is independently associated with prevalent and incident atrial fibrillation. Further research is needed to determine whether interventions to extend sleep can lower atrial fibrillation risk., (Published by Elsevier Inc.)

Pulmonary hypertension (PH), a heterogeneous vascular disease, consists of subtypes with overlapping clinical phenotypes. MicroRNAs, small non-coding RNAs that negatively regulate gene expression, have emerged as regulators of PH pathogenesis. The muscle-specific micro RNA (miR)-204 is known to be depleted in diseased pulmonary artery smooth muscle cells (PASMCs), furthering proliferation and promoting PH. Alterations of circulating plasma miR-204 across the trans-pulmonary vascular bed might provide mechanistic insights into the observed intracellular depletion and may help distinguish PH subtypes. MiR-204 levels were quantified at sequential pulmonary vasculature sites in 91 patients with World Health Organization (WHO) Group I pulmonary arterial hypertension (PAH) (n = 47), Group II PH (n = 22), or no PH (n = 22). Blood from the right atrium/superior vena cava, pulmonary artery, and pulmonary capillary wedge was collected. Peripheral blood mononuclear cells (PBMCs) were isolated (n = 5/group). Excretion of miR-204 by PAH-PASMCs was also quantified in vitro. In Group I patients only, miR-204 concentration increased sequentially along the pulmonary vasculature (log fold-change slope = 0.22 [95% CI = 0.06-0.37], P = 0.008). PBMCs revealed insignificant miR-204 variations among PH groups ( P = 0.12). Cultured PAH-PAMSCs displayed a decrease of intracellular miR-204 ( P = 0.0004), and a converse increase of extracellular miR-204 ( P = 0.0018) versus control. The stepwise elevation of circulating miR-204 across the pulmonary vasculature in Group I, but not Group II, PH indicates differences in muscle-specific pathobiology between subtypes. Considering the known importance of miR-204 in PH, these findings may suggest pathologic excretion of miR-204 in Group I PAH by PASMCs, thereby accounting for decreased intracellular miR-204 concentration.

Objective: Drowsy driving is a significant cause of traffic accidents and fatalities. Although previous reports have shown an association between race and drowsy driving, the reasons for this disparity remain unclear., Study Design: A cross-sectional analysis of responses from 193,776 White, Black, and Hispanic adults participating in the US Behavioral Risk Factor Surveillance System from 2009 to 2012 who answered a question about drowsy driving., Measurements: Drowsy driving was defined as self-reporting an episode of falling asleep while driving in the past 30 days. All analyses were adjusted for age, sex, and medical comorbidities. Subsequent modeling evaluated the impact of accounting for differences in health care access, alcohol consumption, risk-taking behaviors, and sleep quality on the race-drowsy driving relationship., Results: After adjusting for age, sex, and medical comorbidities, the odds ratio (OR) for drowsy driving was 2.07 (95% confidence interval [CI] 1.69-2.53) in Blacks and 1.80 (95% CI 1.51-2.15) in Hispanics relative to Whites. Accounting for health care access, alcohol use, and risk-taking behaviors had little effect on these associations. Accounting for differences in sleep quality resulted in a modest reduction in the OR for drowsy driving in Blacks (OR = 1.55, 95% CI 1.27-1.89) but not Hispanics (OR = 1.74, 95% CI 1.45-2.08)., Conclusion: US Blacks and Hispanics have approximately twice the risk of drowsy driving compared to whites. Differences in sleep quality explained some of this disparity in Blacks but not in Hispanics. Further research to understand the root causes of these disparities is needed., (Copyright © 2018 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

Pulmonary arterial hypertension (PAH) is a deadly vascular disease, characterized by increased pulmonary arterial pressures and right heart failure. Considering prior non-US studies of atrial arrhythmias in PAH, this retrospective, regional multi-center US study sought to define more completely the risk factors and impact of paroxysmal and non-paroxysmal forms of atrial fibrillation and flutter (AF/AFL) on mortality in this disease. We identified patients seen between 2010 and 2014 at UPMC (Pittsburgh) hospitals with hemodynamic and clinical criteria for PAH or chronic thromboembolic pulmonary hypertension (CTEPH) and determined those meeting electrocardiographic criteria for AF/AFL. We used Cox proportional hazards regression with time-varying covariates to analyze the association between AF/AFL occurrence and survival with adjustments for potential cofounders and hemodynamic severity. Of 297 patients with PAH/CTEPH, 79 (26.5%) suffered from AF/AFL at some point. AF/AFL was first identified after PAH diagnosis in 42 (53.2%), identified prior to PAH diagnosis in 27 (34.2%), and had unclear timing in the remainder. AF/AFL patients were older, more often male, had lower left ventricular ejection fractions, and greater left atrial volume indices and right atrial areas than patients without AF/AFL. AF/AFL (whether diagnosed before or after PAH) was associated with a 3.81-fold increase in the hazard of death (95% CI 2.64-5.52, p < 0.001). This finding was consistent with multivariable adjustment of hemodynamic, cardiac structural, and heart rate indices as well as in sensitivity analyses of patients with paroxysmal versus non-paroxysmal arrhythmias. In these PAH/CTEPH patients, presence of AF/AFL significantly increased mortality risk. Mortality remained elevated in the absence of a high burden of uncontrolled or persistent arrhythmias, thus suggesting additional etiologies beyond rapid heart rate as an explanation. Future studies are warranted to confirm this observation and interrogate whether other therapies beyond rate and rhythm control are necessary to mitigate this risk.