Using electronic medical records to identify patients at risk for underlying cardiac amyloidosis.

BACKGROUND: Identification of transthyretin cardiac amyloidosis (ATTR-CA) patients is largely based on pattern recognition by providers, and this can be automated through electronic medical systems (EMR). METHODS: All patients in a large academic hospital with age > 60, ICD-10 code for chronic diastolic heart failure and no previous diagnosis of any amyloidosis were included. An Epic EMR scoring logic assigned risk scores to patients for ICD-10 and CPT codes associated with ATTR-CA, as follows: carpal tunnel syndrome (score 5), aortic stenosis/TAVR (5), neuropathy (4), bundle branch block (4), etc. The individual patients' scores were added, and patients were arranged in descending order of total scores- ranging from 50 to 0. Data is reported as median (interquartile range) and analyzed with non-parametric tests. RESULTS: Of the total 11,648 patients identified, 132 consecutive patients with highest risk scores (score ≥ 30) were enrolled as cases, while 132 patients with scores between 10 and 19 with available echocardiography data served as age-matched controls. Strain echocardiography is not routinely performed. Patients with high scores were more likely to have CA associated findings- African-American race, higher left ventricular (LV) mass index and left atrial volume and lower LV ejection fraction. High score patients had higher troponin and a trend towards high NT-proBNP. CONCLUSION: The modern EMR can be used to flag patients with high risk for ATTR-CA (score ≥ 30 using the proposed logic) through best practice advisory. This could encourage screening during echocardiography using strain or during unsuspected clinic visits.

Sex differences in heart transplantation - analysis of the national inpatient sample 2012-2019.

INTRODUCTION: Advanced heart failure therapies and heart transplantation (HT) have been underutilized in women. Therefore, we aimed to explore the clinical characteristics and outcomes of HT by sex. METHODS: We conducted a retrospective analysis of adult discharges from the National Inpatient Sample (NIS) between 2012 and 2019. International Classification of Disease (ICD) procedure codes were used to identify those who underwent HT. RESULTS: A total of 20,180 HT hospitalizations were identified from 2012-2019. Among them, 28 % were female. Women undergoing HT were younger (mean age 51 vs. 54.5 years, p<0.001). HT hospitalizations among men were more likely to have atrial fibrillation, diabetes, hypertension, renal failure, dyslipidemia, smoking, and ischemic heart disease. HT hospitalizations among women were more likely to have hypothyroidism and valvular heart disease. HT hospitalizations in women were associated with no significant difference in risk of in-hospital mortality (adjusted odds ratio [OR] 0.82; 95 % confidence interval [CI] 0.58-1.16, p=0.271), no significant difference in length of stay or inflation-adjusted cost. Men were more likely to develop acute kidney injury during HT hospitalization (69.2 % vs. 59.7 %, adjusted OR 0.71, 95 % CI 0.61-0.83, p<0.001). CONCLUSIONS: HT utilization is lower in women. However, most major in-hospital outcomes for HT are similar between the sexes. Further studies are need to explore the causes of lower rates of HT in women.

Bedside ultrasound of the internal jugular vein to assess fluid status and right ventricular function: The POCUS-JVD study.

BACKGROUND: Accurate estimation of fluid status is important in the management of heart failure patients, however, the current methods for bedside assessment can be unreliable or impractical for daily use. METHODS: Non-ventilated patients were enrolled immediately prior to scheduled right heart catheterization (RHC). Using M-mode, IJV maximum (Dmax) and minimum (Dmin) anteroposterior diameters were measured during normal breathing, while supine. Respiratory variation in diameter (RVD) was calculated as [(Dmax - Dmin)/Dmax] in percentage. Collapsibility with sniff maneuver (COS) was assessed. Lastly, inferior vena cava (IVC) was assessed. Pulmonary artery pulsatility index (PAPi) was calculated. Data was obtained by five investigators. RESULTS: Total 176 patients were enrolled. Mean BMI was 30.5 kg/m2, LVEF 14-69% (range), 38% with LVEF ≤35%. The POCUS of IJV could be performed in all patients in <5 min. Increasing RAP demonstrated progressive increase in IJV and IVC diameters. For high filling pressure (RAP ≥10 mmHg), an IJV Dmax ≥1.2 cm or IJV-RVD < 30% had specificity >70%. Combining the POCUS of IJV to physical examination improved the combined specificity to 97% for RAP ≥10 mmHg. Conversely, a finding of IJV-COS was 88% specific for normal RAP (<10 mmHg). An IJV-RVD <15% is suggested as a cutoff for RAP ≥15 mmHg. The performance of IJV POCUS was comparable to IVC. For RV function assessment, IJV-RVD < 30% had 76% sensitivity and 73% specificity for PAPi <3, while IJV-COS was 80% specific for PAPi ≥3. CONCLUSION: POCUS of IJV is an easy to perform, specific and reliable method for volume status estimation in daily practice. An IJV-RVD < 30% is suggested for estimation of RAP ≥10 mmHg and PAPi <3.

Covid-19 positive donor utilization for heart transplantation: The new frontier for donor pool expansion.

BACKGROUND: Hearts from COVID-19 positive donors (CPD) are being utilized for heart transplantation by some centers; however, this is in the setting of the lack of guidelines or robust evidence. The paucity of evidence is reflected in the recent Organ Procurement and Transplantation Network (OPTN) communication describing CPD utilization as an "unknown risk." METHODS AND RESULTS: We analyzed the UNOS database for adult heart transplants performed between January 2021 to December 2022, and CPD comprised of a significant percentage of donors, being used in >10% of recipients in some UNOS regions. Between July 2022 and December 2022, 7.9% of heart transplants were with CPD, and in the same period Hepatitis C positive donors accounted for 7.1% and donation after circulatory death (DCD) accounted for 10.3%. CONCLUSION: If the transplant community comes up with a standardized approach and guidance in using CPD hearts, this could provide an effective donor pool expansion strategy.

Evaluation of adjusted international normalized ratio goal in patients with HeartMate 3 left ventricular assist devices.

BACKGROUND: The HeartMate3 left ventricular assist device (HM3 LVAD) has shown a low incidence of thrombosis, but bleeding risk is as high as 43%. We aim to describe the impact of lower international normalization ratio (INR) goal on clinical outcomes. METHODS: In February 2019, our tertiary care institution lowered INR goal in HM3 patients from manufacturer recommendations to 1.8-2.2 and retrospectively analyzed the data. Two cohorts were compared: patients with lower INR goal upon implant (De novo) and those with subsequently lowered INR goal (Adjusted). The Adjusted group also served as its own historical control. Both groups continued aspirin 81 milligrams daily per manufacturer recommendations. The primary outcomes were incidences of bleed and thrombosis events within 12 months. Secondary outcomes included survival free of disabling stroke or reoperation to remove or replace the device and Rosendaal time in therapeutic range (TTR) over 12 months. RESULTS: Thirty-one patients were evaluated for inclusion with 26 meeting criteria. Within 12 months, incidence of bleeding events was 25% and 28.6% in the De novo and Adjusted groups, respectively. Incidence of thrombotic events within 12 months was 0% in the De novo group and 7.1% in the Adjusted group. Twelve-month survival free of disabling stroke or reoperation to remove or replace the device was higher over 12 months for patients in the De novo group (91.7% vs. 78.6%). Median 12-month TTR was 36%, which was primarily attributable to subtherapeutic deviations. CONCLUSIONS: A lower INR goal may be safe when initiated De novo following implantation of the HM3. This study informs the need for larger prospective studies.

Patterns and outcomes of COVID-19 donor utilization for heart transplant.

BACKGROUND: The outcomes following COVID-19 positive donor (CPD) utilization for heart transplant are unknown. METHODS: UNOS database was analyzed for heart transplants performed from the declaration of COVID-19 pandemic until September 30, 2022. RESULT: Since the onset of pandemic, there were 9876 heart transplants reported. COVID-19 antigen or NAT results were available in 7698 adult donors within 14 days of donation, of which 177 (2.3%) were positive. There was no difference in recipient demographics, including age (COVID positive donor vs. negative: 55 vs. 56 years, p = .2) and BMI. Listing status 1 and 2 were similar in both groups (7% vs. 10% and 48% vs. 49% respectively, p = .4). Durable and temporary mechanical support were similar in both groups pre-transplant (both groups 33%, p = .9). There was no difference in days on the waitlist (median 31 days, p = .9). Simultaneous renal transplant rates were similar (11% vs. 10%, p = .9). CPD utilization has increased since the onset of the pandemic, and the adoption is present across most UNOS regions. Post-transplant, there was no difference in length of stay (median 16 vs. 17 days, p = .9) and acute rejection episodes prior to discharge (3% vs. 8%, p = .1). In survival analysis of 90-day follow up, number of deaths reported were comparable (5% in both groups, p = .9) Follow-up LVEF was comparable (62% vs. 60%, p = .4). CONCLUSION: Active COVID-19 infection in donors did not affect survival or rejection rates in the short-term post-heart transplant.

Biology of myocardial recovery in advanced heart failure with long-term mechanical support.

Cardiac remodeling is an adaptive, compensatory biological process following an initial insult to the myocardium that gradually becomes maladaptive and causes clinical deterioration and chronic heart failure (HF). This biological process involves several pathophysiological adaptations at the genetic, molecular, cellular, and tissue levels. A growing body of clinical and translational investigations demonstrated that cardiac remodeling and chronic HF does not invariably result in a static, end-stage phenotype but can be at least partially reversed. One of the paradigms which shed some additional light on the breadth and limits of myocardial elasticity and plasticity is long term mechanical circulatory support (MCS) in advanced HF pediatric and adult patients. MCS by providing (a) ventricular mechanical unloading and (b) effective hemodynamic support to the periphery results in functional, structural, cellular and molecular changes, known as cardiac reverse remodeling. Herein, we analyze and synthesize the advances in our understanding of the biology of MCS-mediated reverse remodeling and myocardial recovery. The MCS investigational setting offers access to human tissue, providing an unparalleled opportunity in cardiovascular medicine to perform in-depth characterizations of myocardial biology and the associated molecular, cellular, and structural recovery signatures. These human tissue findings have triggered and effectively fueled a "bedside to bench and back" approach through a variety of knockout, inhibition or overexpression mechanistic investigations in vitro and in vivo using small animal models. These follow-up translational and basic science studies leveraging human tissue findings have unveiled mechanistic myocardial recovery pathways which are currently undergoing further testing for potential therapeutic drug development. Essentially, the field is advancing by extending the lessons learned from the MCS cardiac recovery investigational setting to develop therapies applicable to the greater, not end-stage, HF population. This review article focuses on the biological aspects of the MCS-mediated myocardial recovery and together with its companion review article, focused on the clinical aspects, they aim to provide a useful framework for clinicians and investigators.

Integrated multi-omic characterization of congenital heart disease.

The heart, the first organ to develop in the embryo, undergoes complex morphogenesis that when defective results in congenital heart disease (CHD). With current therapies, more than 90% of patients with CHD survive into adulthood, but many suffer premature death from heart failure and non-cardiac causes1. Here, to gain insight into this disease progression, we performed single-nucleus RNA sequencing on 157,273 nuclei from control hearts and hearts from patients with CHD, including those with hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot, two common forms of cyanotic CHD lesions, as well as dilated and hypertrophic cardiomyopathies. We observed CHD-specific cell states in cardiomyocytes, which showed evidence of insulin resistance and increased expression of genes associated with FOXO signalling and CRIM1. Cardiac fibroblasts in HLHS were enriched in a low-Hippo and high-YAP cell state characteristic of activated cardiac fibroblasts. Imaging mass cytometry uncovered a spatially resolved perivascular microenvironment consistent with an immunodeficient state in CHD. Peripheral immune cell profiling suggested deficient monocytic immunity in CHD, in agreement with the predilection in CHD to infection and cancer2. Our comprehensive phenotyping of CHD provides a roadmap towards future personalized treatments for CHD.

Retrospective review of secondary prevention strategies for gastrointestinal bleeding and associated clinical outcomes in left ventricular assist device patients.

BACKGROUND: Gastrointestinal bleeding (GIB) is one of the most common bleeding complications associated with left ventricular assist devices (LVAD). Currently, there is no strong evidence or clear guidance for which secondary GIB prophylaxis strategy should be implemented after the discontinuation of aspirin. METHODS: Our single-center study describes the outcomes of 26 LVAD patients who experienced a total of 49 GIB events: these individuals were either in Group-1 (lower INR target range) or Group-2 (lower INR target plus a hemostatic agent) as the secondary prophylaxis strategy. Each GIB event was considered an independent event. Outcomes assessed were bleeding reoccurrence rates, time to next GIB, acute GIB strategies, GIB-free days, thromboembolic events, survival, coagulation, and hematologic parameters. RESULTS: GIB reoccurrence rates were not statistically different: Group-1, 9 (40.9%), versus Group-2, 15 (55.6%); p = 0.308. Danazol was utilized 81.5% of the time as the designated hemostatic agent. Additionally, no significant differences were observed with all of our secondary outcome measures for bleeding, ischemic events, or survival. CONCLUSION: While our study was not powered to assess the clinical outcomes related to survival and thromboembolic events, no discernable increased risk for ischemic events including pump thrombosis were observed. Our data suggest that a lower INR target range plus danazol does not confer any additional benefit over a lower INR target range only approach. The results of this report are hypothesis-generating and additional studies are warranted to elucidate the optimal antithrombotic strategy and role of hemostatic agents in reducing the risk of recurrent GIB events.

SUMOylation does not affect cardiac troponin I stability but alters indirectly the development of force in response to Ca2.

Post-translational modification of the myofilament protein troponin I by phosphorylation is known to trigger functional changes that support enhanced contraction and relaxation of the heart. We report for the first time that human troponin I can also be modified by SUMOylation at lysine 177. Functionally, TnI SUMOylation is not a factor in the development of passive and maximal force generation in response to calcium, however this modification seems to act indirectly by preventing SUMOylation of other myofilament proteins to alter calcium sensitivity and cooperativity of myofilaments. Utilising a novel, custom SUMO site-specific antibody that recognises only the SUMOylated form of troponin I, we verify that this modification occurs in human heart and that it is upregulated during disease.

Prior Freezing Has Minimal Impact on the Contractile Properties of Permeabilized Human Myocardium.

Background Experiments measuring the contractile properties of human myocardium are important for translational research but complicated by the logistical difficulties of acquiring specimens. Accordingly, many groups perform contractile assays using samples that are acquired from patients at one institution and shipped to another institution for experiments. This necessitates freezing the samples and performing subsequent assays using chemically permeabilized preparations. It is unknown how prior freezing affects the contractile function of these preparations. Methods and Results To examine the effects of freezing we measured the contractile function of never-frozen and previously frozen myocardial samples. Samples of left ventricular tissue were obtained from 7 patients who were having a ventricular assist device implanted. Half of each sample was chemically permeabilized and used immediately for contractile assays. The other half of the sample was snap frozen in liquid nitrogen and maintained at -180 °C for at least 6 months before being thawed and tested in a second series of experiments. Maximum isometric force measured in pCa 4.5 solution, passive force measured in pCa 9.0 solution, and Hill coefficients were not influenced by prior freezing (P=0.07, P=0.14, and P=0.27 respectively). pCa50 in never-frozen samples (6.11±0.04) was statistically greater (P<0.001) than that measured after prior freezing (5.99±0.04) but the magnitude of the effect was only ≈0.1 pCa units. Conclusions We conclude that prior freezing has minimal impact on the contractile properties that can be measured using chemically permeabilized human myocardium.

High Prevalence of Cardiac Amyloidosis in Clinically Significant Aortic Stenosis: A Meta-Analysis.

Background: There is growing evidence of coexistence of aortic stenosis (AS) and transthyretin cardiac amyloidosis (CA). Not screening AS patients at the time of hospital/clinic visit for CA represents a lost opportunity. Methods: We surveyed studies that reported the prevalence of CA among AS patients. Studies that compared patients with aortic stenosis with cardiac amyloidosis (AS-CA) and AS alone were further analyzed, and meta-regression was performed. Results: We identified nine studies with 1,321 patients of AS, of which 131 patients had concomitant CA, with a prevalence of 11%. When compared to AS-alone, the patients with AS-CA were older, more likely to be males, had higher prevalence of carpal tunnel syndrome, right bundle branch block. On echocardiogram, patients with AS-CA had thicker interventricular septum, higher left ventricular mass index (LVMI), lower myocardial contraction fraction, and lower stroke volume index. Classical low-flow low-gradient (LFLG) physiology was more common among patients with AS-CA. Patients with AS-CA had higher all-cause mortality than patients with AS alone (33% vs. 22%, P = 0.02) in a follow-up period of at least 1 year. Conclusions: CA has a high prevalence in patients with AS and is associated with worse clinical, imaging, and biochemical parameters than patients with AS alone.

Mechanical circulatory support in pre and postheart transplant period.

PURPOSE OF REVIEW: Progression of heart failure (HF) and its unpredictable and volatile nature, often requires advanced therapies including heart transplant. Mechanical circulatory support plays an integral part in the advanced treatment options. This technology can be deployed in several ways, particularly in the preparation and patient optimization for heart transplants. This article discusses the use of temporary and durable devices and their deployment strategies in the pre and posttransplant period. RECENT FINDINGS: Recently temporary mechanical support devices have allowed us to improve survival to transplant as well as posttransplant. Early implementation of temporary devices both for stabilization of advanced HF patients being considered for transplant as well as those with posttransplant primary graft dysfunction (although utilization of extracorporeal membrane oxygenation has repeatedly shown to be associated with worse outcomes compared to the other devices discussed), is reflective of the degree of disease progression in these patients. The outcomes of patients supported with durable devices have significantly improved with advancing technology. HeartMate 3 device has not only been shown to improve survival as well as the quality of life but in comparison to its predecessor, has been shown to decrease the morbidity associated with this technology. SUMMARY: Both temporary and durable devices are now associated with improved survival and allow us to transplant patients in a more stable and safer manner with fewer adverse events. Based on the new United Network of Organ Sharing allocation system, it allows us to upgrade those who do not have the luxury of time to wait for a transplant. Primary graft dysfunction now also can be assisted with those devices, which is reflected in improved survival of posttransplant patients.

The Impact of Adverse Events on Functional Capacity and Quality of Life After HeartWare Ventricular Assist Device Implantation.

Left ventricular assist devices (LVADs) improve quality of life (QoL) and functional capacity (FC) for patients with advanced heart failure. The association between adverse events (AEs) and changes in QoL and FC are unknown. Patients treated with the HeartWare ventricular assist device (HVAD) with paired 6-minute walk distance (6MWD, n = 263) and Kansas City Cardiomyopathy Questionnaires (KCCQ, n = 272) at baseline and 24 months in the ENDURANCE and ENDURANCE Supplemental Trial databases were included. Patients were stratified based upon occurrence of clinically significant AEs during the first 24 months of support and analyzed for the mean change in 6MWD and KCCQ. The impact of AE frequency on change in 6MWD and KCCQ from baseline to 24 months was evaluated. Of the AEs examined, only sepsis was associated with an improvement in 6MWD (109 m vs. 16 m, p = 0.002). Patients without improvement in 6MWD test from baseline to 24 months had significantly more AEs than those with FC improvement (p = 0.0002). Adverse events did not affect the KCCQ overall summary score. In this analysis, patients with fewer AEs had greater improvement in FC during the 24-month follow up. The frequency of AEs did not have a significant impact on QoL after LVAD implantation.

Prospective Multicenter Study of Myocardial Recovery Using Left Ventricular Assist Devices (RESTAGE-HF [Remission from Stage D Heart Failure]): Medium-Term and Primary End Point Results.

BACKGROUND: Left ventricular assist device (LVAD) unloading and hemodynamic support in patients with advanced chronic heart failure can result in significant improvement in cardiac function allowing LVAD removal; however, the rate of this is generally considered to be low. This prospective multicenter nonrandomized study (RESTAGE-HF [Remission from Stage D Heart Failure]) investigated whether a protocol of optimized LVAD mechanical unloading, combined with standardized specific pharmacological therapy to induce reverse remodeling and regular testing of underlying myocardial function, could produce a higher incidence of LVAD explantation. METHODS: Forty patients with chronic advanced heart failure from nonischemic cardiomyopathy receiving the Heartmate II LVAD were enrolled from 6 centers. LVAD speed was optimized with an aggressive pharmacological regimen, and regular echocardiograms were performed at reduced LVAD speed (6000 rpm, no net flow) to test underlying myocardial function. The primary end point was the proportion of patients with sufficient improvement of myocardial function to reach criteria for explantation within 18 months with sustained remission from heart failure (freedom from transplant/ventricular assist device/death) at 12 months. RESULTS: Before LVAD, age was 35.1±10.8 years, 67.5% were men, heart failure mean duration was 20.8±20.6 months, 95% required inotropic and 20% temporary mechanical support, left ventricular ejection fraction was 14.5±5.3%, end-diastolic diameter was 7.33±0.89 cm, end-systolic diameter was 6.74±0.88 cm, pulmonary artery saturations were 46.7±9.2%, and pulmonary capillary wedge pressure was 26.2±7.6 mm Hg. Four enrolled patients did not undergo the protocol because of medical complications unrelated to the study procedures. Overall, 40% of all enrolled (16/40) patients achieved the primary end point, P<0.0001, with 50% (18/36) of patients receiving the protocol being explanted within 18 months (pre-explant left ventricular ejection fraction, 57±8%; end-diastolic diameter, 4.81±0.58 cm; end-systolic diameter, 3.53±0.51 cm; pulmonary capillary wedge pressure, 8.1±3.1 mm Hg; pulmonary artery saturations 63.6±6.8% at 6000 rpm). Overall, 19 patients were explanted (19/36, 52.3% of those receiving the protocol). The 15 ongoing explanted patients are now 2.26±0.97 years after explant. After explantation survival free from LVAD or transplantation was 90% at 1-year and 77% at 2 and 3 years. CONCLUSIONS: In this multicenter prospective study, this strategy of LVAD support combined with a standardized pharmacological and cardiac function monitoring protocol resulted in a high rate of LVAD explantation and was feasible and reproducible with explants occurring in all 6 participating sites. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01774656.