Abstract: The amyloidogenic V122I variant of the transthyretin (TTR) gene is found in ∼3% of African American individuals and increases cardiovascular mortality risk after the age of 65 years. Sickle cell disease (SCD) primarily affects individuals of African descent, leading to multiorgan damage and premature mortality, with cardiopulmonary issues being a major cause of death. We assessed the impact of TTR V122I on cardiac phenotype and survival in a study of 584 patients with SCD (mean age, 35.9 years; 50.7% women). The prevalence was 3.1% (18/584), mainly female (72.2%). Age, blood pressure, body mass index, and liver/renal markers were similar between carriers and noncarriers, except for higher blood urea nitrogen levels in carriers. Echocardiography showed that carriers had increased septal thickness and left ventricular mass index and lower diastolic function indices. Over a median follow-up of 6.5 years, 219 patients died. The coinheritance of TTR V122I with SCD was associated with increased mortality (hazard ratio, 2.82; 95% confidence interval, 1.57-5.06). At 5 years, the cumulative incidence of death was 52.9% among carriers compared with 14.5% among noncarriers, corresponding to an approximate relative risk of 3.6. TTR protein levels were significantly lower in carriers. In conclusion, TTR V122I prevalence in patients with SCD mirrors that of the general African American population but affects cardiovascular function much earlier, and a contributing factor may be the underlying oxidative stress and chronic anemia. Genetic screening for TTR V122I is important and should be considered for patients with SCD. This trial was registered at www.clinicaltrials.gov as NCT00011648.

Recent scientific and technological innovations presage a future wherein heart, lung, blood, and sleep (HLBS) health threats are preempted and wherein precision medicine reduces the burden of HLBS disease. The research priorities of the National Heart, Lung, and Blood Institute (NHLBI) Strategic Vision guide Institute activities toward this future. To realize the Strategic Vision, NHLBI has drawn upon its rich resources, including its cohort studies, clinical trial infrastructure, and precision medicine programs. Strategic Vision implementation also requires leveraging datasets of scale and scope expansive enough to deconstruct the complexity of human biology and disease. The large platform of participants and datatypes in the All of Us Research Program (All of Us) facilitates exploration of scientific questions toward improved knowledge, prevention, and management of HLBS conditions. Here, we discuss how utilizing All of Us has stimulated novel HLBS research and provide examples of future research that can be conducted via this platform. Overall, Strategic Vision implementation through All of Us will elucidate how biology, lifestyle, and social and physical environment influence health and disease; deepen understanding of population and individual differences or disparities; and accelerate development, implementation, and dissemination of targeted diagnostic, prevention, and treatment strategies for HLBS conditions.

BACKGROUND Cardiopulmonary changes in noncirrhotic portal hypertension (NCPH) are poorly understood. AIM To investigate cardiopulmonary changes using transthoracic echocardiography (TTE) in NCPH and their correlation with clinical features. METHODS Prospective cohort including 10 preclinical NCPH [without portal hypertension (PH)] and 32 NCPH subjects who underwent TTE with agitated saline injection and comprehensive clinical evaluation were assessed. PH was defined by presence of either varices, ascites or portosystemic shunting. Intrapulmonary vascular dilatation (IPVD) is defined as appearance of microbubbles in the left atrium after three heartbeats. Right ventricular systolic pressure (RVSP) > 38 mmHg was used to identify possible porto-pulmonary hypertension. Cardiomyopathy is defined using cirrhotic cardiomyopathy consortium criteria. RESULTS Among 42 subjects, 17 (40%) had IPVD, 4 (9.5%) had RVSP > 38 mmHg, and 6 (14%) had cardiomyopathy. Aspartate aminotransferase to alanine aminotransferase (AST/ALT) (1.3 vs 1, P = 0.04) and liver stiffness measurement (LSM) (12.4 kPa vs 7.1 kPa, P = 0.03) were higher in those with IPVD. Presence of either LSM > 10 or AST/ALT > 1.2 aided in identifying subjects with IPVD-sensitivity, specificity, and accuracy of 76%. RVSP correlated with oxygen saturation (r = -0.33), and free right hepatic vein pressure (r = 0.43). Those with PH had higher left atrial volume (LAV) (62 mL vs 48 mL, P < 0.01), and LAV index (LAVI) (35 m2 vs 23 m2, P < 0.01) compared to those without PH. Total bile acids, especially primary bile acids positively correlated with LAV (r = 0.36), and LAVI (r = 0.41). CONCLUSION Similar to cirrhotic patients, cardiopulmonary changes are prevalent in NCPH, especially among those with PH. In NCPH, cardiopulmonary changes occur despite preserved synthetic function, suggesting the NCPH model's value in understanding cardiopulmonary dysfunction in liver disease.

Heart failure with preserved ejection fraction (HFpEF) has risen to become the most common form of heart failure (HF) worldwide. The pathophysiology of HFpEF is complex and intimately tied to cardiac-metabolic-kidney abnormalities, spanning cardiac, vascular, and noncardiovascular organ systems. Large-scale prospective phenotyping studies that comprehensively examine these abnormalities in the same patient are not available, an evidence gap recognized by a NHLBI (National Heart, Lung, and Blood Institute)-assembled working group of experts as a major bottleneck impeding new therapeutic innovations. Here, we present the rationale and design for the HeartShare/AMP-HF (Accelerating Medicines Partnership-Heart Failure) program, supported through the NHLBI, the FNIH (Foundation for the National Institutes of Health), the U.S. FDA (Food and Drug Administration), and multiple industry and nonprofit partners.

AIMS:Exercise training (ET) is an effective therapy in heart failure with preserved ejection fraction (HFpEF), but the influence of different ET characteristics is unclear. We aimed to evaluate the associations between ET frequency, duration, intensity [% heart rate reserve (%HRR)] and estimated energy expenditure (EEE) with the change in peak oxygen consumption (V̇O2) over 3 months of moderate continuous training (MCT, 5×/week) or high-intensity interval training (HIIT, 3×/week) in HFpEF. METHODS AND RESULTS:ET duration and heart rate (HR) were recorded with a smartphone application. EEE was calculated using the HR data during ET and the individual HR-V̇O2 relationships during cardiopulmonary exercise testing. Differences between groups and associations between ET characteristics and peak V̇O2 change were assessed with linear regression analyses. Peak V̇O2 improved by 9.2 ± 13.2% after MCT and 8.7 ± 15.9% after HIIT (P = 0.67). The average EEE of 1 HIIT session was equivalent to ∼1.42 MCT sessions and when adjusted for EEE, the mean difference between MCT and HIIT was -0.1% (P = 0.98). For both MCT and HIIT, peak V̇O2 change was positively associated with ET frequency (MCT: R2 = 0.103; HIIT: R2 = 0.149) and duration/week (MCT: R2 = 0.120; HIIT: R2 = 0.125; all P < 0.05). Average %HRR was negatively associated with peak V̇O2 change in MCT (R2 = 0.101; P = 0.034), whereas no significant association was found in HIIT (P = 0.234). Multiple regression analyses explained ∼1/3 of the variance in peak V̇O2 change. CONCLUSION:In HFpEF, isocaloric HIIT and MCT seem to be equally effective over 3 months. Within each mode, increasing ET frequency or duration/week may be more effective to improve peak V̇O2 than increasing ET intensity.

Purpose: Patients with heart failure with preserved ejection fraction (HFpEF) have significant impairments in patient-reported outcomes (PRO) including physical functioning and quality of life (QOL). We conducted a meta-analysis of randomized clinical trials of supervised exercise training (SET) to examine the efficacy of such training. Methods: We included six single-blinded SET trials in patients with HFpEF, defined as a left ventricular EF >= 50%, published since 2010 in which participants were randomized to a facility-based exercise training program or usual care. We identified trials from a 2024 Cochrane review of exercise-based cardiac rehabilitation for adults with heart failure as well as other reviews and meta-analyses in PubMed. We used random effects meta-analysis to estimate the respective SET effects for five endpoints: the 36-Item Short Form Survey (SF-36) Physical Functioning Scale (PFS), the SF-36 Physical Component Summary, the Minnesota Living With Heart Failure Questionnaire (MLWHFQ) total score, the Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score, and the KCCQ QOL subscale. Results: The treatment effect estimate favored SET for all five endpoints. However, the SET effect was only statistically significant for the SF-36 PFS (P < .0001) and the MLWHFQ total score (P = .01). Conclusions: This meta-analysis demonstrated clear evidence that patient-reported physical functioning, an outcome that patients with HFpEF identify as a prominent disability, is significantly improved with SET. It also showed consistent improvements across several other multi-dimensional measures of QOL.

The American Society of Echocardiography (ASE) plays a vital role in establishing practice standards and guidelines within the echocardiography field. Its influence is comprehensive, covering training, image acquisition, nomenclature, measurements, diagnosis, and quality improvement. This report focuses on the final phases of the diagnostic imaging process, specifically reporting and communicating exam results. It provides updates to previously published guidelines on the required components of a comprehensive echocardiography report. Standardization within echocardiography reports is essential to uphold quality, consistency, and interoperability across various echocardiography (echo) labs, institutions, and healthcare systems, as well as over different time points. Additionally, standardized reporting is crucial for facilitating big data analysis, aligning with the current emphasis on machine learning and artificial intelligence. This document delineates core measurements and statements applicable to transthoracic, transesophageal, and stress echocardiography. It also elucidates abbreviations, acronyms, terminology, and definitions to enhance communication. The path from preliminary report to final submission is clarified, alongside examples of critical, urgent, and significant findings. Recommendations include comparison of serial echocardiograms and, when clinically relevant, comparisons with other imaging modalities. The document addresses the integration of simple congenital heart disease (CHD) findings appropriate for an adult echo lab. Standardization facilitates clinical and research endeavors by ensuring clear and consistent data reporting, thereby enabling seamless data sharing and reusability.

Background Abbreviation use in clinical and academic cardiology is widespread, yet there are few guidelines regulating the creation and utilization of abbreviations. Inconsistent abbreviations can introduce ambiguity and pose challenges to practice and research. Objectives The authors aimed to analyze how abbreviations are created and utilized in general cardiology and cardiac imaging society guidelines in order to assess whether ambiguities and discrepancies exist between societies. Methods Abbreviation data were collected from 7 national and international societies of general cardiology and cardiac imaging over a 6-year span (2018-2023). Data were linguistically coded for abbreviation type, unique occurrence, meaning or sense count, and frequency of discrepancy between societies. Results Among a total of 5,394 abbreviation tokens, there were 1,782 unique entries. Among the unique entries, 227 (12.7%) had 2 or more associated meanings (senses), and thus were potentially ambiguous. Cardiac societies differed from each other, and also internally, in their use of abbreviations, with the European Society of Cardiology representing the highest frequency of discrepant abbreviation usage (14.5%). Conclusions More than 12.7% of abbreviations in cardiology society guidelines had 2 or more corresponding meanings, potentially increasing the risks of miscommunication and misrepresentation. We call on cardiology and cardiac imaging societies to define and publish best practices regarding abbreviation creation and utilization.

Much work has been done on developing hierarchical composite end point analysis methods, which meaningfully measure the effect of a treatment for patients with heart failure. Two motivations for this work have been as follows: (1) trying to ensure that more severe outcomes are weighted more heavily in the analysis; (2) combining different types of end points such as death, number of recurrent hospitalizations, and continuous functional or biologic end points. Such methods include the win ratio, the win odds, and the proportion in favor of treatment. In this article, our focus is when all components are clinical end points such as death or hospitalizations and do not include continuous end points. We review these methods using HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training). We also describe recent methods for combining different clinical end points, which take into account the time a subject is in a particular clinical state. These include the pairwise win time, the restricted mean time in favor of treatment, the expected win time, and the expected win time against reference. We discuss the US Food and Drug Administration guidances and make general recommendations.

Clinical application of cardiac magnetic resonance (CMR) is expanding but CMR assessment of LV diastolic function is still being validated. The purpose of this study was to validate assessments of left ventricular (LV) diastolic dysfunction (DD) using CMR by comparing with transthoracic echocardiography (TTE) performed on the same day. Patients with suspected or diagnosed cardiomyopathy (n = 63) and healthy volunteers (n = 24) were prospectively recruited and included in the study. CMR diastolic parameters were measured on cine images and velocity-encoded phase contrast cine images and compared with corresponding parameters measured on TTE. A contextual correlation feature tracking method was developed to calculate the mitral annular velocity curve. LV DD was classified by CMR and TTE following 2016 guidelines. Overall DD classification was 78.1% concordant between CMR and TTE (p < 0.0001). The trans-mitral inflow parameters correlated well between the two modalities (E, r = 0.78; A, r = 0.90; E/A, r = 0.82; all p < 0.0001) while the remaining diastolic parameters showed moderate correlation (e’, r = 0.64; E/e’, r = 0.54; left atrial volume index (LAVi), r = 0.61; all p < 0.0001). Classification of LV diastolic function by CMR showed good concordance with standardized grades established for TTE. CMR-based LV diastolic function may be integrated in routine clinical practice. Name of the registry: Technical Development of Cardiovascular Magnetic Resonance Imaging. Trial registration number: NCT00027170. Date of registration: November 26, 2001. URL of trial registry record: https://clinicaltrials.gov/ct2/show/NCT00027170

The amyloidogenic V122I variant (valine to isoleucine substitution at position 122) of the transthyretin (TTR) gene is carried almost exclusively in people of African descent, about 3% African-Americans carry the variant. In the general population, carriers for TTR V122I have a higher risk of heart failure, cardiovascular death and increased mortality after age 65 years compared with non-carriers. Sickle cell disease (SCD), one of the most common genetic blood diseases, predominantly affects individuals of African descent and 1 in 365 African-American births. In adults, SCD manifests as a chronic degenerative illness characterized by progressive multiorgan damage, with cardiopulmonary complications being a leading cause of mortality. The impact of TTR V122I in patients with SCD remains unclear. Objectives: To examine the association between TTR V122I and cardiac phenotype and survival in a cohort of adults with SCD. Methods: We conducted a prospective observational study of 584 adult patients with SCD (mean ± SD age: 35.9 ± 12.9 years, 296 women [50.7%]) enrolled at the National Heart, Lung, and Blood Institute (NCT00011648) between Sept 2006 and Feb 2017. The cohort had previously been utilized to develop a phenotypic risk score for disease severity and prediction of mortality. TTR V122I genotype was derived from whole genome sequence data or targeted DNA sequence analysis. Clinical profiles, laboratory variables, cardiac phenotype as assessed by echocardiography, and the NIH phenotypic risk score were compared between TTR V122I carriers and non-carriers. All-cause mortality was ascertained by online obituary search, reporting by patient's family members, National Death Index, and Social Security Death Index search with a final follow-up in June 2024. The cohort was further stratified by gender to evaluate potential sex differences in genotype and phenotype. All analyses were performed using R 4.3.2 with P<0.05 considered as significant. Results: The prevalence of TTR V122I carriers (Age, 42.2 ± 17.2) was 3.1% (n/N=18/584), and predominantly female at 72.2% (n/N=13/18) compared to males. TTR V122I carriers and non-carriers were similar in age, with no significant differences in blood pressure, BMI, eGFR, creatine and other serologic markers of liver or renal function, except for a higher blood urea nitrogen among carriers (BUN, 16.6 ± 12.2 vs.12.0 ± 12.6 mg/dL; P=0.032). Carriers also exhibited higher baseline septal thickness (10.7 ± 1.4 vs. 9.7 ± 1.7 mm; P=0.004 and higher left ventricular (LV) mass index (110.7 ± 25.3 vs. 99.1 ± 31.0 g/m2; P=0.029). Indices of diastolic function were also lower in carriers (mitral E/A ratio (1.3 ± 0.5 vs. 1.7 ± 0.6; P=0.020) and septal e' velocity (8.8 ± 2.0 vs. 10.3 ± 2.9; P=0.020). TTR V122I carriers had an elevated NIH risk score (2.7 ± 1.9 vs. 1.8 ± 3.0; P=0.002). Overall, 219 patients died during a median follow-up of 6.5 years, with TTR V122I TTR carriers showing a higher risk of all-cause mortality (Hazard Ratio [HR] 2.82, 95% CI 1.57-5.06; P<0.001). The median survival time was 4.4 years for carriers versus 12.0 years for non-carriers. Gender differences were evaluated due to the higher prevalence in women, and besides increased septal thickness and LV mass index, female carriers had significantly higher tricuspid regurgitation velocity (TRV, 2.9 ± 0.6 vs. 2.6 ± 0.5 m/s; P=0.032) and a more pronounced risk of mortality (HR 3.48, 95% CI 1.81 - 6.68; P<0.001) compared to female non-carriers. Conclusion: While prevalence of TTR V122I in patients withSCD is comparable to that in the general African-American population, the variant appears to impact cardiovascular function at a much younger age in SCD patients (mean age ~36 years). SCD patients who are also carriers for TTR V122I have higher septal thickness and LV mass index, lower parameters of diastolic function, a higher NIH risk score, and higher all-cause mortality than non-carriers. It is not clear why females have a higher prevalence of TTR V122I compared to males in our SCD cohort. Female carriers experienced more pronounced cardiac dysfunction with increased mortality compared to female non-carriers. We propose that the high oxidative stress environment and chronic anemia are factors that contribute to the accelerated clinical penetrance of the TTR V122I phenotype in SCD, and that genetic screening for TTR V122I should be included in decision-making in choosing SCD patients for high-risk curative therapies.

Background:Septic shock, in humans and in our well-established animal model, is associated with increases in biventricular end diastolic volume (EDV) and decreases in ejection fraction (EF). These abnormalities occur over 2 days and reverse within 10 days. Septic non-survivors do not develop an increase in EDV. The mechanism for this cardiac dysfunction and EDV differences is unknown. Methods:Purpose-bred beagles randomized to receive intrabronchial Staphylococcus aureus (n=27) or saline (n=6) were provided standard ICU care including sedation, mechanical ventilation, and fluid resuscitation to a pulmonary arterial occlusion pressure of over 10mmHg. No catecholamines were administered. Over 96h, cardiac magnetic resonance imaging, echocardiograms, and invasive hemodynamics were serially performed, and laboratory data was collected. Tissue was obtained at 66h from six septic animals. Results:From 0-96h after bacterial challenge, septic animals vs. controls had significantly increased left ventricular wall edema (6%) and wall thinning with loss of mass (15%) which was more pronounced at 48h in non-survivors than survivors. On histology, edema was located predominantly in myocytes, the interstitium, and endothelial cells. Edema was associated with significantly worse biventricular function (lower EFs), ventricular-arterial coupling, and circumferential strain. In septic animals, from 0-24h, the EDV decreased from baseline and, despite cardiac filling pressures being similar, decreased significantly more in non-survivors. From 24-48h, all septic animals had increases in biventricular chamber sizes. Survivors biventricular EDVs were significantly greater than baseline and in non-survivors, where biventricular EDVs were not different from baseline. Preload, afterload, or HR differences did not explain these differential serial changes in chamber size. Conclusion:Systolic and diastolic cardiac dysfunction during sepsis is associated with ventricular wall edema. Rather than differences in preload, afterload, or heart rate, structural alterations to the ventricular wall best account for the volume changes associated with outcome during sepsis. In non-survivors, from 0-24h, sepsis induces a more severe diastolic dysfunction, further decreasing chamber size. The loss of left ventricular mass with wall thinning in septic survivors may, in part explain, the EDV increases from 24-48h. However, these changes continued and even accelerated into the recovery phase consistent with a reparative process rather than ongoing injury.

BackgroundPECOS is an ongoing study aimed to characterize long-term outcomes following pediatric SARS-CoV-2 infection.MethodsThis is a cross-sectional analysis of infected and uninfected cohorts at baseline. Participants (0-21 years) with laboratory-confirmed SARS-CoV-2 infection were enrolled as infected. Uninfected were defined as individuals without history or laboratory evidence of SARS-CoV-2 infection. Outcome measures included demographics, medical history, review of symptoms, physical exam, cardiopulmonary evaluation and validated psychological and developmental surveys. Primary outcomes were cohort comparisons for abnormalities on all measures.Results654 participants (541 infected, 113 uninfected) completed baseline visits by June 30, 2023. Infected participants were more likely to report constitutional (OR: 2.24), HEENT (OR: 3.74); respiratory (OR: 2.41), or gastrointestinal (OR: 2.58) symptoms. Infected had worse scores in domains of Pain, Fatigue, Global Health, Physical and Cognitive functioning, Mobility and Sleep disturbances when compared to uninfected controls using Patient Reported Outcomes. Cardiopulmonary findings were similar among cohorts.ConclusionsThe first report of this ongoing longitudinal study demonstrates that infected participants were more likely to report symptoms compared to uninfected controls, which may affect performance and quality of life of these individuals. Longitudinal data will increase understanding of long-term effects of SARS-CoV-2 infection in children. ClinicalTrials.gov Identifier: NCT04830852ImpactThis study establishes a large, diverse, prospective, longitudinal, multi-center cohort of children with history of SARS-CoV-2 infection compared to an uninfected cohort to be followed for 3 years.Cross-sectional cohort analysis at study entry showed infected participants were more likely to report constitutional, respiratory, and GI symptoms compared to uninfected controls.Infected participants were more likely to have significantly worse parent-reported performance in 6 of 10 Patient Reported Outcome Measures domains.Continued study of this cohort will help identify clinical sequelae of COVID-19, characterize the immune response to SARS-CoV-2 infection, and identify potential genetic/immunologic factors associated with long-term outcomes.

Background Septic shock is associated with increases in end‐diastolic volume (EDV) and decreases in ejection fraction that reverse within 10 days. Nonsurvivors do not develop EDV increases. The mechanism is unknown. Methods and Results Purpose‐bred beagles (n=33) were randomized to receive intrabronchial Staphylococcus aureus or saline. Over 96 hours, cardiac magnetic resonance imaging and echocardiograms were performed. Tissue was obtained at 66 hours. From 0 to 96 hours after bacterial challenge, septic animals versus controls had significantly increased left ventricular wall edema (6%) and wall thinning with loss of mass (15%). On histology, the major finding was nonocclusive microvascular injury with edema in myocytes, the interstitium, and endothelial cells. Edema was associated with significant worsening of biventricular ejection fractions, ventricular‐arterial coupling, and circumferential strain. Early during sepsis, (0–24 hours), the EDV decreased; significantly more in nonsurvivors (ie, greater diastolic dysfunction). From 24 to 48 hours, septic animals' biventricular chamber sizes increased; in survivors significantly greater than baseline and nonsurvivors, whose EDVs were not different from baseline. Preload, afterload, or heart rate differences did not explain these differential changes. Conclusions The cardiac dysfunction of sepsis is associated with wall edema. In nonsurvivors, at 0 to 24 hours, sepsis induces a more severe diastolic dysfunction, further decreasing chamber size. The loss of left ventricular mass with wall thinning in septic survivors may, in part, explain the EDV increases from 24 to 48 hours because of a potentially reparative process removing damaged wall tissue. Septic cardiomyopathy is most consistent with a nonocclusive microvascular injury resulting in edema causing reversible systolic and diastolic dysfunction with more severe diastolic dysfunction being associated with a decreased EDV and death.

Cardiopulmonary complications account for approximately 40% of deaths in patients with sickle cell disease (SCD). Diffuse myocardial fibrosis, elevated tricuspid regurgitant jet velocity (TRV) and iron overload are all associated with early mortality. Although HLA-matched sibling hematopoietic cell transplantation (HCT) offers a potential cure, less than 20% of patients have a suitable donor. Haploidentical HCT allows for an increased donor pool and has recently demonstrated improved safety and efficacy. Our group has reported improved cardiac morphology via echocardiography at 1 year after HCT. Here we describe the first use of cardiac magnetic resonance imaging (CMR), the gold standard for measuring volume, mass, and ventricular function, to evaluate changes in cardiac morphology post-HCT in adults with SCD. We analyzed baseline and 1-year data from 12 adults with SCD who underwent nonmyeloablative haploidentical peripheral blood HCT at the National Institutes of Health. Patients underwent noncontrast CMR at 3 T, echocardiography, and laboratory studies. At 1 year after HCT, patients showed marked improvement in cardiac chamber morphology by CMR, including left ventricular (LV) mass (70.2 to 60.1 g/m2; P = .02) and volume (114.5 to 90.6 mL/m2; P = .001). Furthermore, mean TRV normalized by 1 year, suggesting that HCT may offer a survival benefit. Fewer patients had pathologically prolonged native myocardial T1 times, an indirect marker of myocardial fibrosis at 1 year; these data showed a trend toward significance. In this small sample, CMR was very sensitive in detecting cardiac mass and volume changes after HCT and provided complementary information to echocardiography. Notably, post-HCT improvement in cardiac parameters can be attributed only in part to the resolution of anemia; further studies are needed to determine the roles of myocardial fibrosis reversal, improved blood flow, and survival impact after HCT for SCD.

Alonso, Windy W. PhD, RN; Keteyian, Steven J. PhD; Leifer, Eric S. PhD; Kitzman, Dalane W. MD; Sachdev, Vandana MD Author Information

Allogeneic haematopoietic cell transplantation (HCT) with HLA-matched sibling donor remains the most established curative therapeutic option for patients with sickle cell disease (SCD). However, it is not without risks, highlighting the need for a risk stratification system. Utilizing a machine learning (ML) approach that combines clinical and imaging variables, we identified red cell distribution width and renal organ damage as important risk factors for patients undergoing HCT. This ML-based algorithm, similar to an approach previously reported for predicting mortality in patients with SCD, should be applicable to risk factor discovery in similar studies.

Cardiopulmonary disease, particularly elevated tricuspid regurgitation velocity (TRV ≥2.5 m/s), remains a significant risk marker for early mortality in individuals with sickle cell disease (SCD). Indeed, diastolic dysfunction and elevated TRV are independent risk factors for mortality.1 Hematopoietic cell transplant (HCT) remains the only available curative therapy for SCD. The degree of organ impairment and co-morbidities in many adults with SCD preclude the use of myeloablative regimens due to the risk of chemotherapy-induced organ toxicity. However, our non-myeloablative (NMA) approach has demonstrated success in adults with SCD, including those with end-organ damage.2 We have previously shown that successful NMA allogeneic HCT improves cardiac size, markers of diastolic dysfunction, TRV, and N-terminal pro-B-type natriuretic peptide within the first year post-HCT.3 In this study, we focused on human leukocyte antigen (HLA)-matched related donors (MRD) and broadened our analyses to three centers with a predominantly adult cohort of patients with SCD, extending our follow-up period to 2 years. These three centers used the same NMA regimen with comparable outcomes.2 Patients with SCD underwent NMA MRD HCT at the National Institutes of Health (NIH, NCT00061568 or NCT02105766), University of Illinois, Chicago (UIC NCT01499888), and King Abdulaziz Medical City in Riyadh, Saudi Arabia (KAMCR, RC20/646/R). Routine laboratory parameters, as well as a transthoracic echocardiogram (TTE), were performed before HCT, and at 1 and 2 years post-HCT. Patients with a successful transplant who were free of dialysis or chronic transfusion therapy were included, and both a pre-HCT TTE and a TTE at least 1 year following HCT were required. All patients received alemtuzumab, 300 cGy total body irradiation, and sirolimus; some also received pentostatin and cyclophosphamide preconditioning. Transthoracic echocardiograms were performed using commercially available systems. Cardiac measurements were performed according to the American Society of Echocardiography guidelines1 A generalized estimating equation regression model approach was used to evaluate TTE and laboratory changes from baseline, adjusting for age, gender, and site. Given the number of outcomes tested, a more stringent p-value threshold of .005 was used for significance. Baseline assessments of differences between sites were conducted using Kruskal–Wallis tests for continuous outcomes and Fisher exact tests for categorical variables. The study population consisted of 123 patients (68 NIH, 19 UIC, 36 KAMCR) who had stable engraftment. The mean ± SD age of patients was 29 ± 10 years, and 49 (40%) were female. Eighty-seven percent of patients at the NIH and UIC had hemoglobin SS, while one-third of KAMCR patients had compound heterozygous hemoglobin S beta0 thalassemia. Patients at the NIH and UIC were also older (mean values of 31.0 years at NIH, 33.8 at UIC, 26.1 at KAMCR p = .02) and had a larger body surface area (BSA mean values of 1.8 m2 at NIH, 1.8 at UIC, 1.6 at KAMCR, p < .0001). The TRV was elevated at ≥2.5 m/s in 40% of patients at baseline and was higher in patients at the US sites (mean values of 3.5 m/s at NIH, 4.0 at UIC, 3.0 at KAMCR, p = .004), reflective of more severe disease. Hemoglobin improved significantly in the first year after HCT and continued to improve at 2 years (Table 1). Laboratory results showed improvements in lactate dehydrogenase, total bilirubin, and absolute reticulocyte count within the first year after HCT (Table 1). The left ventricular size, as measured by the left ventricular end-diastolic volume index/BSA (LVEDV/BSA), decreased at 1 year after successful HCT (baseline 76.6 mL/m2 ± 21.9, 1 year 65.9 mL/m2 ± 15.7, p < .0001) and remained stable at 2 years (60.7 mL/m2 ± 15.1, p = .03). Almost all patients have normal right ventricular function at baseline, 1 year, and 2 years post-HCT. Although there is a statistically significant reduction in the tricuspid annular plane systolic excursion (TAPSE) value post-HCT, it remains within the normal range. To assess the extent to which improvement in hemoglobin is responsible for this improved parameter after HCT, we performed correlative analyses. There was a moderate inverse correlation between the change in hemoglobin and the change in LVEDV/BSA at 1 year (r = −0.37; p = .0002) and 2 years (r = −0.3; p = .006) after HCT. There was no significant correlation between change in hemoglobin and change in TRV one and 2 years after HCT (r = −0.08, p = .55 at both timepoints). At baseline, there were 3 individuals with concentric remodeling, 12 individuals with eccentric left ventricular hypertrophy (LVH), and none with concentric hypertrophy out of a total of 122 individuals from all 3 sites (individuals with missing data were excluded). The number of individuals with eccentric LVH decreased to 8 by 1 year and 4 in the second year. LV mass index did not change in the first year (baseline 82.3 g/m2 ± 21.9, 1 year 82.7 g/m2 ± 20.4, p = .81); however, it improved significantly by 2 years (75.5 g/m2 ± 20.2, p < .0001). The left atrial volume index decreased in the first year (baseline 38.1 mL/m2 ± 13.8, 1 year 28.3 mL/m2 ± 8.5, p < .0001) with no further significant change in the second year (26.5 mL/m2 ± 8, p = .03). Diastolic filling parameters were seen to parallel the volume changes with baseline E/A ratio decreasing in the first year (baseline 1.7 ± 0.6, 1 year 1.5 ± 0.5, p < .0001) then remaining unchanged at 2 years (1.4 ± 0.5, p = .03). In the first year after HCT, TRV decreased significantly (baseline 2.5 ± 0.4; 1 year 2.3 ± 0.4, p < .0001) and remained stable in the second year (2.3 ± 0.3, p = .01). At the 2-year time point, 28% of patients had an elevated TRV ≥2.5 m/s compared to 40% at baseline. Although the mean TRV in this elevated TRV subgroup was 2.8 m/s at baseline, it improved to 2.5 m/s at 1 year (p < .0001), and 2.4 m/s by 2 years, p < .0001. As expected, the right ventricular systolic pressure (RVSP) showed a similar trend of a significant reduction in the first year (baseline 30.6 ± 10.7, 1 year 26.4 ± 7, p < .0001) and remained improved at the 2-year timepoint (26.1 ± 7.8, p < .0001). Our findings from three independent centers demonstrate significant improvements in cardiac size, mass, diastolic function, and TRV up to 2 years after NMA HCT. Volume overload secondary to the anemia in SCD is in part responsible for cardiac remodeling.4 As the anemia resolves and high flow states decrease following HCT, many cardiac changes also reverse. LV volume and LV mass index decreased significantly in the first year and these improvements continued in the second year. Following HCT, there was a statistically significant increase in diastolic blood pressure (BP) at 1 and 2 years post-HCT. The systolic BP also slightly increased, which approached but did not meet our stringent definition of significance (p < .005). The increase in BP was likely related to the weight gain post-HCT, as reflected by the rise in BSA. Others have shown a positive correlation between BP and body weight, and this association may be even more pronounced in diastolic BP.5 Correlative analyses to evaluate the role of improved hemoglobin in changes in cardiac parameters demonstrate a moderate negative correlation between change in hemoglobin and change in LVEDV at 1-year post-HCT. The chronic impact of anemia reversal on oxygen delivery and cardiac parameters remains unclear. The improvements reported here are likely not due to improved hemoglobin alone. Decreased sickling events and ischemia–reperfusion injury, improved blood flow, and improved myocardial fibrosis may contribute to the improved cardiac parameters seen after HCT. Further study to elucidate the mechanism of change is required. Cardiac structural and functional improvements following HCT have significant implications. Abnormal diastolic function and elevated TRV are linked with early mortality in SCD, and both of these parameters improved following HCT. The mean TRV decreased in the entire group and also the subgroup with elevated TRV at baseline to the normal range by 2 years post-HCT. Left ventricular size and hypertrophy are closely linked to diastolic function and pulmonary pressures and improved. This three-center study confirms our prior report on reversing the rheologic cardiomyopathy in SCD patients undergoing HLA-matched and haploidentical HCT.3 We now see that LV dimension and LV mass index continue to improve up to 2 years following HCT from HLA-MRD. Despite one recent report on hydroxyurea therapy leading to reductions in LV dilation and hypertrophy in children,6 HCT is the only therapy in adults that has been shown to reverse cardiac abnormalities. Limitations of our study include some baseline differences in the patient population across the three centers. We were limited to small sample sizes and only 2 years of follow-up after HCT. Other conditioning regimens were not evaluated since we limited the analysis to NMA HLA-MRD HCT. Moreover, we did not have access to additional laboratory (e.g., brain natriuretic peptide), TTE (e.g., strain), and functional capacity (e.g., 6-min walk distance), variables that may have been informative. In conclusion, we have shown for the first time that cardiac morphology and TRV improve 2 years after HLA-matched sibling HCT for SCD. As diastolic dysfunction and TRV have been associated with early mortality in adults with SCD, our results suggest that successful HCT may impact survival. A larger multicenter study with longer follow-up is indicated. This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, and the Cooperative Study of Late Effects for SCD Curative Therapies (COALESCE, 1U01HL156620-01, NHLBI). The content of this manuscript is solely the responsibility of the authors and does not necessarily reflect the official views of the National Heart, Lung, and Blood Institute, National Institutes of Health, or the United States Department of Health and Human Services. The authors declare no conflicts of interest. Requests for data should be sent to the corresponding author at [email protected].

In most people's vocabularies, design means veneer. . . . But to me . . . design is the fundamental soul of a human-made creation that ends up expressing itself in successive outer layers of the product or service.—Steve Jobs Machine learning (ML) and big data hold the potential to revolutionize cardiovascular imaging.1Quer G. Arnaout R. Henne M. et al.Machine learning and the future of cardiovascular care: JACC State-of-the-Art Review.J Am Coll Cardiol. 2021; 77: 300-313Crossref PubMed Scopus (118) Google Scholar In echocardiography, ML has been used for image enhancement, view classification and guidance, chamber quantification, and even diagnosis. With or without ML, big data analytics can power increasingly scalable outcomes research and quality improvement. Machine-learning performance is inextricably linked to the data it is trained and tested on.1Quer G. Arnaout R. Henne M. et al.Machine learning and the future of cardiovascular care: JACC State-of-the-Art Review.J Am Coll Cardiol. 2021; 77: 300-313Crossref PubMed Scopus (118) Google Scholar,2Chinn E. Arora R. Arnaout R. et al.ENRICHing medical imaging training sets enables more efficient machine learning.J Am Med Inform Assoc. 2023; : ocad055Crossref PubMed Google Scholar Furthermore, efficient and effective data storage and organization can have significant benefits to hospital systems and patient care.3Kim S.H. Song H. How digital transformation can improve hospitals' operational decisions. Harvard Business Review [Internet].https://hbr.org/2022/01/how-digital-transformation-can-improve-hospitals-operational-decisionsDate: 2022Date accessed: April 12, 2023Google Scholar However, legacy echocardiography picture archiving and communication systems (Echo-PACS) are not designed to leverage clinical imaging and related metadata for big data analytics. Historically, echocardiogram data design was considered only in as much as it supported day-to-day clinical operations. With increased need to access echocardiographic data quickly and at large scale across institutions, current data design falls unacceptably short. For example, despite conformance statements, metadata accompanying Digital Imaging and Communications in Medicine (DICOM) imaging is not optimally standardized across manufacturers and lacks specific tags that would greatly aid data mining, curation, and preprocessing4Hirsch J.D. Siegel E.L. Balasubramanian S. et al.We built this house; it's time to move in: leveraging existing DICOM structure to more completely utilize readily available detailed contrast administration information.J Digit Imaging. 2015; 28: 407-411Crossref PubMed Scopus (4) Google Scholar (Figure 1). Image deidentification is hampered by burned-in patient health information (PHI). Measurements performed on ultrasound machines are not seamlessly interoperable with Echo-PACS across manufacturers, causing measurements obtained on cart to frequently be lost.5Interoperability: how to measure data interoperability and communication across health systems | HIMSS [internet].https://www.himss.org/resources/interoperability-how-measure-data-interoperability-and-communication-across-healthDate: 2021Date accessed: April 12, 2023Google Scholar Databases for clinical measurements storage and query are inefficient, outdated, and/or proprietary. These obstacles make it challenging to perform clinical quality control and education, to mine and harmonize data for research, to connect echocardiographic data to the rest of the electronic health record, and to collaborate across institutions and with industry.3Kim S.H. Song H. How digital transformation can improve hospitals' operational decisions. Harvard Business Review [Internet].https://hbr.org/2022/01/how-digital-transformation-can-improve-hospitals-operational-decisionsDate: 2022Date accessed: April 12, 2023Google Scholar Even large, well-resourced medical centers face these obstacles; smaller health care entities are doubly affected and are therefore at risk of being excluded from the big data revolution, at great cost to the goal of inclusive, unbiased analytics. A big data–enabled future for echocardiography requires redesigning clinical data processing and storage at the level of ultrasound hardware and software manufacturers to be inclusive of all health care settings (Figure 1). This will need investment and cooperation across institutions and with industry partners but will offer several benefits. Redesigning ultrasound data will improve the cost-efficiency and quality of patient care as well as lower the activation energy for research. Ultimately, manufacturers who do not solve these problems may become marginalized as users migrate to systems that provide seamless big data functionality. We ask our industry partners to further standardize DICOM metadata, address burned-in PHI, provide and support better database tools, and offer software development kits for implementation research using ML algorithms in the clinical workflow. Where manufacturers may already offer these capabilities, we ask them to help us implement them at our institutions. With a proliferation of cardiovascular ultrasound technologies including three-dimensional imaging, intracardiac echocardiography, and therapeutic ultrasound as well as platforms like point-of-care ultrasound and cloud solutions, ultrasound data will only become more complex. The time to update data design for echocardiography is now.

Alkaptonuria, a rare disorder of homogentisic acid metabolism, can lead to aortic valvular calcification and stenosis. This report describes the case of a 71-year-old woman with alkaptonuria-associated aortic stenosis in whom minimally invasive surgical aortic valve replacement was attempted but abandoned because of extensive aortic root calcification. She subsequently underwent transfemoral transcatheter aortic valve replacement with an Edwards SAPIEN 3 valve (Edwards Lifesciences, Irvine, CA). This report of transcatheter aortic valve replacement for treating alkaptonuria-associated aortic stenosis expands the potential treatment options for these patients.