Diffusion Tensor Phenomapping of the Healthy and Pressure-Overloaded Human Heart.

Current techniques to image the microstructure of the heart with diffusion tensor MRI (DTI) are highly under-resolved. We present a technique to improve the spatial resolution of cardiac DTI by almost 10-fold and leverage this to measure local gradients in cardiomyocyte alignment or helix angle (HA). We further introduce a phenomapping approach based on voxel-wise hierarchical clustering of these gradients to identify distinct microstructural microenvironments in the heart. Initial development was performed in healthy volunteers (n=8). Thereader, subjects with severe but well-compensated aortic stenosis (AS, n=10) were compared to age-matched controls (CTL, n=10). Radial HA gradient was significantly reduced in AS (8.0±0.8°/mm vs. 10.2±1.8°/mm, p=0.001) but the other HA gradients did not change significantly. Four distinct microstructural clusters could be idenJfied in both the CTL and AS subjects and did not differ significantly in their properties or distribution. Despite marked hypertrophy, our data suggest that the myocardium in well-compensated AS can maintain its microstructural coherence. The described phenomapping approach can be used to characterize microstructural plasticity and perturbation in any organ system and disease.

Home Hospital Outcomes for Acute Decompensated Heart Failure and Factors Associated With Escalation of Care.

BACKGROUND: Overall outcomes and the escalation rate for home hospital admissions for heart failure (HF) are not known. We report overall outcomes, predict escalation, and describe care provided after escalation among patients admitted to home hospital for HF. METHODS: Our retrospective analysis included all patients admitted for HF to 2 home hospital programs in Massachusetts between February 2020 and October 2022. Escalation of care was defined as transfer to an inpatient hospital setting (emergency department, inpatient medical unit) for at least 1 overnight stay. Unexpected mortality was defined as mortality excluding those who desired to pass away at home on admission or transitioned to hospice. We performed the least absolute shrinkage and selection operator logistic regression to predict escalation. RESULTS: We included 437 hospitalizations; patients had a median age of 80 (interquartile range, 69-89) years, 58.1% were women, and 64.8% were White. Of the cohort, 29.2% had reduced ejection fraction, 50.9% had chronic kidney disease, and 60.6% had atrial fibrillation. Median admission Get With The Guidelines HF score was 39 (interquartile range, 35-45; 1%-5% predicted inpatient mortality). Escalation occurred in 10.3% of hospitalizations. Thirty-day readmission occurred in 15.1%, 90-day readmission occurred in 33.8%, and 6-month mortality occurred in 11.5%. There was no unexpected mortality during home hospitalization. Patients who experienced escalation had significantly longer median length of stays (19 versus 7.5 days, P<0.001). The most common reason for escalation was progressive renal dysfunction (36.2%). A low mean arterial pressure at the time of admission to home hospital was the most significant predictor of escalation in the least absolute shrinkage and selection operator regression. CONCLUSIONS: About 1 in 10 home hospital patients with HF required escalation; none had unexpected mortality. Patients requiring escalation had longer length of stays. A low mean arterial pressure at the time of admission to home hospital was the most important predictor of escalation of care in the least absolute shrinkage and selection operator logistic regression model.

Detection and Characterization of Thrombosis in Humans Using Fibrin-Targeted Positron Emission Tomography and Magnetic Resonance.

OBJECTIVES: The authors present a novel technique to detect and characterize LAA thrombus in humans using combined positron emission tomography (PET)/cardiac magnetic resonance (CMR) of a fibrin-binding radiotracer, [64Cu]FBP8. BACKGROUND: The detection of thrombus in the left atrial appendage (LAA) is vital in the prevention of stroke and is currently performed using transesophageal echocardiography (TEE). METHODS: The metabolism and pharmacokinetics of [64Cu]FBP8 were studied in 8 healthy volunteers. Patients with atrial fibrillation and recent TEEs of the LAA (positive n = 12, negative n = 12) were injected with [64Cu]FBP8 and imaged with PET/CMR, including mapping the longitudinal magnetic relaxation time (T1) in the LAA. RESULTS: [64Cu]FBP8 was stable to metabolism and was rapidly eliminated. The maximum standardized uptake value (SUVMax) in the LAA was significantly higher in the TEE-positive than TEE-negative subjects (median of 4.0 [interquartile range (IQR): 3.0-6.0] vs 2.3 [IQR: 2.1-2.5]; P < 0.001), with an area under the receiver-operating characteristic curve of 0.97. An SUVMax threshold of 2.6 provided a sensitivity of 100% and specificity of 84%. The minimum T1 (T1Min) in the LAA was 970 ms (IQR: 780-1,080 ms) vs 1,380 ms (IQR: 1,120-1,620 ms) (TEE positive vs TEE negative; P < 0.05), with some overlap between the groups. Logistic regression using SUVMax and T1Min allowed all TEE-positive and TEE-negative subjects to be classified with 100% accuracy. CONCLUSIONS: PET/CMR of [64Cu]FBP8 is able to detect acute as well as older platelet-poor thrombi with excellent accuracy. Furthermore, the integrated PET/CMR approach provides useful information on the biological properties of thrombus such as fibrin and methemoglobin content. (Imaging of LAA Thrombosis; NCT03830320).

Normative cardiopulmonary exercise data for endurance athletes: the Cardiopulmonary Health and Endurance Exercise Registry (CHEER).

AIMS: Accurate interpretation of cardiopulmonary exercise testing (CPET) relies on age, gender, and exercise modality-specific reference values. To date, clinically applicable CPET reference values derived from a source population of endurance athletes (EAs) have been lacking. The purpose of this study was to generate CPET reference values for use in the clinical assessment of EA. METHODS AND RESULTS: Prospective data accrued during the clinical care of healthy EA were used to derive CPET reference values and to develop novel equations for V˙O2peak. The performance of these equations was compared to the contemporary standard of care equations and assessed in a discrete EA validation cohort. A total of 272 EA (age = 42 ± 15 years, female = 31%, V˙O2peak = 3.6 ± 0.83 L/min) met inclusion criteria and comprised the derivation cohort. V˙O2peak prediction equations derived from general population cohorts described a modest amount of V˙O2peak variability [R2 = 0.58-0.70, root mean square error (RMSE) = 0.46-0.54 L/min] but were mis-calibrated (calibration-in-the-large = 0.45-1.18 L/min) among EA leading to significant V˙O2peak underestimation. Newly derived, externally validated V˙O2peak prediction equations for EA that included age, sex, and height for both treadmill (R2 = 0.74, RMSE = 0.42 L/min) and cycle ergometer CPET (Cycle: R2 = 0.69, RMSE = 0.42 L/min) demonstrated improved accuracy. CONCLUSION: Commonly used V˙O2peak prediction equations derived from general population cohorts perform poorly among competitive EA. Newly derived CPET reference values including novel V˙O2peak prediction equations may improve the clinical utility of CPET in this rapidly growing patient population.

Utility of the oxygen pulse in the diagnosis of obstructive coronary artery disease in physically fit patients.

Cardiopulmonary exercise testing (CPET) guidelines recommend analysis of the oxygen (O2 ) pulse for a late exercise plateau in evaluation for obstructive coronary artery disease (OCAD). However, whether this O2 pulse trajectory is within the range of normal has been debated, and the diagnostic performance of the O2 pulse for OCAD in physically fit individuals, in whom V˙O2 may be more likely to plateau, has not been evaluated. Using prospectively collected data from a sports cardiology program, patients were identified who were free of other cardiac disease and underwent clinically-indicated CPET within 90 days of invasive or computed tomography coronary angiography. The diagnostic performance of quantitative O2 pulse metrics (late exercise slope, proportional change in slope during late exercise) and qualitative assessment for O2 pulse plateau to predict OCAD was assessed. Among 104 patients (age:56 ± 12 years, 30% female, peak V˙O2 119 ± 34% predicted), the diagnostic performance for OCAD (n = 24,23%) was poor for both quantitative and qualitative metrics reflecting an O2 pulse plateau (late exercise slope: AUC = 0.55, sensitivity = 68%, specificity = 41%; proportional change in slope: AUC = 0.55, sensitivity = 91%, specificity = 18%; visual plateau/decline: AUC = 0.51, sensitivity = 33%, specificity = 67%). When O2 pulse parameters were added to the electrocardiogram, the change in AUC was minimal (-0.01 to +0.02, p ≥ 0.05). Those patients without OCAD with a plateau or decline in O2 pulse were fitter than those with linear augmentation (peak V˙O2 133 ± 31% vs. 114 ± 36% predicted, p < 0.05) and had a longer exercise ramp time (9.5 ± 3.2 vs. 8.0 ± 2.5 min, p < 0.05). Overall, a plateau in O2 pulse was not a useful predictor of OCAD in a physically fit population, indicating that the O2 pulse should be integrated with other CPET parameters and may reflect a physiologic limitation of stroke volume and/or O2 extraction during intense exercise.

Cardiac Structure and Function in Elite Female and Male Soccer Players.

Importance: Population-specific normative data are essential for the evaluation of competitive athletes. At present, there are limited data defining normal electrocardiographic (ECG) and echocardiographic values among elite US soccer players. Objective: To describe ECG and echocardiographic findings in healthy elite US soccer players. Design, Setting, and Participants: This cross-sectional study analyzed Fédération Internationale de Football Association-mandated screening sessions performed at US Soccer National Team training locations from January 2015 to December 2019. US women's and men's national team soccer players undergoing mandated cardiovascular screening were included. Main Outcomes and Measures: Normal training-related and abnormal ECG findings were reported using the International Recommendations for Electrocardiographic Interpretation in Athletes. Echocardiographic measurements of structural and functional parameters relevant to cardiovascular remodeling were assessed relative to American Society of Echocardiography guideline-defined normal ranges. Results: A total of 238 athletes (122 [51%] female; mean [SD] age, 20 [4] years; age range, 15-40 years) were included. Male athletes demonstrated a higher prevalence of normal training-related ECG findings, while female athletes were more likely to have abnormal ECG patterns (14 [11%] vs 0 in male cohort), largely accounted for by abnormal T-wave inversions. Echocardiography revealed no pathologic findings meeting criteria for sport restriction, but athletes frequently exceeded normal ranges for structural cardiac parameters responsive to exercise-induced remodeling including body surface area-indexed left ventricular (LV) mass (58 of 113 female athletes [51%] and 67 of 114 male athletes [59%]), indexed LV volume (89 of 115 female athletes [77%] and 76 of 111 male athletes [68%]), and LV wall thickness (37 of 122 female athletes [30%] and 47 of 116 male athletes [41%]). Age-stratified analysis revealed age-dependent increases in LV wall thickness, mass, and volumes among female athletes and LV wall thickness and mass among male athletes. Conclusions and Relevance: These data represent the first set of comprehensive normative values for elite US soccer players and one of the largest sport-specific echocardiographic remodeling studies in female athletes. Abnormal ECG findings were more common in female athletes, while both female and male athletes frequently exceeded clinical normality cut points for remodeling-associated echocardiographic parameters.

Personalized treatment for coronary artery disease patients: a machine learning approach.

Current clinical practice guidelines for managing Coronary Artery Disease (CAD) account for general cardiovascular risk factors. However, they do not present a framework that considers personalized patient-specific characteristics. Using the electronic health records of 21,460 patients, we created data-driven models for personalized CAD management that significantly improve health outcomes relative to the standard of care. We develop binary classifiers to detect whether a patient will experience an adverse event due to CAD within a 10-year time frame. Combining the patients' medical history and clinical examination results, we achieve 81.5% AUC. For each treatment, we also create a series of regression models that are based on different supervised machine learning algorithms. We are able to estimate with average R2 = 0.801 the outcome of interest; the time from diagnosis to a potential adverse event (TAE). Leveraging combinations of these models, we present ML4CAD, a novel personalized prescriptive algorithm. Considering the recommendations of multiple predictive models at once, the goal of ML4CAD is to identify for every patient the therapy with the best expected TAE using a voting mechanism. We evaluate its performance by measuring the prescription effectiveness and robustness under alternative ground truths. We show that our methodology improves the expected TAE upon the current baseline by 24.11%, increasing it from 4.56 to 5.66 years. The algorithm performs particularly well for the male (24.3% improvement) and Hispanic (58.41% improvement) subpopulations. Finally, we create an interactive interface, providing physicians with an intuitive, accurate, readily implementable, and effective tool.

Impact of Appropriate Use Criteria for Transthoracic Echocardiography in Valvular Heart Disease on Clinical Outcomes.

BACKGROUND: The association between appropriate use criteria for transthoracic echocardiography (TTE) and clinical outcomes is unknown for patients with valvular heart disease (VHD). The aim of this study was to identify the association of TTE appropriateness with downstream cardiac tests and clinical outcomes in patients with VHD over 365 days. METHODS: A subset of 2,297 patients with VHD across six Ontario academic hospitals was selected from the Echo WISELY (Will Inappropriate Scenarios for Echocardiography Lessen Significantly) trial and linked to administrative databases. Each patient's index TTE was classified as "rarely appropriate" (rA) versus "appropriate" (comprising "appropriate" and "may be appropriate" TTE according to the 2011 appropriate use criteria). Overall, 431 of 452 patients with rA TTE were matched 1:1 with patients with appropriate TTE using propensity scores to account for measured confounding. RESULTS: Matched patients with rA TTE were less likely to undergo repeat TTE (relative risk, 0.46; 95% CI, 0.33-0.66) or cardiac catheterization (relative risk, 0.27; 95% CI, 0.16-0.47) at 90 days compared with patients with appropriate TTE. rA TTE was significantly associated with a decreased hazard of aortic valve intervention (hazard ratio, 0.40; 95% CI, 0.14-0.42), all-cause hospitalization (hazard ratio, 0.44; 95% CI, 0.34-0.57), and death (hazard ratio, 0.31; 95% CI, 0.15-0.66) over 365 days of follow-up. CONCLUSIONS: Patients with appropriate TTE for VHD were more likely to undergo subsequent cardiac testing within 90 days and valve intervention within 1 year than those with a rA TTE. The 2011 appropriate use criteria for TTE have important clinical implications for outcomes in patient with VHD.

Association of Ascending Aortic Dilatation and Long-term Endurance Exercise Among Older Masters-Level Athletes.

Importance: Aortic dilatation is frequently encountered in clinical practice among aging endurance athletes, but the distribution of aortic sizes in this population is unknown. It is additionally uncertain whether this may represent aortic adaptation to long-term exercise, similar to the well-established process of ventricular remodeling. Objective: To assess the prevalence of aortic dilatation among long-term masters-level male and female athletes with about 2 decades of exercise exposure. Design, Setting, and Participants: This cross-sectional study evaluated aortic size in veteran endurance athletes. Masters-level rowers and runners aged 50 to 75 years were enrolled from competitive athletic events across the United States from February to October 2018. Analysis began January 2019. Exposures: Long-term endurance exercise. Main Outcomes and Measures: The primary outcome was aortic size at the sinuses of Valsalva and the ascending aorta, measured using transthoracic echocardiography in accordance with contemporary guidelines. Aortic dimensions were compared with age, sex, and body size-adjusted predictions from published nomograms, and z scores were calculated where applicable. Results: Among 442 athletes (mean [SD] age, 61 [6] years; 267 men [60%]; 228 rowers [52%]; 214 runners [48%]), clinically relevant aortic dilatation, defined by a diameter at sinuses of Valsalva or ascending aorta of 40 mm or larger, was found in 21% (n = 94) of all participants (83 men [31%] and 11 women [6%]). When compared with published nomograms, the distribution of measured aortic size displayed a rightward shift with a rightward tail (all P < .001). Overall, 105 individuals (24%) had at least 1 z score of 2 or more, indicating an aortic measurement greater than 2 SDs above the population mean. In multivariate models adjusting for age, sex, body size, hypertension, and statin use, both elite competitor status (rowing participation in world championships or Olympics or marathon time under 2 hours and 45 minutes) and sport type (rowing) were independently associated with aortic size. Conclusions and Relevance: Clinically relevant aortic dilatation is common among aging endurance athletes, raising the possibility of vascular remodeling in response to long-term exercise. Longitudinal follow-up is warranted to establish corollary clinical outcomes in this population.

Association Between Physicians' Appropriate Use of Echocardiography and Subsequent Healthcare Use and Outcomes in Patients With Heart Failure.

Background There is little understanding of whether a physician's tendency to order an inappropriate cardiac service is associated with the use of other cardiac services and clinical outcomes in their patients with heart failure (HF). Methods and Results We conducted a secondary analysis of 35 Ontario-based cardiologists who participated in the control arm of the Echo WISELY (Will Inappropriate Scenarios for Echocardiography Lessen Significantly) trial. Transthoracic echocardiograms, ordered during the trial, were classified as rarely appropriate (rA), appropriate, or maybe appropriate on the basis of the 2011 appropriate use criteria. Cardiologists were grouped into tertiles of rA transthoracic echocardiogram ordering frequency: low ordering (bottom tertile), n=11; moderate ordering, n=12; or high ordering (top tertile), n=12. The main outcomes were measures of cardiac service use, including cardiology-related physician visits, tests, and medications. Among 1677 patients with heart failure and an outpatient visit to 1 of 35 cardiologists, we found no significant association between rA transthoracic echocardiogram ordering frequency (by tertile) and cardiac testing use, although patients of cardiologists in the high ordering group had fewer physician visits, on average, than patients seen by low ordering cardiologists. In addition, patients of cardiologists in the highest rA ordering tertile had significantly lower odds of receiving potentially effective interventions, such as ß blockers (odds ratio, 0.62; 95% CI, 0.43-0.89), than the low ordering group. Conclusions Although patients of cardiologists who frequently order rA transthoracic echocardiograms do not appear more (or less) likely to have subsequent cardiac tests, these patients have fewer follow-up visits and lower odds of receiving evidence-based medications. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02038101.

Low-Value Transthoracic Echocardiography, Healthcare Utilization, and Clinical Outcomes in Patients With Coronary Artery Disease.

BACKGROUND: The relationship between ordering frequency of rarely appropriate transthoracic echocardiograms on healthcare utilization and patient outcomes in coronary artery disease (CAD) is not known. Our objective was to investigate practice patterns of cardiologists who order a high frequency of low-value transthoracic echocardiograms in patients with CAD and whether practice behavior influences patient outcomes. METHODS AND RESULTS: A retrospective cohort of outpatient CAD patients was accrued by identifying patients with at least 1 visit to 1 of 35 Ontario-based cardiologists in the EchoWISELY randomized clinical trial (Will Inappropriate Scenarios for Echocardiography Lessen Significantly) control group. The main outcomes of interest were patient-level receipt of diagnostic tests, physician visits, medication prescriptions, and clinical outcomes at 1 year. Our cohort consisted of 3966 patients with CAD (mean [SD] age, 67.8 [12.0] years; 72% men), with an outpatient visit to 1 of 35 eligible cardiologists, stratified into 3 ordering tertiles. Patients of cardiologists in the top ordering tertile of rarely appropriate transthoracic echocardiograms had significantly lower odds of receiving the following services at 1 year compared with patients in the low ordering group: cholesterol assessment (odds ratio [OR], 0.77 [95% CI, 0.65-0.91]); hemoglobin A1c assessment (OR, 0.79 [95% CI, 0.66-0.94]); ß-blocker prescription (OR, 0.70 [95% CI, 0.55-0.90]); and aldosterone receptor antagonist prescription (OR, 0.46 [95% CI, 0.22-0.98]). Patients of high ordering cardiologists had greater odds of all-cause mortality at 1 year (OR, 1.54 [95% CI, 1.04-2.28]), although all other outcomes were similar. CONCLUSIONS: Patients with CAD seen by cardiologist who ordered a high rate of rarely appropriate transthoracic echocardiograms were less likely to receive potentially high-value screening tests and evidence-based medications than low ordering cardiologists. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02038101.

Selection of endurance capabilities and the trade-off between pressure and volume in the evolution of the human heart.

Chimpanzees and gorillas, when not inactive, engage primarily in short bursts of resistance physical activity (RPA), such as climbing and fighting, that creates pressure stress on the cardiovascular system. In contrast, to initially hunt and gather and later to farm, it is thought that preindustrial human survival was dependent on lifelong moderate-intensity endurance physical activity (EPA), which creates a cardiovascular volume stress. Although derived musculoskeletal and thermoregulatory adaptations for EPA in humans have been documented, it is unknown if selection acted similarly on the heart. To test this hypothesis, we compared left ventricular (LV) structure and function across semiwild sanctuary chimpanzees, gorillas, and a sample of humans exposed to markedly different physical activity patterns. We show the human LV possesses derived features that help augment cardiac output (CO) thereby enabling EPA. However, the human LV also demonstrates phenotypic plasticity and, hence, variability, across a wide range of habitual physical activity. We show that the human LV's propensity to remodel differentially in response to chronic pressure or volume stimuli associated with intense RPA and EPA as well as physical inactivity represents an evolutionary trade-off with potential implications for contemporary cardiovascular health. Specifically, the human LV trades off pressure adaptations for volume capabilities and converges on a chimpanzee-like phenotype in response to physical inactivity or sustained pressure loading. Consequently, the derived LV and lifelong low blood pressure (BP) appear to be partly sustained by regular moderate-intensity EPA whose decline in postindustrial societies likely contributes to the modern epidemic of hypertensive heart disease.