Background: During exercise stress echocardiography (ESE), there are patients with normal left ventricular ejection fraction (LVEF) who paradoxically develop reduced LVEF during exercise despite absence of coronary artery disease (CAD) and a significant hypertensive response. This study sought to describe the clinical features and outcomes of this population. Methods: Among ESEs performed between 2003 and 2022, patients without CAD by angiogram within 90 days of ESE and resting LVEF >= 50% with a >= 5% LVEF decrease during ESE were included. Outcomes assessed were all-cause mortality, heart failure (HF) hospitalization, and atrial fibrillation (AF). Kaplan-Meier and Cox regression methods were used to analyze time-to-event outcomes. Results: Among 213,643 ESE, 134 patients met the eligibility criteria. The mean age of the population was 66 +/- 10 years, 76% were women, and 16% had AF at baseline. Mean LVEF was 58% +/- 4% at rest and 43% +/- 4% at peak stress. Stress ECG met the criteria for ischemia in 14% of these patients. The 10-year estimated incidence of HF hospitalization was 17.6% (95% CI, 9.0%-26.2%). Among the subgroup without AF at baseline, the 10-year estimated incidence of developing AF was 23.4% (95% CI, 13.4%-33.4%). The 10-year estimated incidence of all-cause mortality was 12.9% (95% CI, 5.5%-20.3%), with 89% of deaths occurring due to noncardiovascular causes. Conclusion: Patients with exercise-induced reduction in LVEF in the absence of obstructive CAD have a high incidence of HF hospitalizations and AF. The underlying pathophysiology of this disease process needs to be further investigated. (J Am Soc Echocardiogr 2025;38:421-30.)

Background: Patients with normal resting left ventricular ejection fraction (LVEF) without either coronary artery disease (CAD) or a hypertensive response can paradoxically develop reduced LVEF during exercise stress echocardiography (ESE). The clinical phenotype and outcomes of these patients is unknown. Hypothesis: Patients who paradoxically develop reduced LVEF during exercise may represent a sub-phenotype of heart failure with preserved LVEF (HFpEF). Aims: To describe the baseline characteristics and clinical outcomes of this unique patient population. Methods: Among all ESE performed between January 2003 and December 2022, patients without a hypertensive response to exercise and without CAD by angiogram within 90 days of ESE, who had a resting LVEF ≥50% with a ≥5% LVEF decrease during ESE were identified. All-cause mortality, HF hospitalization, and atrial fibrillation (AF) outcomes were assessed. Kaplan-Meier and Cox regression methods were used to analyze time-to-event outcomes. Results: Among 213,643 stress echocardiograms performed, 134 patients met eligibility criteria (Table 1). The mean age of the population was 66±10 years, 76% were women, and 16% had AF at baseline. Mean LVEF was 58±4% at rest and 43±4% at peak stress. Stress electrocardiogram met criteria for ischemia in 14%. The 10-year all-cause mortality risk was 12.9% (95% CI 5.5-20.3) with 10 (37%) of 27 deaths due to cancer (Figure 1, Panel A). The 10-year estimated risk of HF hospitalization was 17.6% (95% CI 9.0-26.2) (Figure 1, Panel B). Among 112 patients without AF at baseline, the 10-year risk of developing AF was 23.4% (95% CI 13.4-33.4). Conclusions: Patients with exercise-induced reduced LVEF in the absence of obstructive CAD have a high incidence of HF hospitalizations and AF. Given the preponderance of women, risk for AF, HF hospitalizations, and cancer-related deaths, the possibility that this condition is an early sub-phenotype of HFpEF should be investigated.

Background: We previously developed deep-learning algorithms that identify coronary artery disease (CAD) risk based on (i) coronary artery calcium (CAC), (ii) obstructive CAD by angiography, and (iii) left ventricular akinesis in ≥1 segment by echocardiogram, using a 12-lead electrocardiogram (CAD ECG-AI). We tested the hypothesis that those with increased probability of CAD by CAD ECG-AI algorithms will have an increased risk of atherosclerotic cardiovascular disease (ASCVD) events and would refine the AHA Predicting Risk of Cardiovascular Disease Events (PREVENT TM ) equations’ predictive capabilities. Methods: We assessed a group of consecutive patients who sought primary care in Olmsted County, MN, between 1997 and 2003. Passive follow-up was conducted using the Rochester Epidemiology Project's record linkage system. Patients included met the same criteria of the original PREVENT TM equations. The probability output of each CAD ECG-AI algorithm was used to predict ASCVD (fatal and non-fatal myocardial infarction and ischemic stroke) and ASCVD-Plus [further including percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), and all-cause mortality]. Events were validated in duplicate. Cox proportional hazard models adjusted for age, sex, and risk factors while modeling each CAD ECG-AI algorithm as an individual and additive predictor (see footnote). PREVENT TM risk categories stratified analysis to evaluate the effect of the CAD ECG-AI models on predicted ASCVD risk. Results: We included 21,193 patients, with mean ± SD age 51.6 ± 12.0, 54% women and 95% white. After 14.2±12.4 years follow-up, 1,351 (6.4%) developed ASCVD, and 2,808 (13.2%) had ASCVD-Plus. The risk of ASCVD and ASCVD-Plus increased with positivity for the CAD ECG-AI algorithms after adjustments for age, sex, and PREVENT TM equations factors, all p for trend <0.001 (data not shown). In additive analyses, the risk of ASCVD and ASCVD-Plus increased with increased CAD ECG-AI factors, all p for trend <0.001 ( Fig. A-B ). Furthermore, the CAD ECG-AI algorithm enhanced the predictive capabilities of PREVENT TM equations across most risk subgroups ( Fig. C-E ). Conclusions: The deep-learning CAD ECG-AI algorithms displayed an independent and additive association with long-term ASCVD and ASCVD-Plus events in the community and improved the PREVENT TM predicted ASCVD risk. The CAD ECG-AI algorithms could help identify individuals at risk in primary prevention of cardiovascular events.

Abstract Chronic lung disease (CLD) is the second leading cause of pulmonary hypertension (PH) and is associated with significant morbidity and mortality. Although PH associated with CLD (PH‐CLD) leads to impaired health‐related quality of life (HRQOL), there are no validated tools to assess HRQOL in PH‐CLD. The Pulmonary Arterial Hypertension–Symptoms and Impact Questionnaire (PAH‐SYMPACT) is an HRQOL instrument aimed at assessing the symptoms and impact of PH on overall function and well‐being. We performed a single‐center prospective cohort study using PAH‐SYMPACT scores to compare symptoms, exercise capacity and HRQOL in patients with PAH and PH‐CLD. One hundred and twenty‐five patients (99 patients with idiopathic/heritable PAH and 26 with PH‐CLD) completed the PAH‐SYMPACT questionnaire which consists of 22 questions that assess HRQOL across four domains: cardiopulmonary (CP) symptoms, cardiovascular (CV) symptoms, physical impact (PI), and cognitive/emotional (CE) impact. Higher scores indicate worse HRQOL. We compared patients with PAH and PH‐CLD using a Wilcoxon rank sum or chi‐squared test as appropriate. Multivariate linear regression analysis was used to assess the relationship between PH classification and SYMPACT scores. Compared to PAH, patients with PH‐CLD were older, more likely to use oxygen and had worse functional class and exercise capacity. While there was no significant difference between the two groups in CP, CV, or CE domain scores, patients with PH‐CLD had significantly worse PI scores by univariate (1.79 vs. 1.13, p < 0.001) and multivariate analysis (1.61 vs. 1.17, p = 0.02) and overall worse SYMPACT scores (1.19 vs. 0.91, p = 0.03). In conclusion, patients with PH‐CLD have worse HRQOL as assessed by the PAH‐SYMPACT questionnaire versus patients with PAH. Although PAH‐SYMPACT has not been validated in PH‐CLD, the results of this study can guide clinicians in understanding the symptoms and impact of PH‐CLD relative to PAH.

Background: Electrocardiography-based artificial intelligence (AI-ECG) validated models that detect cardiac disease are increasingly being applied in clinical practice. The utility of such tools to detect insidious cardiac disease in patients with normal baseline left ventricular ejection fraction (LVEF) who paradoxically develop reduced LVEF during exercise stress echocardiography (ESE), and do not have coronary artery disease (CAD) or hypertension, is unknown. Hypothesis: AI-ECG is useful to diagnose insidious cardiac disease and predict clinical outcomes in patients with exercise-induced cardiomyopathy. Aims: To assess the utility of AI ECG in patients with exercise-induced cardiomyopathy. Methods: Among all ESE performed between January 2003 and December 2022, patients without a hypertensive response to exercise and without CAD (confirmed by coronary angiography within 90 days after ESE), with resting LVEF ≥50% and a paradoxical ≥5% LVEF decrease during ESE were identified. A previously validated AI-ECG algorithm that predicts atrial fibrillation (AF), reduced LVEF, and cardiac amyloidosis (CA) was applied to the baseline ECG closest to the time of ESE. The predicted probability of AF, reduced LVEF, and CA if above the published thresholds, was determined. Results: There were 134 patients with exercise-induced cardiomyopathy who were identified. The mean age of this cohort was 66±10 years, 76% were women and 16% had AF at baseline. Mean LVEF was 58±4% at rest and 43±4% at peak stress. The median follow-up period was 6.8 years (IQR 3.0-12.2). Among patients without a baseline history of AF (n=112), AI-ECG identified 29% with a significant probability of AF, which was associated with a subsequent AF diagnosis at univariable analysis (HR 2.505, 95%CI 1.016-6.177, p=0.046). There were 10 patients with an AI-ECG prediction of reduced LVEF among whom 3 were subsequently hospitalized with HF. AI-ECG was positive for CA in 8 and 3 amongst these had subsequent HF hospitalizations (Table). Conclusions: Baseline AI-ECG may help predict subsequent AF and diagnose preclinical amyloid cardiomyopathy in patients who by resting echocardiography do not seem to have cardiac disease but with exercise develop reduced LVEF.

Background Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide, driven primarily by coronary artery disease (CAD). ASCVD risk estimators such as the pooled cohort equations (PCE) facilitate risk stratification and primary prevention of ASCVD but their accuracy is still suboptimal. Methods Using deep electronic health record data from 7,116,209 patients seen at 70+ hospitals and clinics across 5 states in the USA, we developed an artificial intelligence-based electrocardiogram analysis tool (ECG-AI) to detect CAD and assessed the additive value of ECG-AI-based ASCVD risk stratification to the PCE. We created independent ECG-AI models using separate neural networks including subjects without known history of ASCVD, to identify coronary artery calcium (CAC) score >= 300 Agatston units by computed tomography, obstructive CAD by angiography or procedural intervention, and regional left ventricular akinesis in >= 1 segment by echocardiogram, as a reflection of possible prior myocardial infarction (MI). These were used to assess the utility of ECG-AI-based ASCVD risk stratification in a retrospective observational study consisting of patients with PCE scores and no prior ASCVD. The study period covered all available digitized EHR data, with the first available ECG in 1987 and the last in February 2023. Findings ECG-AI for identifying CAC >= 300, obstructive CAD, and regional akinesis achieved area under the receiver operating characteristic (AUROC) values of 0.88, 0.85, and 0.94, respectively. An ensembled ECG-AI identified 3, 5, and 10-year risk for acute coronary events and mortality independently and additively to PCE. Hazard ratios for acute coronary events over 3-years in patients without ASCVD that tested positive on 1, 2, or 3 versus 0 disease-specific ECG-AI models at cohort entry were 2.41 (2.14-2.71), 4.23 (3.74-4.78), and 11.75 (10.2-13.52), respectively. Similar stratification was observed in cohorts stratified by PCE or age. Interpretation ECG-AI has potential to address unmet need for accessible risk stratification in patients in whom PCE under, over, or insufficiently estimates ASCVD risk, and in whom risk assessment over time periods shorter than 10 years is desired.

BACKGROUND:Exercise echocardiography can assess for cardiovascular causes of dyspnea other than coronary artery disease. However, the prevalence and prognostic significance of elevated left ventricular (LV) filling pressures with exercise is understudied. METHODS:We evaluated 14,338 patients referred for maximal symptom-limited treadmill echocardiography. In addition to assessment of LV regional wall motion abnormalities (RWMAs), we measured patients' early diastolic mitral inflow (E), septal mitral annulus relaxation (e'), and peak tricuspid regurgitation velocity before and immediately after exercise. RESULTS:Over a mean follow-up of 3.3 ± 3.4 years, patients with E/e' ≥15 with exercise (n = 1,323; 9.2%) had lower exercise capacity (7.3 ± 2.1 vs 9.1 ± 2.4 metabolic equivalents, P < .0001) and were more likely to have resting or inducible RWMAs (38% vs 18%, P < .0001). Approximately 6% (n = 837) had elevated LV filling pressures without RWMAs. Patients with a poststress E/e' ≥15 had a 2.71-fold increased mortality rate (2.28-3.21, P < .0001) compared with those with poststress E/e' ≤ 8. Those with an E/e' of 9 to 14, while at lower risk than the E/e' ≥15 cohort (hazard ratio [HR] = 0.58 [0.48-0.69]; P < .0001), had higher risk than if E/e' ≤8 (HR = 1.56 [1.37-1.78], P < .0001). On multivariable analysis, adjusting for age, sex, exercise capacity, LV ejection fraction, and presence of pulmonary hypertension with stress, patients with E/e' ≥15 had a 1.39-fold (95% CI, 1.18-1.65, P < .0001) increased risk of all-cause mortality compared with patients without elevated LV filling pressures. Compared with patients with E/e' ≤ 15 after exercise, patients with E/e' ≤15 at rest but elevated after exercise had a higher risk of cardiovascular death (HR = 8.99 [4.7-17.3], P < .0001). CONCLUSION:Patients with elevated LV filling pressures are at increased risk of death, irrespective of myocardial ischemia or LV systolic dysfunction. These findings support the routine incorporation of LV filling pressure assessment, both before and immediately following stress, into the evaluation of patients referred for exercise echocardiography.

Right ventricular (RV) systolic function is the major determinant of prognosis among patients with pulmonary hypertension (PH), irrespective of etiology. 1 Fine N.M. Chen L. Bastiansen P.M. et al. Outcome prediction by quantitative right ventricular function assessment in 575 subjects evaluated for pulmonary hypertension. Circ Cardiovasc Imaging. 2013; 6: 711-721 Crossref PubMed Scopus (301) Google Scholar , 2 Muraru D. 22nd annual feigenbaum lecture: right heart, right now: the role of three-dimensional echocardiography. J Am Soc Echocardiogr. 2022; 35: 893-909 Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar , 3 Kane C.J. Salama A.A. Pislaru C. et al. Low pulsatility index by echocardiography is associated with increased mortality in pulmonary hypertension. J Am Soc Echocardiogr. 2023; 36: 189-195 Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Right ventricular free-wall longitudinal strain (RVFWLS) has emerged as a primary echocardiographic tool for the assessment of RV myocardial performance 1 Fine N.M. Chen L. Bastiansen P.M. et al. Outcome prediction by quantitative right ventricular function assessment in 575 subjects evaluated for pulmonary hypertension. Circ Cardiovasc Imaging. 2013; 6: 711-721 Crossref PubMed Scopus (301) Google Scholar , 2 Muraru D. 22nd annual feigenbaum lecture: right heart, right now: the role of three-dimensional echocardiography. J Am Soc Echocardiogr. 2022; 35: 893-909 Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar , 3 Kane C.J. Salama A.A. Pislaru C. et al. Low pulsatility index by echocardiography is associated with increased mortality in pulmonary hypertension. J Am Soc Echocardiogr. 2023; 36: 189-195 Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar , 4 Lang R.M. Badano L.P. Mor-Avi V. et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiac Imaging. J Am Soc Echocardiogr. 2015; 28: 1-39 Abstract Full Text Full Text PDF PubMed Scopus (7363) Google Scholar , 5 Li Y. Sun C. Zhang L. et al. Feasibility, reproducibility, and prognostic value of fully automated measurement of right ventricular longitudinal strain. J Am Soc Echocardiogr. 2022; 35: 609-619 Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar , 6 Mirea O. Duchenne J. Voight J.-U. Comparison between nondedicated and novel dedicated tracking tool for right ventricular and left atrial strain. J Am Soc Echocardiogr. 2022; 35: 419-425 Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar and to date has primarily used a software package designed for the left ventricle (LV) and adapted to the RV. A dedicated, now clinically available, RV-specific system (automated functional imaging [AFI]-RV) will likely improve feasibility, consistency, reproducibility, and time for analysis as it uses machine learning algorithms that permit automatic detection of the RV endocardial borders and precise estimation of the RVFWLS. 6 Mirea O. Duchenne J. Voight J.-U. Comparison between nondedicated and novel dedicated tracking tool for right ventricular and left atrial strain. J Am Soc Echocardiogr. 2022; 35: 419-425 Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Accordingly, the aims of our study were to compare the relative efficiency, feasibility, and reproducibility of the AFI-RV compared to the LV algorithm and demonstrate the prognostic significance of RVFWLS, as assessed using AFI-RV, in patients with known or suspected PH.

Objectives Prior data indicate a very rare risk of serious adverse drug reaction (ADR) to ultrasound enhancement agents (UEAs). We sought to evaluate the frequency of ADR to UEA administration in contemporary practice. Methods We retrospectively reviewed 4 US health systems to characterize the frequency and severity of ADR to UEA. Adverse drug reactions were considered severe when cardiopulmonary involvement was present and critical when there was loss of consciousness, loss of pulse, or ST-segment elevation. Rates of isolated back pain and headache were derived from the Mayo Clinic Rochester stress echocardiography database where systematic prospective reporting of ADR was performed. Results Among 26,539 Definity and 11,579 Lumason administrations in the Mayo Clinic Rochester stress echocardiography database, isolated back pain or headache was more frequent with Definity (0.49% vs 0.04%, P < .0001) but less common with Definity infusion versus bolus (0.08% vs 0.53%, P = .007). Among all sites there were 201,834 Definity and 84,943 Lumason administrations. Severe and critical ADR were more frequent with Lumason than with Definity (0.0848% vs 0.0114% and 0.0330% vs 0.0010%, respectively; P < .001 for each). Among the 3 health systems with >2,000 Lumason administrations, the frequency of severe ADR with Lumason ranged from 0.0755% to 0.1093% and the frequency of critical ADR ranged from 0.0293% to 0.0525%. Severe ADR rates with Definity were stable over time but increased in more recent years with Lumason (P = .02). Patients with an ADR to Lumason since the beginning of 2021 were more likely to have received a COVID-19 vaccination compared with matched controls (88% vs 75%; P = .05) and more likely to have received Moderna than Pfizer-Biotech (71% vs 26%, P < .001). Conclusion Severe and critical ADR, while rare, were more frequent with Lumason, and the frequency has increased in more recent years. Additional work is needed to better understand factors, including associations with recently developed mRNA vaccines, which may be contributing to the increased rates of ADR to UEA since 2021.

Abstract Background Atherosclerotic cardiovascular disease (ASCVD), of which coronary artery disease (CAD) is the primary manifestation, is the leading cause of death worldwide. The AHA/ACC Pooled Cohort Equation (PCE) facilitates risk stratification and initiation of primary prevention of ASCVD, however their performance is suboptimal. Purpose We develop an artificial intelligence-based electrocardiogram (ECG) analysis (AI-ECG) algorithm to detect different stages of CAD and assessed the value of AI-ECG over PCE to predict incident myocardial infarction (MI) and survival over 3-years. Methods Using electronic health record data from approximately 7 million patients seen at over 70 hospitals and clinics across 5 states in the USA, we created independent AI-ECG models to identify elevated coronary artery calcium (CAC) by computer tomography, the presence of obstructive CAD by stress test or angiography, and left ventricular regional akinesis by echocardiogram, presumed to represent prior MI. Deep structured data, AI-enabled natural language processing of unstructured data were used to ensure cohort, and physician review of labeling were used to ensure cohort accuracy. These models were ensembled into a single model that was used to assess the utility of AI-ECG for predicting new occurrence MI in PCE- and age-stratified cohorts of patient with no prior history of ASCVD, over a 3-year timeframe using Cox’s proportional hazards analysis. Results A total of 6,080 patients (15,192 ECGs) were labeled positive for CAC ≥ 300, 12,561 patients (18,915 ECGs) positive for obstructive CAD, and 10,767 patients (23,870 ECGs) positive for regional akinesis. AI-ECG for identifying elevated CACS, obstructive CAD, and regional akinesis achieved AUROCs of 0.86, 0.80, and 0.93, respectively. All AI-ECG models identified increased 3-year risk for MI and death in AI-ECG positive versus AI-ECG negative patients and subgroups with 2 or 3 positive results had stepwise increased risk (Figure A). In a 3-year survival analysis of all-comer patients, the hazard ratio for those that tested positive on 1, 2, or 3 versus 0 positive disease-specific models were 1.61 (1.53-1.69). 2.40 (2.27-2.55), 3.42 (3.21-3.65), respectively. Risk stratification was also observed in cohorts without prior ASCVD stratified by low and high PCE-derived 10-year ASCVD risk (Figure B) and in cohorts stratified by age, including under the age of 40. Conclusions AI-ECG has potential to address unmet need for accessible risk stratification in patients in whom PCE under, over, or insufficiently estimate ASCVD risk, and in whom risk assessment over periods of time shorter than 10 years is desired.

Background: Atrial fibrillation (a-fib) occurs in up to 40% of patients after noncardiac surgery and is associated with increased risk of adverse outcomes. Practice guidelines recommend stress testing, including stress echocardiography (SE) to assess for coronary artery disease in selected high-risk patients prior to noncardiac surgery. The utility of using SE findings for predicting postoperative a-fib is unknown. Hypothesis: Myocardial ischemia can contribute to arrhythmogenic potential; other echocardiographic variables are likely associated with a-fib. Findings on SE may identify patients at risk for a-fib after noncardiac surgery. Aims: To determine if certain SE findings predict a-fib following noncardiac surgery. Methods: The study included patients undergoing pharmacological and exercise SE before noncardiac surgery. The primary outcome was a-fib/flutter within 30 days after surgery. Multivariate analysis was adjusted for age, cardiovascular comorbidities, and markers of surgical risk. Results: This analysis included 2,376 patients (mean age 68 +/- 7 years; 60% male); 1,986 patients had no known history of a-fib/flutter. Of these, 48 (2.4%) developed postoperative a-fib/flutter. In multivariate analysis, SE variables associated with development of new a-fib/flutter included left ventricular dilation (OR 2.11, p=0.049), increased left atrial volume (OR 1.19, p=0.045), and increased left ventricular mass index (OR 1.13, p=0.043) on rest images. The presence of ischemia or infarct on stress echocardiogram was not associated with postoperative a-fib/flutter. A total of 390 patients had a history of paroxysmal a-fib/flutter and were in sinus rhythm at the time of surgery. Of these, 90 (23%) experienced recurrent a-fib/flutter within 30 days of surgery. Multivariate analysis did not reveal any SE variables significantly associated with recurrence, including presence of myocardial ischemia or infarct at the time of SE. Conclusions: All SE variables associated with postoperative a-fib following noncardiac surgery are available from resting images alone. Therefore, SE that includes comprehensive resting images may offer benefit in the pre-operative evaluation of selected patients.

Objective. To determine the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in patients with PH as well as precapillary PH. Methods. Olmsted County residents with PH, diagnosed between 1/1/1995 and 9/30/2017, were identified, and age and sex were matched to a normal control group. The PH group and normal control group were then cross-referenced with the Mayo Clinic MGUS database. Charts were reviewed to verify MGUS and PH. Heart catheterization data were then analyzed in these patients for reference to the gold standard for diagnosis. Results. There were 3419 patients diagnosed with PH by echocardiography between 1995 and 2017 in Olmsted County that met the criteria of our study. When the PH group (N = 3313) was matched to a normal control group (3313), a diagnosis of MGUS was significantly associated with PH 10.2% (OR = l.84 [95% CI 1.5–2.2], p < 0.001 ), compared with controls 5.8% based on echo diagnosis. Using heart catheterization data (484 patients), a diagnosis of MGUS was associated with PH 13.0% (OR = 3.94 [95% CI 2.28–6.82], p < 0.001 ). For pulmonary artery hypertension (N = 222), a diagnosis of MGUS was associated with PH at similar 12.2% (OR = 4.50 [95%CI 1.86–10.90], p < 0.001 . Conclusions. There is a higher prevalence of MGUS in patients with PH and precapillary PH compared with normal controls. This association cannot be explained fully by other underlying diagnoses associated with PH. Assessing for this in patients with PH of unclear etiology may be reasonable in the workup of patients found to have PH.

Abstract Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease that negatively impacts health‐related quality of life (HRQOL). The PAH‐symptoms and impact (PAH‐SYMPACT) questionnaire is a validated disease‐specific patient‐reported outcome (PRO) instrument that assesses a patient's symptoms and the impact of PAH and its treatment on well‐being. We performed a single‐center prospective cohort study of patients with PAH to determine the feasibility of assessing PROs in clinical practice and to determine the association between PAH‐SYMPACT domains and clinical characteristics and outcomes. One hundred and ten patients completed the 1‐day version of the PAH‐SYMPACT questionnaire which consists of 22 Likert‐scale questions that assess HRQOL across four domains: cardiopulmonary (CP) symptoms, cardiovascular (CV) symptoms, physical impact (PI), and cognitive and emotional (CE) impact. Higher scores indicate worse HRQOL. Patients were predominantly female (n = 86, 78%) with a mean age of 57.8 ± 16.2 years. While several patient characteristics were associated with CP and PI domains, few were associated with CV and CE domains. PI and CE impact scores were associated with recent hospitalizations and mortality and CE impact score was independently associated with an increased risk of death after adjustment for disease severity (hazard ratio: 3.29, 95% confidence interval: 1.56–6.91, p = 0.002). In conclusion, the assessment of PROs in clinical practice using the PAH‐SYMPACT questionnaire is both feasible and valuable. PAH‐SYMPACT scores have independent prognostic value and are not adequately reflected by traditional measures of disease severity. These findings underscore the importance of assessing HRQOL in clinical practice.

An appropriate-for-gestational-age boy is born at 38 and 5/7 weeks to a 33-year-old gravida 2 now para 2 mother by vacuum-assisted vaginal delivery. The results of all antenatal maternal testing are within normal limits, including group B Streptococcus, and she denies a history of herpes simplex virus (HSV) infection. The length of time between rupture of membranes and delivery is 13 hours and 22 minutes. The delivery is complicated by maternal preeclampsia requiring magnesium therapy, and the neonate has Apgar scores of 7 and 8 at 1 and 5 minutes, respectively. His weight is 3,130 g (35th percentile), length is 50.5 cm (59th percentile), and head circumference is 36.5 cm (93rd percentile). The neonate receives vitamin K, hepatitis B vaccination, and ophthalmic erythromycin ointment after delivery. At birth there is a documented caput succedaneum, but no cephalohematoma, scalp bruising, or other signs of trauma. His anterior fontanelle is soft and flat, and there are no abnormalities found on cardiac, pulmonary, neurologic, or skin examination. There are no abdominal masses or hepatosplenomegaly. Vital signs remain within normal limits throughout the hospital stay. Infant blood typing is not completed at birth because the mother is AB+ and direct antiglobulin testing negative. His bilirubin level is 10.5 mg/dL (179.59 µmol/L) at 42 hours of life, which is high intermediate risk for hyperbilirubinemia but below the treatment threshold of 14.5 mg/dL (248.01 µmol/L). Before discharge, the infant’s weight is down 8% from birthweight and head circumference is 35 cm (67th percentile), with resolution of caput succedaneum. The neonate is discharged 48 hours after birth.Four days after birth the neonate presents to the pediatric clinic for follow-up and has an axillary temperature of 103.6°F (39.8°C). The neonate is noted to be wrapped appropriately in a onesie, the mother is afebrile, and the room is not abnormally warm. After unwrapping the neonate, a repeated axillary temperature is 102.1°F (38.9°C). The infant’s heart rate is 190 beats/min, respiratory rate is 44 breaths/min, and oxygen saturation is 99% on room air. The infant’s weight is 2,718 g, down 13% from birthweight. Length and head circumference are not measured during the visit. The mother denies feeding difficulties, fussiness, or lethargy. The patient is breastfeeding for 10 to 30 minutes on each breast every 2.5 to 3 hours. He is making greater than 2 meconium stools per day. Physical examination shows a well-appearing infant with jaundice to the lower extremities. His anterior fontanelle is soft and flat, and there are no other abnormalities noted on cardiac, pulmonary, abdominal, skin, or neurologic examination. The infant is admitted to the pediatric service for evaluation of neonatal fever. The complete blood cell count shows a white blood cell count of 15,880/µL (15.88 × 109/L) (reference range, 900–3,400/µL [9–34 × 109/L]), hemoglobin level of 17.0 g/dL (170 g/L) (reference range, 14.5–18.5 g/dL [145–185 g/L]), platelet count of 314 × 103/µL (314 × 109/L) (reference range, 180–327 × 103/µL [180–327 × 109/L]), red blood cell count of 4.82 × 106/µL (4.82 × 1012/L) (reference range, 3.9–5.5 × 106/µL [3.9–5.5 × 1012/L]), and a normal manual differential cell count. The reticulocyte count is 2.68% (reference range, 1.8%–4.6%). Urinalysis, C-reactive protein level, and coagulation studies are within normal limits. The cerebrospinal fluid (CSF) is grossly bloody, with a white blood cell count greater than 999/µL (>1 × 109/L) and a red blood cell count greater than 0.34 × 106/µL (>0.34 × 1012/L). The total bilirubin level is 22.2 mg/dL (379.71 µmol/L), with a direct bilirubin level of 0.9 mg/dL (15.39 µmol/L), after which the infant is transferred to the NICU for possible exchange transfusion. A type and screen is obtained, and his blood type is A+ and direct antiglobulin test results are negative. The infant is started on ampicillin, gentamicin, and acyclovir. Intravenous fluids containing 10% dextrose are started on admission and are weaned off by hospital day 3, after adequate weight gain with breastfeeding is demonstrated. Antimicrobial therapy is discontinued once the results of the blood culture, urine culture, CSF culture, and CSF meningitis/encephalitis panel by polymerase chain reaction are negative. The first newborn screen is also negative. Additional imaging is obtained and reveals the diagnosis.Because fever in an infant younger than 28 days is concerning for serious bacterial infections, the standard of care includes blood, urine, and CSF cultures as well as admission for antibiotic therapy. In infants younger than 90 days, viral infections can be a significant cause of fever, and some evidence suggests that serious bacterial infection is less common in infants with identified viral syndromes compared with those without identified viral syndromes. Thus, additional viral testing can be helpful in this population. HSV should be considered in neonates with pleocytosis on CSF analysis, increased transaminase levels, seizures, or skin lesions. HSV-2 accounts for most neonatal HSV infections, with 85% of these being acquired during delivery and the remainder being acquired in the postpartum period. (1)Head ultrasonography is performed and shows bilateral grade 3 intraventricular hemorrhage (IVH).IVH is more common in preterm infants compared with term infants due to the fragility of the highly vascularized germinal matrix, which involutes by 36 to 37 weeks of gestation. (2) IVH is a rare form of intracranial hemorrhage (ICH) in term infants and has an estimated incidence of 0.2%. (3) However, the overall incidence of ICH in term infants is difficult to estimate because it is often asymptomatic. The incidence of asymptomatic ICH in term infants has been reported to be 26% to 46%, with subdural hemorrhage being the most common form of ICH. (4)(5) In symptomatic infants, the incidence of ICH has been estimated to be 4.9 in 10,000. (6) Mode of delivery may play a role in ICH incidence, as the highest incidence was associated with forceps use (1 in 664), followed by vacuum extraction (1 in 860), spontaneous vaginal delivery (1 in 1,900), and cesarean delivery without labor (1 in 2,750). (7)In adults, fever occurs in up to 40% of patients after ICH and is associated with poor outcomes. The cause of fever in adults is uncertain and has been linked to infection, stroke, or damage to the hypothalamus. (8) In neonates, the relationship between ICH and fever is not well-described. A prospective study found that of 153 term infants admitted for neonatal fever between 2003 and 2004 without evidence of infection, 11 (7.2%) had ICH. This study also evaluated 28 infants who developed ICH within the first week after birth and found that 11 (39.3%) developed fever within the first 4 days after birth. (9) Other studies have found fever to be a less common presenting feature of ICH. A retrospective review of 24 term neonates admitted to the NICU with ICH reported that the most common presenting symptom was seizure (46%), followed by cyanosis (29%), tachypnea (21%), and fever, hypothermia, and poor feeding (4% each). (10) A cross-sectional study of 30 term infants with IVH found that 3 had a presenting sign of fever. However, this study also found that 50% of infants had coagulopathy. (11) The presented case is unique in that the infant had no signs or symptoms other than fever and hyperbilirubinemia to point toward ICH as the diagnosis.A few mechanisms have been proposed to explain how ICH causes fever. Hemoglobin has been shown to convert arachidonic acid to prostaglandin E2 (PGE2) and prostaglandin F2α, (12) which are known factors in fever production. When hemoglobin is injected into the subarachnoid space of live rabbits, the CSF concentration of PGE2 increases and causes a linear increase in rectal temperature. (13) In addition, interleukin-6 has been shown to be a factor in fever production independent of PGE2, (14) and increased levels of interleukin-6 have been reported in CSF samples of patients with subarachnoid hemorrhage. (15)Currently, no studies have investigated hyperbilirubinemia as an independent cause of fever. In this case, hyperbilirubinemia is likely due to intraventricular red blood cell lysis. The lysis of red blood cells within IVH has also been thought to contribute to its progression to obstructive hydrocephalus. Up to 55% of patients with IVH progress to hydrocephalus, (16) making serial head circumference measurements crucial during follow-up.The infant defervesced within 9 hours of admission. A dilated ophthalmologic examination revealed no retinal or vitreous hemorrhage. He was discharged after 5 days of intensive phototherapy, without the need for an exchange transfusion. He is followed closely in the pediatric clinic after discharge for serial head circumference measurements. Approximately 2 weeks after discharge he is found to have a rapid increase in head circumference from the 56th to the 85th percentile. Repeated head ultrasonography shows resolved IVH but enlarged lateral and third ventricles concerning for obstructive hydrocephalus. The infant is admitted for ventriculoperitoneal shunt placement.Intracranial hemorrhage in term infants is often asymptomatic, making a high index of suspicion necessary for its timely diagnosis.In term infants presenting with isolated fever without other signs of infection, investigation of intracranial hemorrhage may be warranted in addition to antibiotic and antiviral therapy.Patients with intraventricular hemorrhage should be followed with serial head circumference measurements to evaluate for hydrocephalus.

Background: Cardiac power reflects cardiac performance in terms of energy transferred by the left ventricle to the aorta per unit time. Peak stress cardiac power has been shown to predict outcomes in patients with reduced left ventricular ejection fraction (LVEF) and, more recently, in patients with normal LVEF referred for exercise stress echocardiography. The aim of this study was to evaluate the prognostic significance of cardiac power in patients with normal LVEF referred for dobutamine stress echocardiography. Methods: Data were studied from 15,576 patients with LVEF >= 50% and no significant valvular or right ventricular dysfunction who underwent dobutamine stress echocardiography. Cardiac power at rest and peak stress and power reserve (peak stress minus rest power) were calculated and normalized to left ventricular mass. Outcome end points were all-cause mortality and new-onset heart failure (HF). Results: The mean age was 66 +/- 13 years, and 49% patients were women. Resting and peak stress power/mass were 0.7 +/- 0.2 and 1.6 +/- 0.6 W/100 g left ventricular myocardium, respectively. During follow-up (median, 3.3 years; interquartile range, 0.7-7.3 years), 2,278 patients died and 2,137 developed HF. After adjusting for age, sex, comorbidities, and stress test results, lower peak stress power/mass was independently associated with mortality (adjusted hazard ratio, highest vs lowest quartile, 0.84; 95% CI, 0.74-0.95; P = .004) and HF at follow-up (adjusted hazard ratio, 0.67; 95% CI, 0.59-0.76; P < .0001). Power reserve showed similar associations with outcomes. Conclusions: Assessment of cardiac power during dobutamine stress echocardiography in patients with normal LVEF provides valuable prognostic information regarding risk for mortality and future HF, in addition to stress test results. It is an important research tool to study cardiac performance, and the development of risk scores incorporating this novel index could be considered after further validation in prospective studies.

Background: Atrial fibrillation (AF) is a low-flow state and may underestimate aortic stenosis (AS) severity. Single-high Doppler signals (HS) consistent with severe AS (peak velocity ≥4 m/s or mean gradient ≥40 mm Hg) are averaged down in current practice. The objective for the study was to determine the significance of HS in AF low-gradient AS (LGAS). Methods: One thousand five hundred forty-one patients with aortic valve area ≤1 cm 2 and left ventricular ejection fraction ≥50% were identified and classified as high-gradient AS (HGAS) (≥40 mm Hg) and LGAS (<40 mm Hg), and AF versus sinus rhythm (SR). Available computed tomography aortic valve calcium scores (AVCS) were retrieved from the medical record. Outcomes were assessed. Results: Mean age was 76±11 years, female 47%. Mean gradient was 51±12 in SR-HGAS, 48±10 in AF-HGAS, 31±5 in SR-LGAS, and 29±7 mm Hg in AF-LGAS, all P ≤0.001 versus SR-HGAS; HS were present in 33% of AF-LGAS. AVCS were available in 34%. Compared with SR-HGAS (2409 arbitrary units; interquartile range, 1581–3462) AVCS were higher in AF-HGAS (2991 arbitrary units; IQR1978–4229, P =0.001), not different in AF-LGAS (2399 arbitrary units; IQR1817–2810, P =0.47), and lower in SR-LGAS (1593 arbitrary units; IQR945–1832, P <0.001); AVCS in AF-LGAS were higher when HS were present ( P =0.048). Compared with SR-HGAS, the age-, sex-, comorbidity index-, and time-dependent aortic valve replacement-adjusted mortality risk was higher in AF-HGAS (hazard ratio=1.82 [1.40–2.36], P <0.001) and AF-LGAS with HS (hazard ratio=1.54 [1.04–2.26], P =0.03) but not different in AF-LGAS without HS or SR-LGAS (both P =not significant). Conclusions: Severe AS was common in AF-LGAS. AVCS in AF-LGAS were not different from SR-HGAS. AVCS were higher and mortality worse in AF-LGAS when HS were present.

AIMS Cardiac power is a measure of cardiac performance that incorporates both pressure and flow components. Prior studies have shown that cardiac power predicts outcomes in patients with reduced left ventricular (LV) ejection fraction (EF). We sought to evaluate the prognostic significance of peak exercise cardiac power and power reserve in patients with normal EF. METHODS AND RESULTS  We performed a retrospective analysis in 24 885 patients (age 59 ± 13 years, 45% females) with EF ≥50% and no significant valve disease or right ventricular dysfunction, undergoing exercise stress echocardiography between 2004 and 2018. Cardiac power and power reserve (developed power with stress) were normalized to LV mass and expressed in W/100 g of LV myocardium. Endpoints at follow-up were all-cause mortality and diagnosis of heart failure (HF). Patients in the higher quartiles of power/mass (rest, peak stress, and power reserve) were younger and had higher peak blood pressure and heart rate, lower LV mass, and lower prevalence of comorbidities. During follow-up [median 3.9 (0.6-8.3) years], 929 patients died. After adjusting for age, sex, metabolic equivalents (METs) achieved, ischaemia/infarction on stress test results, medication, and comorbidities, peak stress power/mass was independently associated with mortality [adjusted hazard ratio (HR), highest vs. lowest quartile, 0.5, 95% confidence interval (CI) 0.4-0.6, P < 0.001] and HF at follow-up [adjusted HR, highest vs. lowest quartile, 0.4, 95% CI (0.3, 0.5), P < 0.001]. Power reserve showed similar results. CONCLUSION The assessment of cardiac power during exercise stress echocardiography in patients with normal EF provides valuable prognostic information, in addition to stress test findings on inducible myocardial ischaemia and exercise capacity.