The Natural History of Atrial Functional Mitral Regurgitation.

BACKGROUND: The natural history of moderate/severe atrial functional mitral regurgitation (AFMR) is unknown. OBJECTIVES: The authors sought to study the incidence of left ventricular (LV) systolic dysfunction (LVSD), progression or regression of ≥mild-moderate AFMR, and impact on mortality. METHODS: Adults with left atrial (LA) volume index ≥40 mL/m2, ≥mild-moderate AFMR, and follow-up echocardiogram were followed for incident LVSD (ejection fraction <50% and ≥10% lower than baseline), progression of mild-moderate/moderate AFMR to severe, and persistent regression of AFMR to no/trivial. Relation of AFMR progression or regression as time-dependent covariates with all-cause mortality was studied. Incidence of LVSD was compared with patients with no/mild AFMR matched on age, sex, comorbidities and ejection fraction. Patients were followed until mitral intervention, myocardial infarction, or last follow-up. RESULTS: A total of 635 patients (median age 75 years, 51% female, 96% mild-moderate/moderate AFMR, 4% severe AFMR) were included. Over a median 2.2 years (Q1-Q3: 1.0-4.3 years), incidence rates per 100 person-years were 3.2 for LVSD (P = 0.52 vs patients with no/mild AFMR), 1.9 for progression of AFMR, and 3.9 for regression. Female sex and larger LA volume index were independently associated with progression, whereas younger age, male sex, absent atrial fibrillation, and higher LA emptying fraction were independently associated with regression. Neither AFMR progression nor regression was independently associated with mortality. Instead, independent risk factors for mortality included older age, concentric LV geometry, and higher estimated LV filling and pulmonary pressures. CONCLUSIONS: In patients with predominantly mild-moderate/moderate AFMR, regression of MR was more common than progression, but neither was associated with mortality. Instead, diastolic function abnormalities were more important. Over a median 2-year follow-up, LVSD risk was not increased.

A Pragmatic Study of Cardiovascular Disease During Long-Term COVID-19.

BACKGROUND: Many patients diagnosed with COVID-19 have persistent cardiovascular symptoms but whether this represents a true cardiac process is unclear. This study assessed whether symptoms associated with long COVID among patients referred for cardiovascular evaluation are associated with objective abnormalities on cardiac testing to explain their clinical presentation. METHODS: A retrospective cohort study of 40,462 unique patients diagnosed with COVID-19 at our tertiary referral was conducted and identified 363 patients with persistent cardiovascular symptoms a minimum of 4 weeks after PCR confirmed COVID-19 infection. Patients had no cardiovascular symptoms prior to COVID-19 infection. Each patient was referred for cardiovascular evaluation at a tertiary referral center. The incidence and etiology of abnormalities on cardiovascular testing among patients with long COVID symptoms are reported here. The cohort was subsequently divided into three categories based on the dominant circulating severe acute respiratory syndrome coronavirus 2 variant at the time of initial infection for further analysis. RESULTS: Among 40,462 unique patients diagnosed with COVID-19 at our tertiary referral center from April 2020 to March 2022, 363 (0.9%) patients with long COVID were evaluated by Cardiology for possible cardiac sequelae from COVID and formed the main study cohort. Of these, 229 (63%) were vaccinated and 47 (12.9%) had severe initial infection receiving inpatient treatment for COVID prior to developing long COVID symptoms. Symptoms were associated with a cardiac cause in 85 (23.4%), of which 52 (14.3%) were attributed to COVID; 39 (10.7%) with new cardiac disease from COVID, and 13 (3.6%) to worsening of pre-existing cardiac disease after COVID infection. The median troponin change in 45 patients with troponin measurements within 4 weeks of acute infection was +4 ng/dl (9 to 13 ng/dl). Among the total cohort with long COVID, 83.7% were diagnosed during the pre-Delta phase, 13.2% during the Delta phase, and 3.1% during the Omicron phase of the pandemic. There were six cases of myocarditis, 11 rhythm disorders, eight cases of pericarditis, five suspected cases of endothelial dysfunction, and 33 cases of autonomic dysfunction. CONCLUSION: This pragmatic retrospective cohort study suggests that patients with long COVID referred for cardiovascular evaluation infrequently have new, objective cardiovascular disease to explain their clinical presentation. A multidisciplinary, patient-centered approach is warranted for symptom management along with conservative use of diagnostic testing.

Coronary Artery Tortuosity and Spontaneous Coronary Artery Dissection: Association With Echocardiography and Global Longitudinal Strain, Fibromuscular Dysplasia, and Outcomes.

BACKGROUND: The etiology and significance of coronary artery tortuosity (TCA) among patients with spontaneous coronary artery dissection (SCAD) are unknown. The aim of this prospective imaging cohort study was to report echocardiographic findings and evaluate whether TCA correlates with cardiac anatomy and function among patients with SCAD. Comorbidities including fibromuscular dysplasia (FMD) and outcomes were also assessed. METHODS: TCA was determined on coronary angiography performed during the diagnosis of SCAD, and cardiac structure and function were evaluated using prospective comprehensive echocardiography. RESULTS: Among 116 patients with SCAD, the mean age at echocardiography was 50.8 ± 8.8 years, a median of 10.9 months after SCAD. Sixty-two patients (53.4%) had FMD, 41 (35.3%) had histories of hypertension, and 17 (14.8%) were hypertensive during echocardiography. Most patients (n = 78 [69%]) had normal left ventricular geometry with normal median ejection fraction (61%; interquartile range, 56% to 64%) and normal global longitudinal strain (-22.2%; interquartile range, -24.0% to -19.9%). Fifteen patients (13.4%) had diastolic dysfunction that was associated with hypertension at the time of echocardiography. Patients with TCA (n = 96 [82.8%]) were older (mean age, 52.1 ± 8.0 vs 44.7 ± 9.9 years; P < .001) with a higher prevalence of FMD (59.4% vs 25%, P = .007) but a similar prevalence of hypertension (35% vs 35%, P > .99) compared with patients without TCA. Across the age range (31.5 to 66.9 years), each decade of age was associated with an approximately 0.89-unit increase in coronary tortuosity score (P < .0001). Echocardiographic parameters were not significantly different between the two groups. Median follow-up duration was 4.4 years (95% CI, 3.8 to 5.2 years). The Kaplan-Meier 3-year SCAD recurrence rate was 9.4% (95% CI, 3.7% to 14.8%). There were no deaths. CONCLUSIONS: The majority of patients with SCAD had normal or near normal echocardiographic results, including global longitudinal strain, with no differences according to TCA. However, patients with SCAD with TCA were older, with a higher prevalence of FMD.

Progression of Mild Mitral Annulus Calcification to Mitral Valve Dysfunction and Impact on Mortality.

BACKGROUND: Mitral annulus calcification (MAC) represents a degenerative process resulting in calcium deposition in the mitral valve apparatus. Mitral annulus calcification is associated with adverse clinical outcomes. We sought to examine the long-term significance of mild MAC and its relationship to subsequent mitral valve dysfunction (MVD) and mortality in patients without MVD on the initial echocardiogram. METHODS: A total of 1,420 patients with mild MAC and no MVD at baseline and 1 or more follow-up echocardiograms at least 1 year after the baseline echocardiogram were included in the analysis. For patients with >1 echocardiogram during follow-up, the last echocardiogram was used. The same criteria were used to identify 6,496 patients without MAC. Mitral valve dysfunction was defined as mitral regurgitation (MR) and/or mitral stenosis (MS) of moderate or greater severity. Mixed disease was defined as the concurrent presence of both moderate or greater MS and MR. The primary end point was development of MVD, and the secondary end point was all-cause mortality. RESULTS: For patients with mild MAC, age was 74 ± 10 years and 528 (37%) were female. Over a median follow-up of 4.7 (interquartile range, 2.7-6.9) years, 215 patients with mild MAC developed MVD, including MR in 170 (79%), MS in 37 (17%), and mixed disease in 8 (4%). In a multivariable regression model compared to patients without MAC, the presence of mild MAC was independently associated with increased mortality (hazard ratio = 1.43; 95% CI 1.24, 1.66; P < .001). Kaplan-Meier 4-year survival rates were 80% and 90% for patients with mild MAC and no MAC, respectively. CONCLUSIONS: Mild MAC observed on transthoracic echocardiography is an important clinical finding with prognostic implications for both valvular function and mortality.

Machine Learning for Diagnosis of Pulmonary Hypertension by Echocardiography.

OBJECTIVE: To evaluate a machine learning (ML)-based model for pulmonary hypertension (PH) prediction using measurements and impressions made during echocardiography. METHODS: A total of 7853 consecutive patients with right-sided heart catheterization and transthoracic echocardiography performed within 1 week from January 1, 2012, through December 31, 2019, were included. The data were split into training (n=5024 [64%]), validation (n=1275 [16%]), and testing (n=1554 [20%]). A gradient boosting machine with enumerated grid search for optimization was selected to allow missing data in the boosted trees without imputation. The training target was PH, defined by right-sided heart catheterization as mean pulmonary artery pressure above 20 mm Hg; model performance was maximized relative to area under the receiver operating characteristic curve using 5-fold cross-validation. RESULTS: Cohort age was 64±14 years; 3467 (44%) were female, and 81% (6323/7853) had PH. The final trained model included 19 characteristics, measurements, or impressions derived from the echocardiogram. In the testing data, the model had high discrimination for the detection of PH (area under the receiver operating characteristic curve, 0.83; 95% CI, 0.80 to 0.85). The model's accuracy, sensitivity, positive predictive value, and negative predictive value were 82% (1267/1554), 88% (1098/1242), 89% (1098/1241), and 54% (169/313), respectively. CONCLUSION: By use of ML, PH could be predicted on the basis of clinical and echocardiographic variables, without tricuspid regurgitation velocity. Machine learning methods appear promising for identifying patients with low likelihood of PH.

High Resting Coronary Flow Velocity by Echocardiography Is Associated With Worse Survival in Patients With Chronic Coronary Syndromes.

BACKGROUND: Resting coronary flow velocity (CFV) in the mid-distal left anterior descending coronary artery can be easily assessed with transthoracic echocardiography. In this observational study, the authors sought to assess the relationship between resting CFV, CFV reserve (CFVR), and outcome in patients with chronic coronary syndromes. METHODS AND RESULTS: In a prospective multicenter study design, the authors retrospectively analyzed 7576 patients (age, 66±11 years; 4312 men) with chronic coronary syndromes and left ventricular ejection fraction ≥50% referred for dipyridamole stress echocardiography. Recruitment (years 2003-2021) involved 7 accredited laboratories, with interobserver variability <10% for CFV measurement at study entry. Baseline peak diastolic CFV was obtained by pulsed-wave Doppler in the mid-distal left anterior descending coronary artery. CFVR (abnormal value ≤2.0) was assessed with dipyridamole. All-cause death was the only end point. The mean CFV of the left anterior descending coronary artery was 31±12 cm/s. The mean CFVR was 2.32±0.60. During a median follow-up of 5.9±4.3 years, 1121 (15%) patients died. At multivariable analysis, resting CFV ≥32 cm/s was identified by a receiver operating curve as the best cutoff and was independently associated with mortality (hazard ratio [HR], 1.24 [95% CI, 1.10-1.40]; P<0.0001) together with CFVR ≤2.0 (HR, 1.78 [95% CI, 1.57-2.02]; P<0.0001), age, diabetes, history of coronary surgery, and left ventricular ejection fraction. When both CFV and CFVR were considered, the mortality rate was highest in patients with resting CFV ≥32 cm/s and CFVR ≤2.0 and lowest in patients with resting CFV <32 cm/s and CFVR >2.0. CONCLUSIONS: High resting CFV is associated with worse survival in patients with chronic coronary syndromes and left ventricular ejection fraction ≥50%. The value is independent and additive to CFVR. The combination of high resting CFV and low CFVR is associated with the worst survival.

Mitral Annulus Calcium Score in Patients With Calcific Mitral Stenosis Undergoing Invasive Hemodynamic Assessment.

BACKGROUND: Aortic valve calcium score is associated with hemodynamic severity of aortic stenosis. Whether this association is present in calcific mitral stenosis remains unknown. METHODS AND RESULTS: This study was a retrospective analysis of consecutive patients with mitral stenosis secondary to mitral annular calcification (MAC) undergoing transseptal catheterization. All patients underwent invasive mitral valve assessment via direct left atrial and left ventricular pressure measurement. Computed tomography within 1 year of cardiac catheterization and with adequate visualization of the mitral annulus was included. MAC calcium score quantification by Agatston method was obtained offline using dedicated software (Aquarius, TeraRecon, V.4). Median patient age was 66.9±11.2 years, 47% of patients were women, 50% had coronary artery disease, 40% had atrial fibrillation, 47% had prior cardiac surgery, and 33% had prior chest radiation. Median diastolic mitral valve gradient was 9.4±3.4 mm Hg on echocardiography and 8.5±4 mm Hg invasively. Invasive median mitral valve area using the Gorlin formula was 1.87±0.9 cm2. Median MAC calcium score for the cohort was 7280±7937 Hounsfield units. MAC calcium score correlated with the presence of atrial fibrillation (P=0.02) but was not associated with other comorbidities. There was no correlation between MAC calcium score and mitral valve area (r=0.07; P=0.6) or mitral valve gradient (r=-0.03; P=0.8). CONCLUSIONS: MAC calcium score did not correlate with invasively measured mitral valve gradient and mitral valve area in patients with MAC-related mitral stenosis, suggesting that calcium score should not be used as a surrogate for invasive hemodynamic parameters.

2023 Multimodality Appropriate Use Criteria for the Detection and Risk Assessment of Chronic Coronary Disease: A Summary for JASE.

This report provides a descriptive summary of the ACC/AHA/ASE/ASNC/ASPC/HFSA/HRS/SCAI/SCCT/SCMR/STS 2023 Multimodality Appropriate Use Criteria for the Detection and Risk Assessment of Chronic Coronary Disease with an emphasis on the role of stress echocardiography.

Incidence of Severe Adverse Drug Reactions to Ultrasound Enhancement Agents in a Contemporary Echocardiography Practice.

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.

Global Longitudinal Strain as Predictor of Inducible Ischemia in No Obstructive Coronary Artery Disease in the CIAO-ISCHEMIA Study.

BACKGROUND: Global longitudinal strain (GLS) is a sensitive marker for identifying subclinical myocardial dysfunction in obstructive coronary artery disease (CAD). Little is known about the relationship between GLS and ischemia in patients with myocardial ischemia and no obstructive CAD (INOCA). OBJECTIVES: To investigate the relationship between resting GLS and ischemia on stress echocardiography (SE) in patients with INOCA. METHODS: Left ventricular GLS was calculated offline on resting SE images at enrollment (n = 144) and 1-year follow-up (n = 120) in the CIAO-ISCHEMIA (Changes in Ischemia and Angina over One year in International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial screen failures with no obstructive CAD on computed tomography [CT] angiography) study, which enrolled participants with moderate or severe ischemia by local SE interpretation (≥3 segments with new or worsening wall motion abnormality and no obstructive (<50% stenosis) on coronary computed tomography angiography. RESULTS: Global longitudinal strain values were normal in 83.3% at enrollment and 94.2% at follow-up. Global longitudinal strain values were not associated with a positive SE at enrollment (GLS = -21.5% positive SE vs GLS = -19.9% negative SE, P = .443) or follow-up (GLS = -23.2% positive SE vs GLS = -23.1% negative SE, P = .859). Significant change in GLS was not associated with positive SE in follow-up (P = .401). Regional strain was not associated with colocalizing ischemia at enrollment or follow-up. Changes in GLS and number of ischemic segments from enrollment to follow-up showed a modest but not clinically meaningful correlation (ß = 0.41; 95% CI, 0.16, 0.67; P = .002). CONCLUSIONS: In this cohort of INOCA patients, resting GLS values were largely normal and did not associate with the presence, severity, or location of stress-induced ischemia. These findings may suggest the absence of subclinical myocardial dysfunction detectable by echocardiographic strain analysis at rest in INOCA.

Impact on Kidney Function and Medium-Term Outcomes of Transcatheter Aortic Valve Replacement in Patients With Chronic Kidney Disease.

Transcatheter aortic valve replacement (TAVR) is now widely approved for the treatment of aortic stenosis, regardless of the patients' surgical risk. However, the outcomes of TAVR and their determinants in patients with chronic kidney disease (CKD) beyond 1 year of follow-up are unknown. We aimed to assess the medium-term outcomes of TAVR in CKD, develop a risk score to estimate the 2-year mortality in patients with CKD, and evaluate the changes in kidney function at discharge after TAVR. Adults who underwent TAVR were retrospectively identified. The CKD stage was determined using the Chronic Kidney Disease Epidemiology 2021 creatinine formula. Improved kidney function was defined as post-TAVR creatinine ≤50% of pre-TAVR creatinine or decrease in creatinine of ≥0.3 mg/100 ml compared with pre-TAVR creatinine. Overall, 1,523 patients (median age 82 years; 59% men; 735 with CKD stage II or less, 661 with CKD III, 83 with CKD IV, and 44 with CKD V [of whom 40 were on dialysis]) were included. The all-cause mortality was higher in CKD stages IV and V on the multivariable analysis (p <0.001) at median follow-up of 2.9 (interquartile range 2.0 to 4.2) years. Moderate or severe tricuspid regurgitation, anemia, right ventricular systolic pressure >40 mm Hg and CKD stages IV and V were independent predictors of 2-year mortality and were used to develop a risk score. At hospital discharge, persisting acute kidney injury after TAVR occurred in 88 of 1,466 patients (6%), whereas improved kidney function occurred in 170 of 1,466 patients (12%). In conclusion, CKD stage was an independent determinant of mortality beyond 2 years after TAVR. Kidney function was more likely to improve than worsen at the time of hospital discharge after TAVR.

Biatrial myopathy in heart failure with preserved ejection fraction.

AIM: Left atrial (LA) myopathy is increasingly recognized as an important phenotypic trait in heart failure (HF) with preserved ejection fraction (HFpEF). Right atrial (RA) remodelling and dysfunction also develop in HFpEF, but little data are available regarding the clinical characteristics and pathophysiology among patients with isolated LA, RA, or biatrial myopathy. METHODS AND RESULTS: Patients with HFpEF underwent invasive haemodynamic exercise testing, comprehensive imaging including speckle tracking strain echocardiography, and clinical follow-up at Mayo Clinic between 2006 and 2018. LA myopathy was defined as LA volume index >34 ml/m2 and/or LA reservoir strain ≤24% and RA myopathy by RA volume index >39 ml/m2 in men and >33 ml/m2 in women and/or RA reservoir strain ≤19.8%. Of 476 consecutively evaluated patients with HFpEF defined by invasive exercise testing with evaluable atrial structure/function, 125 (26%) had no atrial myopathy, 147 (31%) had isolated LA myopathy, 184 (39%) had biatrial myopathy, and 20 (4%) had isolated RA myopathy. Patients with HFpEF and biatrial myopathy had more atrial fibrillation, poorer left ventricular systolic and diastolic function, more severe pulmonary vascular disease, tricuspid regurgitation, ventricular interdependence and right ventricular dysfunction, and poorer cardiac output reserve with exercise. There were 94 patients with events over a median follow-up of 2.9 (interquartile range 1.4-4.6) years. Individuals with biatrial myopathy had an 84% higher risk of HF hospitalization or death as compared to those with isolated LA myopathy (hazard ratio 1.84; 95% confidence interval 1.16-2.92, p = 0.01). CONCLUSIONS: Biatrial myopathy identifies patients with more advanced HFpEF characterized by more severe pulmonary vascular disease, right HF, poorer cardiac reserve, and a greater risk for adverse outcomes. Further study is required to define optimal strategies to treat and prevent biatrial myopathy in HFpEF.

Multiple Phenotypes of Chronic Coronary Syndromes Identified by ABCDE Stress Echocardiography.

BACKGROUND: Regional wall motion abnormality is considered a sensitive and specific marker of ischemia during stress echocardiography (SE). However, ischemia is a multifaceted entity associated with either coronary artery disease (CAD) or angina with normal coronary arteries, a distinction difficult to make using a single sign. The aim of this study was to evaluate the diagnostic potential of the five-step ABCDE SE protocol for CAD detection. METHODS: From the 2016-2022 Stress Echo 2030 study data bank, 3,229 patients were selected (mean age, 66 ± 12 years; 2,089 men [65%]) with known CAD (n = 1,792) or angina with normal coronary arteries (n = 1,437). All patients were studied using both the ABCDE SE protocol and coronary angiography, within 3 months. In step A, regional wall motion abnormality is assessed; in step B, B-lines and diastolic function; in step C, left ventricular contractile reserve; in step D, coronary flow velocity reserve in the left anterior descending coronary artery; and in step E, heart rate reserve. RESULTS: SE response ranged from a score of 0 (all steps normal) to a score of 5 (all steps abnormal). For CAD, rates of abnormal results were 347 for step A (19.4%), 547 (30.5%) for step B, 720 (40.2%) for step C, 615 (34.3%) for step D, and 633 (35.3%) for step E. For angina with normal coronary arteries, rates of abnormal results were 81 (5.6%) for step A, 429 (29.9%) for step B, 432 (30.1%) for step C, 354 (24.6%) for step D, and 445 (31.0%) for step E. The dominant "solitary phenotype" was step B in 109 patients (9.1%). CONCLUSIONS: Stress-induced ischemia presents with a wide range of diagnostic phenotypes, highlighting its complex nature. Using a comprehensive approach such as the advanced ABCDE score, which combines multiple markers, proves to be more valuable than relying on a single marker in isolation.