Pellikka, Patricia A.

Abstract Background/Introduction Cardiac stress tests are carried out in populations with a low probability of ischemic heart disease (IHD) much more frequently than in the past. Stress ECG remains a frequently used modality for the diagnosis of IHD in vast areas of the world with limited facilities. Purpose To assess the diagnostic value of stress ECG for diagnosing IHD using inducible regional wall motion abnormalities (RWMA) on stress echocardiography (SE) as the gold standard method of diagnosis. Methods The 12-lead ECG response was retrospectively analyzed in 4317 patients (age 64±13 years, 59.6% males) undergoing SE for chronic coronary syndromes who were prospectively recruited from 39 cardiac centers between March 2021 and February 2024. Exclusion criteria were left bundle branch block or pacemaker rhythm. ECG response was considered ischemic according to standard criteria (if ST-segment deviated >1.0 mm from baseline in ≥2 contiguous leads at 80 ms from J point) during an exercise (n=2980, 69.8%), dobutamine (n = 766, 18.0%), or vasodilator (n=519, 12.2%) SE. All patients underwent a comprehensive SE protocol with an assessment of wall motion score index (WMSI), B-lines (4-site simplified score), left ventricular contractile reserve (LVCR) based on force, coronary flow velocity reserve (CFVR) in the mid-distal left anterior descending artery (LAD), and heart rate reserve (HRR). Results ECG changes occurred in 641 patients (14.8%, Group 1) for the overall studied population. Compared to patients without ECG changes (Group 2, n=3676, 85.2%), patients with ECG changes showed higher values of peak WMSI and lower values of CFVR and LVCR (see table).Amongst patients without inducible RWMA (n=3553), there were 392 (11%) patients with an ischemic ECG at stress (89% specificity). Of 764 patients with inducible RWMA during SE, 249 had an ischemic ECG trace (sensitivity 33%). In patients without inducible RWMA, those with ischemic ECG changes showed similar abnormal stress B-lines (23% vs. 21%, p=0.719), LVCR (61% vs. 63%, p=0.602), CFVR (31% vs 33%, p=0.607) and HRR (37% vs 41%, p=0.097) compared to those without ECG changes. Amongst patients with inducible RWMA and ECG changes, CFVR was significantly lower in patients with ECG changes (39.2% and 60.8%, respectively, p<0.001). Conclusions Simple standard stress ECG diagnostic value in the current era in populations with a low probability of IHD seems to be low. However, during SE, stress-induced ischemic ECG changes are associated with more extensive RWMA and blunted global LVCR, with reduced CFVR in the LAD. Therefore, analysis of ST segment changes during stress imaging studies can offer additional, significant information.

Abstract Background Patients with lower extremity peripheral arterial disease (PAD) have a higher risk of cardiovascular events. Stress echocardiography (SE) based on regional wall motion abnormality (RWMA) is imperfect for risk stratification in PAD, but it can be complemented with an assessment of coronary flow velocity reserve (CFVR) in the mid-distal left anterior descending coronary artery. Purpose To assess the value of SE with RWMA and CFVR to predict survival in PAD. Methods In a retrospective analysis of prospectively acquired data in an observational, multicenter study, we recruited 359 patients (age 69±8 years, 240 [67%] males) with PAD referred for dipyridamole SE in 3 accredited laboratories. We assessed RWMA and CFVR (abnormal value <2.0). All patients were followed up for a median of 4.7 (interquartile range: 2.0 to 8.2 years). All-cause death was the outcome end-point. Results The positivity rate was 37/359 (10%) for RWMA and 159/359 (44%) for CFVR. During follow-up, 97 (27%) deaths were registered. At multivariable analysis, inducible RWMA and/or CFVR <2.0 (HR 2.58, 95% CI 1.65-4.04; p<0.0001), age ≥70 years, diabetes, dialysis treatment, and ejection fraction ≤50% were associated with decreased survival. The annual mortality was 7.4% in patients with RWMA and/or CFVR <2.0 and 2.7% in those with no RWMA and CFVR >2.0 (Figure, p<0.0001). Conclusion In patients with PAD, SE shows more than 4-fold higher prevalence of abnormal CFVR compared to RWMA. The prognostic value of CFVR outperforms RWMA, showing the importance of coronary microvascular dysfunction and diffuse, subcritical coronary atherosclerosis in determining the outcome.

ABSTRACT Artificial intelligence (AI) is revolutionizing cardiac imaging, including echocardiography. However, AI has scarce penetration in resource‐limited regions. The implementation of AI‐aided echocardiography (AIE) poses unique challenges and opportunities in resource‐limited areas. Some obvious advantages of AIE include aiding image acquisition, interpretation, and triaging patients based on severity. The challenges AIE faces in resource‐limited regions include a lack of data accessibility for model development, physician apprehension, and an outdated regulatory framework. Based on our early experience with AI, we believe AIE in resource‐limited regions will enhance health equity, improve access to the technology, and lead to cost savings. However, significant efforts are needed to realize these objectives.

Abstract Aims Degenerative mitral stenosis (DMS) is due to degenerative mitral annular calcification (MAC) and valvular calcification. However, DMS impacts on the outcome, and therefore, potential treatment needs are poorly known. We aimed at evaluating survival after DMS diagnosis by Doppler echocardiography in routine practice. Methods and results A cohort of 2937 (75 ± 12 years, 67% women) consecutive patients were diagnosed between 2003 and 2014 with DMS (diastolic mean gradient ≥ 5 mmHg), with analysis of short- and long-term survival. All patients had overt mitral annular/valvular degenerative calcification without rheumatic involvement. Mean gradient was 6.5 ± 2.4 mmHg, and DMS was considered mild in 50%, moderate in 44%, and severe in 6%. DMS was associated with left atrial enlargement (52 ± 23 mL/m2) and elevated pulmonary pressure (49 ± 16 mmHg) despite generally normal ejection fraction (61 ± 13%). DMS was associated with frequent comorbid conditions (74% hypertension, 58% coronary disease, and 52% heart failure) and humoural alterations (haemoglobin 11.3 ± 1.8 g/dL and creatinine 1.5 ± 1.4 mg/dL). One-year mortality was 22%, most strongly related to older age, higher comorbidity, and abnormal haemoglobin/creatinine but only weakly to DMS severity (with anaemia 42% irrespective of DMS severity, P = 0.99; without anaemia 18, 23, and 28% with mild, moderate, and severe DMS, respectively, P < 0.0004). Long-term mortality was high (56% at 5 years) also mostly linked to aging and weakly to DMS severity [with anaemia P = 0.90; without anaemia: adjusted-hazard ratio: 1.30 (1.19–1.42), P < 0.0001, for moderate vs. mild DMS and 1.63 (1.34–1.98), P < 0.0001, for severe vs. mild DMS]. Conclusion DMS is a condition of the elderly potentially resulting in severe mitral obstruction and haemodynamic alterations. However, DMS is frequently associated with severe comorbidities imparting considerable mortality following diagnosis, whereas DMS severity is a weak (albeit independent) determinant of mortality. Hence, patients with DMS should be carefully evaluated and interventional/surgical treatment prudently considered in those with limited comorbidity burden, particularly without anaemia. Keywords: Degenerative Mitral Stenosis; Outcome; Natural history; Ecocardiography; Mitral Stenosis.

Abstract Background Hypercontractile phenotype (HP) of the left ventricle (LV) is an actionable therapeutic target in patients with chronic coronary syndromes (CCS) or heart failure (HF), but its clinical recognition remains difficult. Objectives To assess the clinical variables associated with the HP. Methods In a prospective, observational, multicenter study, we recruited 5,122 patients (age 65 ± 11 years, 2974 males, 58%) with CCS and/or HF with preserved ejection fraction (EF). Systolic blood pressure (SBP) was measured. We assessed wall motion score index (WMSI), LV end-diastolic volume (EDV), end-systolic volume (ESV), EF, force (SBP/ESV), stroke volume (SV), arterial elastance (SBP/SV), and ventricular-arterial coupling (VAC, as SV/ESV). Univariable and multivariable logistic regression analysis assessed independent factors associated with the highest force sextile. Results For all the studied patients, force was 4.51 ± 2.11 mmHg/ml, with the highest sextile (Group 6) > 6.36 mmHg/ml. By multivariable logistic regression model, the highest sextile of force was associated with age > 65 years (OR 1.62, 95% CI 1.36–1.93, p < 0.001), hypertension (OR 1.76, 95% CI 1.40–2.21, p < 0.001), female sex (OR 4.52, 95% CI 3.77–5.42, p < 0.001), absence of beta-blocker therapy (OR 1.41, 95% CI 1.16–1.68), rest SBP ≥ 160 mmHg (OR 2.81, 95% CI 2.21–3.56, p < 0.001), high heart rate (OR 2.08, 95% CI 1.61–2.67, p < 0.001), and absence of prior myocardial infarction (OR 1.34, 95% CI 1.07–1.68, p = 0.012). Patients in the highest sextile of force showed lower values of WMSI, SV, EDV, and ESV, and higher values of arterial elastance and VAC. Conclusions HP of the LV with high force was clinically associated with advanced age, female sex, high resting SBP, and the absence of 𝛽-blocker therapy. By transthoracic echocardiography, HP was associated with a small heart with reduced EDV, reduced SV despite high EF, and higher arterial elastance.

Abstract Background and Aims Incidence and types of secondary tricuspid regurgitation (TR) are not well defined in atrial fibrillation (AFib) and sinus rhythm (SR). Atrial secondary TR (A-STR) is associated with pre-existing AFib; however, close to 50% of patients with A-STR do not have AFib. The aim of this study was to assess incidence, types, and outcomes of ≥ moderate TR in AFib vs. SR. Methods Adults with and without new-onset AFib without structural heart disease or ≥ moderate TR at baseline were followed for the development of ≥ moderate TR. Tricuspid regurgitation types were pacemaker, left-sided valve disease, left ventricular (LV) dysfunction, pulmonary hypertension (PH), isolated ventricular, and A-STR. Results Among 1359 patients with AFib and 20 438 in SR, 109 and 378 patients developed ≥ moderate TR, respectively. The individual types of TR occurred more frequently in AFib related to the higher pacemaker implantation rates (1.12 vs. 0.19 per 100 person-years, P &lt; .001), larger right atrial size (median 78 vs. 53 mL, P &lt; .001), and higher pulmonary pressures (median 30 vs. 28 mmHg, P &lt; .001). The most common TR types irrespective of rhythm were LV dysfunction-TR and A-STR. Among patients in SR, those with A-STR were older, predominantly women with more diastolic abnormalities and higher pulmonary pressures. All types of secondary TR were associated with all-cause mortality, highest in PH-TR and LV dysfunction-TR. Conclusions New-onset AFib vs. SR conferred a higher risk of the individual TR types related to sequelae of AFib and higher pacemaker implantation rates, although the distribution of TR types was similar. Secondary TR was universally associated with increased mortality.

Background The mortality risk attributable to moderate aortic stenosis (AS) remains incompletely characterized and has historically been underestimated. We aim to evaluate the association between moderate AS and all‐cause death, comparing it with no/mild AS (in a general referral population and in patients with heart failure with reduced ejection fraction). Methods and Results A systematic review and pooled meta‐analysis of Kaplan–Meier‐derived reconstructed time‐to‐event data of studies published by June 2023 was conducted to evaluate survival outcomes among patients with moderate AS in comparison with individuals with no/mild AS. Ten studies were included, encompassing a total of 409 680 patients (11 527 with moderate AS and 398 153 with no/mild AS). In the overall population, the 15‐year overall survival rate was 23.3% (95% CI, 19.1%–28.3%) in patients with moderate AS and 58.9% (95% CI, 58.1%–59.7%) in patients with no/mild aortic stenosis (hazard ratio [HR], 2.55 [95% CI, 2.46–2.64]; P <0.001). In patients with heart failure with reduced ejection fraction, the 10‐year overall survival rate was 15.5% (95% CI, 10.0%–24.0%) in patients with moderate AS and 37.3% (95% CI, 36.2%–38.5%) in patients with no/mild AS (HR, 1.83 [95% CI, 1.69–2.0]; P <0.001). In both populations (overall and heart failure with reduced ejection fraction), these differences correspond to significant lifetime loss associated with moderate AS during follow‐up (4.4 years, P <0.001; and 1.9 years, P <0.001, respectively). A consistent pattern of elevated mortality rate associated with moderate AS in sensitivity analyses of matched studies was observed. Conclusions Moderate AS was associated with higher risk of death and lifetime loss compared with patients with no/mild AS.

Introduction: Asymptomatic LV systolic dysfunction is often underdiagnosed, leading to missed opportunities for treatment. In a recently completed pragmatic RCT, an AI algorithm performed on the ECGs ordered as part of routine practice increased early diagnosis of low EF. The current study aimed to understand whether the effectiveness of the AI algorithm integrated into routine care differed by the socioeconomic status of the patient. Methods: The main findings of the RCT were previously published. Clinicians in the intervention group had access to AI results (i.e., a positive or negative screening result, with positive results indicating a high likelihood of low EF). When a positive result was found, clinicians in the intervention group received an alert that encouraged them to order TTE if considered clinically appropriate. Clinicians in the control group did not have access or received alerts. Area deprivation index (ADI) was used to measure area-level social determinants of health. This study included 16,992 patients (control 8,225; intervention: 8,767) who had ECG performed for any indications between 8/5/2019 and 3/31/2020, no prior HF, and a valid address to derive ADI. The primary endpoint was a new diagnosis of EF≤50% within 3 months. Results: The mean age was 60.5±17.6 y. AI increased the diagnosis of low EF in the overall cohort (OR 1.42 [1.13, 1.78], p=0.01). The magnitude of benefit was greater in patients with higher socioeconomic status, e.g., living in an area that is less deprived (OR 1.88 [1.16, 3.05]), with higher median income, lower poverty rate, higher education level, better housing conditions, and higher proportion of white-collar workers, although the interaction was not statistically significant (Figure). Conclusions: AI enables early diagnosis of low EF and the magnitude of benefit might be numerically greater in patients with higher socioeconomic status, possibly due to variations in access to or referral for subsequent testing.

Introduction: Carcinoid heart disease (CHD) is a rare sequelae of hormonally active neuroendocrine tumors that often requires cardiac surgical intervention. Little is reported on cardiac implantable electronic device (CIED) implantation in the CHD patient population. Hypothesis: We sought to establish the safety and efficacy of CIED implantation in patients with CHD. Methods: We retrospectively reviewed patients with a diagnosis of CHD who underwent CIED implantation at our institution (Mayo Clinic) and evaluated indications for implant, perioperative complications, and mortality. Results: A total of 27 patients with a cumulative follow up of 75 patient-years were identified during the study period. The most common indication for device implant was high grade atrioventricular block (n=18, 66.7%). 14 (51.8%) had baseline conduction disease and 26 (96.2%) underwent cardiac surgery prior to CIED implant. The majority of devices implanted were dual chamber permanent pacemakers (PPM) (n=17, 63.0%), while other devices included single chamber PPM, epicardial PPM, chronic resynchronization devices, and intracardiac defibrillators. Peri-operative complication occurred in 6 patients (22.2%), with 2 patients requiring ICU level care. No patient suffered carcinoid crisis during implantation and there was no peri-implant mortality. Long term, 3 patients required device extraction: 1 for infection, 1 for lead related pain, and 1 for generator migration. The median time to death from implant was 2.5 years, with one-year mortality at 15%. Conclusions: In this unique cohort of patients with CHD, CIED can be performed safely. CIED most often occurred in the post cardiac surgical period and carcinoid crisis was uncommon.

Introduction: Hypertrophic cardiomyopathy (HCM) is associated with excessive left ventricular (LV) hypertrophy (LVH), myocyte disarray and expansion of interstitial collagen. These factors alter mechanical properties of the myocardial tissue. Intrinsic velocity propagation (iVP) of myocardial stretch is a new validated measure of myocardial elasticity. Hypothesis: iVP in left ventricular (LV) myocardium of patients with HCM will be increased compared to normal subjects. Methods: We studied prospectively 100 subjects: 42 with HCM (age 57 ± 14 years; 79% with asymmetric septal LVH) and 58 normal controls without cardiovascular disease (age 48 ± 13 years). Patients had comprehensive transthoracic echocardiography and cardiac magnetic resonance imaging (MRI; n=29). iVP was measured throughout the LV myocardium during late diastole using ultra-high frame rate tissue Doppler imaging (350-460 fps) (6 LV walls, 3 standard apical views). Chamber stiffness (CS) was evaluated from end-diastolic pressure-volume relationship (EDPVR) estimated noninvasively by the single-beat method (EDP=αV β ). End-diastolic pressure (EDP) was estimated from E/e’. Results: LV ejection fraction was normal in both groups (HCM: 68 ± 7%; Controls: 65 ± 5%). Myocardial stiffness by iVP was markedly higher in HCM vs. controls (Fig.A, left panel). This was confirmed by EDPVRs, which were steeper and shifted leftward (Fig. B, left). The slope (β, load-independent) of EDPVR and CS (dP/dV) were higher and LV capacitance (V 30 , estimated volume at 30 mmHg EDP) was lower in HCM (Fig. B, right) and correlated significantly, though weakly, with iVP (β: r = 0.41; CS dP/dV: r = 0.48; EDP: r = 0.61; p<0.002 for all). Patients with apical variant had lower levels of global iVP compared to patients with predominant septal LVH and diffuse concentric LVH (Fig. A, right). Conclusions: Myocardial stiffness measured noninvasively by the intrinsic wave method is highly abnormal in HCM. This novel approach allows mapping of myocardial elasticity of the entire left ventricle and shows promise to become a clinical tool for evaluation of patients with diastolic tissue abnormalities.