Mohananey, Akanksha

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: 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: Although genetic testing (GT) in dilated cardiomyopathy (DCM) enables molecular diagnosis, family screening and provides prognostic information, it is underutilized. Our hypothesis was that systemic intervention (INT) in the heart failure (HF) clinic could increase the frequency of GT for DCM. Methods: Eligible DCM patients in a 17-month period before and after the INT were compared for frequency of genetic counseling and GT uptake. The INT comprised of the following: 1. Pre-emptive cardiovascular genomics e-consult (with a specialist in genetic DCM) for all new HF patients that could be canceled by the treating physician if the patient was considered ineligible or was uninterested. If eligible and patient was willing, 2. They were shown a video in person on genetic testing for DCM prepared by a genetics counselor 3. A trained HF clinic nurse provided answers to questions and completed the test requisition 4. Educational material was provided to the patient 5. Results were reviewed electronically and communicated to the patient via letter or phone call by the physician completing the e-consult. Clinical genetics consultation was available throughout the study period. Standard commercially available cardiomyopathy gene panels were used for GT. Results: There were 162 eligible DCM patients before and 194 after the INT. DCM patients were more likely to undergo genetic counseling post-INT versus (vs) pre-INT (33.5% vs 14.8%, OR 2.9, 95% CI 1.7-4.8, P <.0001). Similarly, DCM patients were more likely to undergo GT post-INT vs pre-INT (27.3% vs 13%, OR 2.5, 95% CI 1.4-4.3, P =.001). Consequently, the total number of patients who were diagnosed to have likely pathogenic or pathogenic DCM-related genetic variants increased from 2 pre-INT to 6 post-INT. These variants were detected in the following genes: FLNC (n=2), TTN (n=2), DES , LMNA , PLN and TNNT2 . Conclusion: An intervention that was pre-emptive, easily accessible and available to the healthcare provider was successful in raising the rates of genetic counseling and testing in DCM patients seen in the HF clinic. Whether such low-cost interventions will enhance cascade screening and provide an opportunity for precision medicine remains to be determined.

Abstract Aims Graft dysfunction (GD) after heart transplantation (HTx) can develop without evidence of cell- or antibody-mediated rejection. Cardiac magnetic resonance imaging (CMR) has an evolving role in detecting rejection; however, its role in biopsy-negative GD has not been described. This study examines CMR findings, evaluates outcomes based on CMR results, and seeks to identify the possibility of rejection missed through endomyocardial biopsy by using CMR in HTx recipients with biopsy-negative GD. Methods and results HTx recipients with GD [defined as a decrease in left ventricular ejection fraction (LVEF) by &gt;5% and LVEF &lt; 50%] in the absence of rejection by biopsy or allograft vasculopathy and who underwent CMR were included in the study. The primary outcome was a composite of all-cause mortality, re-transplantation, or persistent LVEF &lt; 50%. Overall, 34 HTx recipients developed biopsy-negative GD and underwent CMR. Left ventricular late gadolinium enhancement (LGE) on CMR was observed in 16 patients with two distinct patterns: diffuse epicardial (n = 13) and patchy (n = 3) patterns. Patients with LGE developed GD later after HTx [4 (1.4–6.8) vs. 0.8 (0.3–1.2) years, P &lt; 0.001], were more often symptomatic (88% vs. 56%, P = 0.06), and had greater haemodynamic derangement (pulmonary capillary wedge pressure: 19 ± 7 vs. 13 ± 3 mmHg, P = 0.002) as compared with those without LGE. No significant difference was observed in the primary composite outcome between patients with LGE and those without LGE (50% vs. 38% of patients with events, P = 0.515). During a median follow-up of 3.8 years, mean LVEF improved similarly in the LGE-negative (37–55%) and LGE-positive groups (32–55%) (P = 0.16). Conclusions Biopsy-negative GD occurs with and without LGE when assessed by CMR, indicative of possible rejection/inflammation occurring only in a subset of patients. Irrespective of LGE, LVEF improvement occurs in most GD patients, suggesting that other neurohormonal or immunomodulatory mechanisms may also contribute to GD development.

Introduction: Prior studies have shown 30-35% of patients with an abnormal stress test had non-obstructive coronary artery disease. The characteristics and outcomes of this patient population have not been well studied. We tested the hypothesis that there is a distinct group of individuals who have an exercise-induced cardiomyopathy not related to the presence of obstructive coronary artery disease or pre-existing structural heart disease. Methods: Our cohort included adults 18 years and older who underwent stress echocardiography at the Mayo Clinic. Patients were included if their resting left ventricular ejection fraction (LVEF) was greater than 50% and decreased by more than 5% to under 50% with exercise. We excluded patients who did not have coronary angiography in the 90 days following stress echocardiography and those with prior diagnosis of coronary artery disease or structural/valvular heart disease. Results: A total of 205627 stress echocardiograms were performed between 2003 and 2019, of which 127 patients were analyzed in our cohort. The median age was 68 years, and 76% were female. The median LVEF was 55% at rest and 45% with stress. Left bundle branch block was present in 9% of patients. Median peak systolic blood pressure was 174 mm Hg. Stress electrocardiogram was positive in 14% of patients. Median functional aerobic capacity [interquartile range] as a percentage of age/sex predicted capacity was 101% [73%, 117%]. Conclusion: We describe a cohort of patients with exercise-induced left ventricular systolic dysfunction not explained by obstructive coronary artery disease or structural heart disease. Forthcoming analyses of long term outcomes will be important to understand how these patients compare to patients without exercise-induced cardiac dysfunction.

Antiplatelet agents are the standard of practice in the management of atherosclerosis and acute coronary syndrome. In contrast to the available antiplatelet agents, vorapaxar represents a novel mechanism of action. It is an antagonist of the platelet protease-activated receptor-1 and inhibits thrombin-induced and thrombin receptor agonist peptide-induced platelet aggregation. The Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50 (TRA 2°P-TIMI 50) trial led to the approval of vorapaxar by the Food and Drug Administration and European Medicines Agency for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or peripheral arterial disease. TRA 2°P-TIMI 50 trial showed that the use of vorapaxar (2.5 mg once/daily) in addition to standard dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor was effective in the secondary prevention of recurrent thrombotic events among patients with previous atherothrombosis, particularly in patients with prior MI; at the expense of an increase in major bleeding. Another recently published Vorapaxar Therapy in Patients With Prior Myocardial Infarction Treated With Newer Generation P2Y12 Receptor Inhibitors Prasugrel and Ticagrelor (VORA-PRATIC) study showed that among post-MI patients treated with potent P2Y12 inhibitors (prasugrel or ticagrelor), vorapaxar reduced platelet-driven global thrombogenicity, an effect that persisted, albeit attenuated, in the absence of aspirin. The current review summarizes an up-to-date literature on pharmacokinetics, pharmacodynamics, and clinical efficacy of vorapaxar and proposes future directions of research.