Prasad, Megha

Abstract Background Patients with ischemia and nonobstructive coronary arteries (INOCA) suffer from a broad range of anginal symptoms that may differ depending on the biologic sex of the patient, the underlying coronary vasomotor disorder, or the type of presentation. Purpose We sought to characterize the symptom description and angina classification of patients referred for invasive coronary function testing (CFT) in the DISCOVER INOCA multicenter registry, stratified by type of presentation (stable vs unstable), biologic sex, and underlying diagnosis, including coronary microvascular dysfunction (CMD), vasospastic angina (VSA), or other disorders such as symptomatic myocardial bridging. Methods DISCOVER INOCA is a prospective, multicenter registry in the United States that includes patients who are referred for clinically indicated coronary angiography and found to have INOCA. All patients underwent protocol-guided angiography, acetylcholine provocation, coronary thermodilution, and intravascular imaging. Symptom characteristics were compared between groups. Results From September 2022 until February 2024, 104 patients were enrolled, 78% were female, and mean age was 57 ± 11 years. The post-procedure diagnosis was CMD in 19%, VSA in 41%, a mixed syndrome in 15%, or other diagnosis in 26%. The average coronary flow reserve (CFR) was 2.9 ± 1.1 in the CMD group and 5.3 ± 3.0 in the VSA group, (p < 0.001). 53% of patients presented with stable angina and 47% with unstable or progressive symptoms. Symptoms included chest pain (89%), chest tightness (42%), chest pressure (39%), shortness of breath (53%), and fatigue (16%), and no significant differences were reported when stratified by diagnostic phenotype. Female patients were more likely to report arm/neck/back/jaw pain (25% vs 5% in men, p = 0.038). Symptom triggers included exertion/activity in 73%, emotional stress in 12%, and resting symptoms in 58%. In female patients 4% reported catamenial symptoms. Of patients with stable angina, the Canadian Cardiovascular Society (CCS) Angina Classification was Grade I in 25%, Grade II in 52%, Grade III in 21%, and Grade IV in 2%. In patients with unstable angina, the Braunwald Angina Classification was Class I in 9%, Class II in 73%, and Class III in 18%. Conclusions Patients with INOCA referred for clinically indicated coronary angiography and CFT were predominantly female and most commonly reported chest pain as a presenting symptom. Female patients were more likely to report arm/neck/back/jaw pain than male patients. Over half of patients reported resting symptoms with no differences between the diagnostic phenotypes (CMD, VSA, or other). The CCS and Braunwald angina classification indicated that most patients had moderate intensity symptoms. Patient-reported outcome measures will be used to systematically categorize the symptom burden in these patients.

Background: Treatment options for refractory angina not amenable to revascularization are limited. Extracorporeal shockwave myocardial revascularization (ESMR) is a novel non-invasive application of low intensity shock waves that stimulates angiogenesis to improve ischemia. We aimed to determine the safety and efficacy of ESMR in patients with refractory angina. Methods: A single-arm multicenter U.S. prospective trial was implemented to assess safety and efficacy of ESMR therapy in patients with Class III/Class IV refractory angina. Each patient received 9 sessions of ESMR to ischemic areas over 9 weeks. Efficacy was assessed at baseline and 4 months after treatment by maximal treadmill exercise time and ischemic burden on pharmacological single photon emission computed tomography (SPECT). Safety was assessed by incidence of adverse events, electrocardiography, echocardiography, laboratory markers, and pain questionnaires. Results: Fifteen patients with medically refractory angina were enrolled. Exercise treadmill time from baseline to last follow-up after ESMR increased significantly (38%) by 122.3±156.9 seconds (319.8±157.2 vs. 422.1±183.3 seconds, p=0.016) (Figure 1). There was no difference in the mean summed stress score (SSS) on pharmacological-SPECT 4 months after treatment vs. baseline (17.8±14.9 vs. 21.2±15.3, p=0.233). However, SPECT SSS revealed that untreated areas had greater progression in ischemic burden vs. treated areas (3.69±6.2 vs. 0.31±4.5, p=0.038). There was no significant change in the mean summed echo score from baseline to post treatment (0.4±5.1, p=0.79).There were no changes in electrocardiography, echocardiographic parameters, or laboratory markers. No serious adverse events or complications occurred, and pain with ESMR was minimal (score of 0.5±1.2 to 1.1±1.2 out of 10). Conclusions: We find that ESMR is a safe and efficacious treatment which may be clinically feasible for patients with refractory angina pectoris.

Background Although endothelial function is a marker for cardiovascular risk, endothelial dysfunction assessment is not routinely used in daily clinical practice. A growing challenge has emerged in identifying patients prone to cardiovascular events. We aim to investigate whether abnormal endothelial function may be associated with adverse 5-year outcomes in patients presenting to a chest pain unit (CPU). Methods Following endothelial function testing using EndoPAT 2000 in 300 consecutive patients without a history of coronary artery disease, patients underwent coronary computerized tomographic angiography (CCTA) or single-photon emission computed tomography according to availability. Results Mean 10-year Framingham risk score (FRS) was 6.6 ± 5.9%; mean 10-year atherosclerotic cardiovascular disease (ASCVD) risk was 7.1 ± 7.2%; median reactive hyperemia index (RHI) as a measure of an endothelial function 2.0 and mean was 2.0 ± 0.4. During a 5-year follow-up, the 30 patients who developed major adverse cardiovascular events (MACE), including all-cause mortality, nonfatal myocardial infarction, hospitalization for heart failure or angina pectoris, stroke, coronary artery bypass grafting, and percutaneous coronary interventions, had higher 10-year FRS (9.6 ± 7.8 vs. 6.3 ± 5.6%; P = 0.032), higher 10-year ASCVD risk (10.4 ± 9.2 vs. 6.7 ± 6.9%; P = 0.042), lower baseline RHI (1.6 ± 0.5 vs. 2.1 ± 0.4; P < 0.001) and a greater degree of coronary atherosclerotic lesions (53 vs. 3%, P < 0.001) on CCTA compared with patients without MACE. Multivariate analysis demonstrated that RHI below the median was an independent predictor of 5-year MACE (odds ratio 5.567, 95% confidence interval 1.955–15.853; P = 0.001). Conclusion Our findings suggest that noninvasive endothelial function testing may contribute to clinical efficacy in triaging patients in the CPU and in predicting 5-year MACE. Clinical Trials.gov Identifier NCT01618123

Background: Uric acid (UA) concentration within carotid plaque and its association with cerebrovascular events have not been detected or quantified. Systemically, serum UA is a marker of inflammation and risk factor for atherosclerosis. However, its association with carotid plaque instability and stroke pathogenesis remains unclear. In patients undergoing carotid endarterectomy, we aimed to determine whether UA is present differentially in symptomatic versus asymptomatic carotid plaques and whether serum UA is associated with cerebrovascular symptoms (stroke, transient ischemic attack, or amaurosis fugax). Methods: Carotid atherosclerotic plaques were collected during carotid endarterectomy. The presence of UA was assessed using Gomori methenamine silver staining as well as anti-UA immunohistochemical staining and its quantity measured using an enzymatic colorimetric assay. Clinical information was obtained through a retrospective review of data. Results: UA was more commonly detected in symptomatic (n=23) compared with asymptomatic (n=9) carotid plaques by Gomori methenamine silver (20 [86.9%] versus 2 [22.2%]; P =0.001) and anti-UA immunohistochemistry (16 [69.5%] versus 1 [11.1%]; P =0.004). UA concentration was higher in symptomatic rather than asymptomatic plaques (25.1 [9.5] versus 17.9 [3.8] µg/g; P =0.021). Before carotid endarterectomy, serum UA levels were higher in symptomatic (n=341) compared with asymptomatic (n=146) patients (5.9 [interquartile range, 4.6–6.9] mg/dL versus 5.2 [interquartile range, 4.6–6.2] mg/dL; P =0.009). Conclusions: The current study supports a potential role of UA as a potential tissue participant and a systemic biomarker in the pathogenesis of carotid atherosclerosis. UA may provide a mechanistic explanation for plaque instability and subsequent ischemic cerebrovascular events.

Background: Coronary endothelial dysfunction(CED) may reflect loss of vascular integrity and permeability. We aimed to test the hypothesis that CED may be associated with increased risk of bleeding events. Methods: Coronary vascular reactivity was evaluated in 444 patients with non-obstructive coronary arteries by administration of intracoronary acetylcholine during angiography. CED was defined as a ≤ 50% increase in coronary blood flow (CBF) from baseline in response to maximal dose of acetylcholine. After a median follow-up of 7 years, patients were assessed for the occurrence of any significant bleeding events. Results: Of 444 patients, 70.7% (314) were female. Average age was 52.3 years. Of 252 patients with CED, 7.9% (20) developed bleeding events compared to 2.1% (4 of 192) without CED (p=0.004). Patients who developed bleeding events had a lower percent change in CBF vs. those who did not median: (IQR) 14.1 (-28.1, 98.7) vs. 40.0 (-11.0, 103.5); p=0.03 (Figure 1). CED was significantly associated with the development of bleeding in univariate analysis(p=0.004, relative risk: 3.81 CI, 1.32, 10.96). In multivariate analysis CED was an independent predictor of development of bleeding (p=0.01) Conclusions: CED is associated with increased risk of bleeding events. This can be explained by the altered vascular function that is inherent to CED. This study underscores the systemic involvement of the endothelium in vascular disease, and the concept of the ‘vulnerable patient’.

Background A growing body of evidence links coronary artery atherosclerosis and calcification to osteoporosis in women. Coronary endothelial dysfunction (CED) is associated with adverse cardiovascular events. We aimed to study the association of CED and development of osteoporosis. Methods Coronary vascular reactivity was evaluated in 225 women, greater than age 50, with non-obstructive coronary arteries, by administration of intracoronary acetylcholine during diagnostic angiography. CED was defined as <50% increase in coronary blood flow (CBF) from baseline in response to maximal dose. After a median follow-up of 7 years, patients were assessed by a questionnaire for development of osteoporosis. Results The average age of the cohort was 60 years. Of 225 women, 60% (135) had CED. 18.2% (41 of 225 women) developed osteoporosis during follow-up. Women with CED were twice more likely to develop osteoporosis vs. women without CED (23% vs. 11.1%, p=0.024). Women who developed osteoporosis compared to those who did not had a markedly lower response (% change) in CBF: median (IQR)-4.3 (-28.3, 51.7) vs. 39.9 (-8.2, 106.0), p=0.007. In univariate analysis, CED was significantly associated with development of osteoporosis (p=0.024, relative risk 2.07, 95% CI: 1.07, 4.00). Multivariate analysis indicated CED as an independent predictor of osteoporosis (p=0.04). Discussion Endothelial dysfunction may account for or share similar mechanisms with development of osteoporosis in cardiac patients.

Introduction: Uric acid (UA) level within carotid plaque specimens and its association with cerebrovascular events has not been detected or quantified. Systemically, serum uric acid (SUA) is a marker of inflammation and risk factor for atherosclerosis. However, its association with carotid plaque instability and subsequent cerebrovascular events remains unclear. Hypothesis: We hypothesized that UA may play a role in carotid artery atherosclerosis and stroke pathogenesis. In patients undergoing carotid endarterectomy (CEA), we aimed to determine whether UA is present differentially in carotid plaques of symptomatic versus asymptomatic patients and whether SUA is associated with cerebrovascular symptoms before surgery and major adverse cardiovascular events (MACE) in the follow-up to CEA. Methods: We prospectively collected 32 carotid plaques during CEA. We qualitatively assessed the presence of UA by using Gomori methenamine silver (GMS) staining and immunohistochemistry with anti-UA antibodies. We extracted and measured the quantity of UA in carotid plaques by using an enzymatic colorimetric assay. A retrospective analysis of a clinical database of 534 consecutive patients who underwent CEA was performed. We defined as symptomatic those patients with history of stroke, TIA and amaurosis fugax. Results: UA positive staining was detected in higher number of carotid plaques from symptomatic compared to asymptomatic patients on both staining, GMS [20 (86.9%) vs 2 (22.2%); p=0.001] and immunohistochemistry anti-UA [16 (69.5%) vs 1 (11.1%); p=0.004]. Moreover, we found a significantly higher concentration of UA in carotid plaque from symptomatic compared to asymptomatic patients [25.1 (9.5) μg/g vs 17.9 (3.8) μg/g; p=0.021]. SUA level in patients prior to CEA was significantly higher in the symptomatic compared to the asymptomatic group [6.0 (4.8-7.1) mg/dL vs 5.2 (4.4-6.3) mg/dL; p<0.001] and it was significantly higher in patients who developed MACE after CEA versus those that did not [6.0 (4.8-7.1) mg/dL vs 5.4 (4.5-6.6) mg/dL; p=0.021]. Conclusions: UA may provide a mechanistic explanation as systemic biomarker and potential tissue contributor for carotid plaque instability and subsequent cerebrovascular and cardiovascular symptoms.

Background: Metabolic syndrome has been associated with increased risk of cardiovascular disease.We aimed to determine the effectiveness of a community-based screening program in identifying cardiovascular risk factors in a healthy young South Asian population. Methods: Between 2006 and 2011, 3,314 patients of all ages were recruited as a part of a prospective cohort study investigating cardiovascular risk in South Asians. We analyzed 1537 patients between the ages of 18 and 40. Demographic and baseline characteristics including baseline laboratory markers and blood pressures were obtained at initial visit. Results: The total cohort of 1537 patients was 66.5% male, and the mean age was 35±5 years. Among participants who denied a history of hypercholesterolemia, 62% had elevated LDL-C (>100 mg/dL), and 8% had markedly elevated LDL-C (>160 mg/dL). Overall, diabetes was present in 4%, hypertension was present in 12% and hyperlipidemia was present in 46%. Low HDL-C (50% of men, 52% of women) and elevated triglycerides (44% of men, 18% of women) were the most prevalent components of metabolic syndrome. Metabolic syndrome was present in 14% of men and 8% of women and one-third (30%) of men and one-fifth (19%) of women had at least two component risk factors. Discussion: This is the largest study to date assessing effectiveness of a community based screening program aiming to identify cardiovascular risk in young South Asians. We note significant modifiable risk at a young age. Such community based interventions can be effective at detecting and managing risk factors early in this vulnerable population.