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BACKGROUND: Myocardial infarction with nonobstructive coronary arteries (MINOCAs) and angina with nonobstructive coronary arteries (ANOCAs) present diagnostic and therapeutic challenges. We assessed the frequency of coronary microvascular disease (CMD) and its subtypes in MINOCA compared with ANOCA and evaluated long-term cardiovascular outcomes. METHODS: Patients with nonobstructive coronary arteries undergoing invasive coronary function testing from 2012 to 2022 were prospectively enrolled and retrospectively classified as MINOCA or ANOCA (reference group). Myocardial infarction due to atherothrombosis, myocarditis, and Takotsubo syndrome were excluded. Invasive provocation testing was performed. CMD was classified as endothelium-independent (coronary flow reserve <2.5 with adenosine) and endothelium-dependent (<50% increase in coronary blood flow with acetylcholine). Major adverse cardiovascular events (cardiac death, nonfatal myocardial infarction, heart failure hospitalization, urgent revascularization, stroke) were recorded over 8 years. RESULTS: Of 622 patients, 73 (12%) had MINOCA (69% female, median age 56 years) and 549 (88%) ANOCA (72% female, median age 53 years). CMD was common in both groups (71% versus 64%; P =0.271), while endothelium-independent CMD was more frequent in MINOCA (41% versus 21%; P <0.001). Over a median follow-up of 4.5 years, major adverse cardiovascular events occurred more often in MINOCA (40% versus 11%; adjusted hazard ratio, 2.4; P =0.001). CMD predicted higher major adverse cardiovascular events in both MINOCA (hazard ratio, 3.6 [95% CI, 1.1–12.0]; P =0.038) and ANOCA (hazard ratio, 7.9 [95% CI, 2.9–21.8]; P <0.001). CONCLUSIONS: CMD is common in both MINOCA and ANOCA. The higher prevalence of endothelium-independent CMD in MINOCA suggests a potential mechanistic role in infarction. Patients with MINOCA have a worse prognosis than ANOCA, particularly when CMD is present.

Background: Coronary microvascular dysfunction (CMD) is a common cause of angina with non-obstructive coronary arteries (ANOCA), but its role in patients with a history of myocardial infarction with non-obstructive coronary arteries (MINOCA) is much less understood. We investigated the incidence of major adverse cardiac and cerebrovascular events (MACCE) in patients undergoing invasive assessment for CMD, divided into patients with MINOCA versus patients with ANOCA. We hypothesized that CMD would be common in both groups. Methods: Serial patients undergoing invasive coronary provocation testing between 2012 and 2022 were divided into MINOCA (n=76) or ANOCA (n=561). Doppler study was performed in the left anterior descending artery. CMD was defined as either coronary flow reserve (CFR) <2.5 with adenosine or <50% increase in flow with acetylcholine. Patients were followed prospectively through 2025. Incidence of MACCE (cardiac death, non-fatal MI, hospitalization for heart failure, urgent revascularization, and stroke) was compared between MINOCA and ANOCA and further analyzed by CMD status. Kaplan-Meier curves were constructed and Cox proportional hazards models were used to estimate hazard ratios (HRs). Results: Among patients with MINOCA, 53 of 76 (70%) had CMD, compared to 363 of 561 (65%) with ANOCA. Invasive provocation testing was performed a median of 163 days (IQR 13 – 255 days) after the MI in the MINOCA group. Patients were then followed for a median of 4.4 years (IQR 3.0 – 6.9 years). MACCE-free survival was significantly lower in patients with MINOCA compared to those with ANOCA (HR = 3.57, p < 0.001; Figure 1). The major contributor to MACCE was non-fatal MI in MINOCA (24%) and heart failure hospitalization in ANOCA (6%). The presence of CMD was associated with worse prognosis in both MINOCA (HR = 3.76, p = 0.02) and ANOCA (HR = 8.35, p < 0.001; Figure 2). Conclusions: Patients with MINOCA experience significantly higher long-term risk of major adverse events compared to those with ANOCA. CMD is common in both groups and is independently associated with worse outcomes. Specifically, patients with CMD had higher rates of MACCE over time, regardless of whether they presented with MINOCA or ANOCA. Invasive assessment of CMD in patients with myocardial infarction and non-obstructive coronary arteries may improve risk stratification and inform management strategies in these understudied populations

Background: Coronary microvascular disease (CMD) may be endothelium-independent (coronary flow reserve, CFR < 2.5) or endothelium-dependent (<50% increase in coronary blood flow in response to acetylcholine). CMD has been implicated in abnormal myocardial relaxation and impaired diastolic function. Wave intensity analysis (WIA) is a hemodynamic method that quantifies the energy of pressure-flow waves driving coronary blood flow. The backward expansion wave (BEW) is the dominant distally originating wave, generated by microvascular suction during ventricular relaxation. Thus, the BEW may offer mechanistic insight into the link between CMD and diastolic dysfunction. Hypothesis: We hypothesized that diastolic dysfunction would be more common in patients with CMD, and that the backward expansion wave (BEW) intensity would be lower in those with diastolic dysfunction compared to those without. Methods: Patients with non-obstructive coronary artery disease undergoing invasive coronary physiology assessment of the left anterior descending artery were included (n = 113). Pressure and Doppler flow were recorded at rest, with adenosine, and with acetylcholine for categorization of CMD as endothelium-independent (CMD-Ei) and/or endothelium-dependent (CMD-Ed). Wave intensity analysis was used to calculate cumulative BEW (J×m -2 ) at rest in CMD, CMD-Ei (endothelium-independent), and CMD-Ed (endothelium-dependent) subgroups. Diastolic dysfunction was diagnosed by transthoracic echocardiogram using the 2016 American Society of Echocardiography (ASE) guidelines. Results: Of the 113 study patients, 88 (77.9%) had CMD and 25 (22.1%) did not. Among those with CMD, 39 patients (44.3%) had diastolic dysfunction (Figure 1). In the patients with CMD, the BEW intensity was significantly lower in patients with diastolic dysfunction compared to those without (6.5 vs. 9.0 × 10 3 W×m -2 ×s -1 , p < 0.05). The same trend was observed for the CMD-Ei (7.2 vs. 9.7 × 10 3 W×m -2 ×s -1 , p < 0.05) and CMD-Ed (6.2 vs. 9.1 × 10 3 W×m -2 ×s -1 , p < 0.05) subtypes. Conclusions: Diastolic dysfunction is frequent in patients with invasively diagnosed CMD. Patients with CMD who have diastolic dysfunction have comparatively lower BEW intensity, regardless of endothelial subtype. Since the BEW is the major driver of coronary flow during diastole, this suggests a mechanism by which CMD may lead to diastolic dysfunction.

Background: Coronary wave intensity analysis (WIA) provides a mechanistic view of coronary hemodynamics and has been increasingly used to phenotype coronary microvascular disease (CMD). Standard WIA requires simultaneous pressure and flow measurements within the same vessel, but intra-coronary pressure measurement may be limited by hardware availability. In patients with non-obstructive coronary arteries, aortic pressure may serve as a surrogate for intra-coronary pressure to enable broader feasibility of WIA. We aimed to determine whether wave profiles derived from intra-aortic and intra-coronary pressure measurements are comparable when paired with intracoronary Doppler flow in patients with non-obstructive coronary artery disease. Methods: Patients undergoing invasive coronary physiology assessment of the left anterior descending artery were included. Intracoronary flow velocity and intra-coronary pressure were simultaneously recorded using a ComboWire (Philips Volcano) in the proximal LAD. Aortic pressure was concurrently measured via the guide catheter to allow comparison of pressure sources. In the intra-aortic pressure group, pressure and flow data were aligned using the R wave of the ECG trace. WIA was performed using conventional methods to quantify the dominant waves: forward compression wave (FCW), backward compression wave (BCW), and backward expansion wave (BEW). Agreement between wave intensity was assessed using Bland-Altman analysis and Pearson correlation. Results: A total of 14 paired waveforms were analyzed with a total of 42 coronary waves compared. Wave intensities calculated using intra-coronary versus intra-aortic pressure showed excellent agreement across all wave types. Mean bias between methods was −0.07 x 10 3 W×m -2 ×s -1 with limits of agreement from −0.63 to +0.49. The correlation between intra-coronary and intra-aortic wave intensities was strong (r = 0.997, p < 0.001), with minimal dispersion and consistent agreement across the full range of wave intensities ( Figure 1 ). Conclusions: In patients with non-obstructive coronary arteries, wave intensity analysis using guide-catheter aortic pressure yields results nearly identical to those obtained with intra-coronary pressure. These findings support the use of aortic pressure as a reliable surrogate for intra-coronary pressure in WIA for the calculation of microvascular coronary hemodynamics, reducing technical barriers and enabling broader clinical and research utilization.

Background: Angina with no obstructive coronary arteries (ANOCA) is clinically challenging to diagnose and manage. The agreement between Doppler-derived coronary flow reserve (CFR Doppl ) and PET-derived CFR (CFR PET ) in patients with ANOCA remains unclear. Aims: To evaluate the correlation between Doppler- and PET-derived CFR in patients with ANOCA. Methods: We conducted a single-center, retrospective study of adult patients (age ≥18 years) with ANOCA who were referred for evaluation of possible microvascular ischemia with Doppler- and PET-derived CFR at the Mayo Clinic (Rochester, MN) between January 1, 2018, and May 1, 2024. Pearson correlation was used to quantify the association between Doppler- and PET-derived CFR. Agreement between Doppler- and PET-derived CFR was assessed by Bland-Altman analysis using a 2-way mixed effects model with measures of absolute agreement. Results: A total of 66 patients were initially identified, of which 40 were included in the final analysis (66.7% female, median age 58 years [Q1-Q3: 45-66 years]). Median time between PET- and Doppler-derived CFR was 8 days (Q1-Q3: 1-31 days). Median CFR Doppl was 2.75 (IQR: 2.23-3.28) and median CFR PET was 2.50 (IQR: 2.10-3.10). Doppler-derived CFR displayed a wider range than PET-derived CFR (0.8-5.2 vs 1.2-4.0). A strong correlation was found between Doppler- and PET-derived CFR ( r= 0.81; p<0.001). The corresponding Bland-Altman plot showed an overall bias of 0.27±0.56 (intraclass coefficient=0.85; p<0.001). Conclusions: While invasive coronary angiography with CFR Doppl is the gold-standard for the diagnostic evaluation of ANOCA, PET imaging with CFR PET offers an excellent first line non-invasive modality for diagnosis of coronary microvascular dysfunction.

Introduction: Spontaneous coronary artery dissection (SCAD) is a poorly understood cause of acute coronary syndrome (ACS), predominantly affecting young women and frequently related to acute stressors. It has been suggested that stress induced cardiomyopathy can cause dissection via mechanical distortion of the vessel at wall-motion hinge points. Whether specific coronary anatomic configurations also predispose to distortion and hence SCAD remains unknown. Hypothesis: Patients with left anterior descending (LAD) SCAD have a higher frequency of a “wrap around” (type IV - perfuses >25% of the inferior wall) LAD. Methods: Coronary angiograms of patients in the Mayo Clinic SCAD Registry were reviewed. Patients from functional angiogram registry with similar characteristics were used as controls. Patients with an LAD SCAD were compared to patients who never had an LAD SCAD. For identifying predictors of LAD SCAD, patients who never had an LAD SCAD were compared to patients that had an LAD SCAD as a recurrent event, but not as the initial presentation. Results: A total of 456 patients with SCAD (46±6 years; 96% women) were included. The control group consisted of 178 patients (44±7 years, 97% women). Type IV LAD was more common in the SCAD cohort (Figure 1), and patients in the LAD SCAD group had a higher proportion of type IV LAD when compared to non-LAD SCAD (47.6% vs 23.0% p < 0.001). Bifurcation involvement was also more frequent (48.6 vs 25.8%, p <0.001). Individual predictors of an LAD SCAD during follow-up were diagnosis of hypertension, peripartum SCAD, involvement of a bifurcation and type IV LAD. After multivariate analysis, only bifurcation involvement (OR 2.49, p = 0.01) and type IV LAD (OR 2.26, p = 0.02) remained as predictors of LAD SCAD during follow-up. In patients in whom the PDA perfused the apex (LAD I and II), PDA was more likely to be involved by SCAD (OR 6.17, p<0.001). There were no other differences in coronary distribution after stratifying by LAD types. Conclusions: Type IV LAD variant is more common in patients with LAD SCAD. This finding suggests that coronary anatomic variants predispose to SCAD and lend further support to the mechanical distortion hypothesis.

AbstractBackgroundThe clinical relevance of cardiac troponin (cTn) elevation in takotsubo syndrome (TTS) remains uncertain. The present study sought to investigate the role of cardiac troponin (cTn) elevations in mortality prediction of patients with Takotsubo syndrome (TTS).MethodsPatients enrolled in the International Takotsubo (InterTAK) Registry from January 2011 to February 2020 with available data on peak cTn levels were included in the analysis. Peak cTn levels during the index hospitalization were used to define clinically relevant myocardial injury. The threshold at which clinically relevant myocardial injury drives mortality at 1 year was identified using restricted cubic spline analysis.ResultsOut of 2′938 patients, 222 (7.6%) patients died during 1‐year follow‐up. A more than 28.8‐fold increase of cTn above the upper reference limit was identified as threshold for clinically relevant myocardial injury. The presence of clinically relevant myocardial injury was significantly associated with an increased risk of mortality at 5 years (adjusted HR 1.58, 95% CI 1.18–2.12, p =.002). Clinically relevant myocardial injury was related to an increased 5‐year mortality risk in patients with apical TTS (adjusted HR 1.57, 95% CI 1.21–2.03, p =.001), in presence of physical stressors (adjusted HR 1.60, 95% CI 1.22–2.11, p =.001), and in absence of emotional stressors (adjusted HR 1.49, 95% CI, 1.17–1.89, p =.001).ConclusionThis study for the first time determined a troponin threshold for the identification of TTS patients at excess risk of mortality. These findings advance risk stratification in TTS and assist in identifying patients in need for close monitoring and follow‐up.

Abstract Background Physical or emotional stress is the most common cause of Takotsubo cardiomyopathy (TS). The exact mechanism of TS remains unclear, and some possible mechanism include myocardial edema and inflammation, coronary vasospasm, microcirculatory dysfunction, catecholamine surge, and sympathetic overdrive. Recently, and consistent with the availability of coronary spasm provocative studies, data suggests that coronary artery vasospasm (CAVS) plays an essential role in the pathogenesis of TS. However, whether CAVS is a consequence or a primary cause of TS is still unclear. The clinical implications of concomitant TS and CAVS have not been studied. Purpose Describe differences in baseline characteristics, comorbidities, cardiovascular risk factors, in-hospital mortality, and outcomes of patients with TS and documented CAVS. Methods The US National Inpatient Database was queried from 2011 to 2019 for relevant ICD-9 and -10 diagnostic and procedural codes. We identified patients admitted with TS who had a coronary angiogram. We then excluded those who underwent coronary percutaneous coronary intervention (PCI), coronary artery bypass graft (CAGB) or had a diagnosis of myocarditis. We compared baseline characteristics and in-hospital outcomes of patients with TS with vs. without documented CAVS. Results We identified 136,732 patients admitted with TS, of which 1,112 (0.8%) had CAVS. We found that those patients with TS and CAVS were younger and less likely to have hypertension, diabetes, atrial fibrillation, hyperlipidemia, coronary artery disease, peripheral artery disease, chronic kidney disease, chronic obstructive pulmonary disease, a prior cancer diagnosis, and smoking history than those without CAVS. Conversely, they were more likely to be obese, have substance abuse disorder, a history of polycystic ovary syndrome, post-traumatic stress disorder, anxiety, history of migraines, and have had a prior myocardial infarction (MI). Regarding in-hospital outcomes, we did not find a significant difference in mortality between groups. Those with TS and CAVS were more likely to have a cardiac arrest, 2nd-degree AV block, ventricular fibrillation, ventricular tachycardia, and more likely to require ICD placement compared to those patients without CAVS. Conclusions Patients with TS and coronary vasospasm were younger, had fewer cardiovascular risk factors but were more likely to have had a prior MI than those without CAVS. We report no significant difference in mortality between groups. However, those with TS and CAVS were more likely to have hospitalizations complicated by cardiac arrest and significant arrhythmias like ventricular fibrillation, ventricular tachycardia, and 2nd-degree AV Block, which led to a higher need for ICD implantation. This large US nationwide retrospective study can provide hypotheses generating ideas for more extensive prospective studies to determine the frequency and role of CAVS in patients with TS.

Background Coronary microvascular dysfunction (CMD) represents an early functional characteristic of coronary vascular aging. Klotho (α‐klotho) is a circulating protein inversely linked to physiological aging. We examined low klotho as a potential marker for vascular aging in patients with CMD and no coronary artery disease. Methods and Results Patients undergoing nonurgent angiogram for chest pain who had no coronary artery disease underwent invasive coronary microvascular and endothelial function testing. CMD was defined by ≤50% increase in coronary blood flow (percentage change in coronary blood flow) in response to intracoronary acetylcholine or coronary flow reserve ≤2. Fresh arterial whole blood was used to analyze circulating endothelial progenitor cells with flow cytometry. Stored arterial plasma was used for klotho analysis by ELISA. Participants with CMD (n=62) were compared with those without CMD (n=36). Those with CMD were age 55±10 years (versus 51±11 years; P =0.07) and 73% women (versus 81%; P =0.38). Traditional risk factors for coronary artery disease were similar between groups. Patients with CMD had less klotho (0.88±1.50 versus 1.75±2.38 ng/mL; P =0.03), and the odds of low klotho in CMD were significant in a logistic regression model after adjusting for traditional cardiovascular risk factors (odds ratio [OR], 0.80 [95% CI, 0.636–0.996]; P =0.05). Higher klotho was associated with higher numbers of endothelial progenitor cells with vascular regenerative potential (CD34 + and CD34 + CD133 + KDR + ). Among a subgroup of patients with atherosclerotic cardiovascular disease risk <5% (n=58), CMD remained associated with lower klotho (OR, 0.80 [95% CI, 0.636–0.996]; P =0.047). Conclusions Klotho may be a biomarker for CMD and may be a therapeutic target for groups of patients without significant traditional cardiovascular risk.