Raphael, Claire E.

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 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.

Introduction: Cardiovascular risks following SARS-CoV-2 infection are incompletely defined. We evaluated evolving cardiovascular outcomes across COVID-19 variant eras using a large community-based cohort to inform risk stratification and clinical care. Methods: We conducted a retrospective cohort study of 162,471 adults with COVID-19 between March 2020 and December 2023 using the Rochester Epidemiology Project. Patients were stratified by variant era (Pre-Delta, Delta, and Omicron). Cardiovascular outcomes included major adverse cardiovascular events (MACE: myocardial infarction, stroke, death), ischemic and inflammatory heart disease, thrombotic events, and dysrhythmias. Diagnoses were identified using ICD-10 codes and validated in a subset. Cumulative incidence was estimated using Kaplan-Meier and competing risk models. Cox proportional hazards regression was used to assess differences by era and age. Results: MACE occurred in 4,922 patients, primarily in those ≥80 (2-year incidence: 17%). Event rates peaked within 30 days post-infection, with marked variation by variant. In patients ≥80, 30-day MACE risk was highest in the Pre-Delta (HR 3.85; 95% CI, 3.14–4.71) and Delta (HR 2.72; 95% CI, 2.13–3.47) eras versus Omicron. After 30 days, event rates fell and era differences narrowed. Thrombotic events (n=2,090; 1.4%) decreased across eras. Ischemic and inflammatory heart disease rates were stable. Myocarditis/pericarditis were rare (0.1%) without age trends. Dysrhythmias affected 6,765 patients (2-year incidence: 4.9%) and rose with age (2.0% in <40 vs. 19.9% in ≥80). Within 30 days, risk was higher in the Pre-Delta and Delta eras for age ≥40, especially ≥80 (Delta HR 3.08; 95% CI, 2.08–4.56) and 60–79 (HR 2.23; 95% CI, 1.75–2.85). Among those 40–59, Delta posed the highest risk (HR 2.74; 95% CI, 1.94–3.86 vs. Pre-Delta HR 1.77; 95% CI, 1.26–2.49). No differences were observed in <40. Beyond 30 days, risk converged across variants. Conclusion: Cardiovascular risk after SARS-CoV-2 infection was concentrated in the first 30 days, with attenuation thereafter. While MACE and thrombotic event rates declined over time, early dysrhythmia risk varied by variant and age, especially in older adults. These findings define a time-sensitive, variant-specific risk window and support short-term, risk-stratified post-COVID monitoring. This work informs targeted follow-up protocols by infection era and age, with implications for quality improvement, resource use, and equitable care.

Abstract Aims Type 2 myocardial infarction due to myocardial oxygen supply–demand imbalance is associated with poor outcomes. There are no guidelines to inform care for these patients. The consensus on the assessment and management of type 2 myocardial infarction is gained. Methods and results An international e-Delphi study including experts in type 2 myocardial infarction identified through systematic review was conducted. Participants were asked to describe their approach to (i) definition and diagnosis, (ii) risk stratification, (iii) assessment of coronary artery disease and cardiac function, (iv) specialty management, (v) treatment and secondary prevention, and (vi) communication and rehabilitation. Statements generated in round one were circulated, with consensus defined a priori as ≥70% agreement on a 5-point Likert scale. Where no consensus was reached, statements were amended and recirculated for a final round. The response rate was 56% (38/68), 54% (37/68), and 72% (49/68) in the first, second, and third rounds, respectively. Following the first round, 67 unique statements were generated across six domains. Overall, consensus was achieved on 64% (43/67) of statements. Consensus was achieved for 42% (5/12) of statements on the diagnosis of type 2 myocardial infarction, 75% (3/4) on risk stratification, 50% (9/18) on the assessment of coronary artery disease and cardiac function, 60% (6/10), on specialty management, 100% (9/9) on treatment and secondary prevention, and 79% (11/15) on communication and rehabilitation. Conclusion Consensus was obtained across a number of domains for the assessment and management of patients with type 2 myocardial infarction. However, there was limited agreement amongst experts on the diagnostic criteria, which may benefit from refinement.

Background We tested whether biologic age, as estimated by deficits, functional impairments, or Age‐Gap or their combination, provide improved estimation of cause‐specific death as compared with chronological age. Methods Cardiovascular and noncardiovascular deficits, functional impairments, and Age‐Gap were prospectively collected in 535 patients aged ≥55 years undergoing percutaneous coronary interventions between August 1, 2014, and March 31, 2018. Age‐Gap was calculated as the difference between chronological age and age estimated by artificial intelligence ECG using a convolutional neural network. The full biological age model included deficits, functional impairments, and Age‐Gap >2 SD. A multivariable reduced model with the least number of variables was also created to provide a comparable C index to the full model. Results The average chronological age was 72.1±9.5 years, and there were 68% of men. During a median follow‐up of 2.61 years, 124 (23%) patients died. There was a modest correlation between Age‐Gap and biological age ( r =0.28 [95% CI, 0.20–0.35]; P <0.001). When modeled with chronologic age as a covariate, Age‐Gap predicted all‐cause (hazard ratio [HR], 1.07 [95% CI, 1.04–1.10]; P <0.001) and cardiovascular (HR, 1.07 [95% CI, 1.04–1.11]; P <0.001) mortality. As compared with chronological age, the full biological age model noted significant improvement in the prediction of long‐term overall (95% CI, 0.65–0.78), cardiovascular (95% CI, 0.69–0.77), and noncardiovascular (95% CI, 0.55–0.86) mortality. In the reduced models, most prognostic information for noncardiovascular mortality (C index: 0.79) was obtained by subjective difficulty in performing tasks, whereas the deficit‐based estimation predicted cardiovascular mortality (C index: 0.72). Conclusions Estimated biological age from deficits and functional impairments was superior to chronological age in predicting long‐term cause‐specific mortality following percutaneous coronary interventions.

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.

Background: Coronary in-stent restenosis (ISR) secondary to neointimal hyperplasia or neoatherosclerosis remains a significant challenge following percutaneous coronary interventions (PCI), with no consensus on the optimal revascularization strategy. We compared the outcome of PCI for ISR using drug-coated balloons (DCB) and drug-eluting stents (DES) and investigated the time trends in their clinical outcomes. Methods: PubMed, Embase, Scopus, and the Cochrane Library databases were searched through May 2024. We included randomized controlled trials (RCTs) comparing DCB versus DES among patients with coronary ISR. The primary outcome was target lesion revascularization (TLR). Secondary outcomes included all-cause mortality, myocardial infarction (MI), stent thrombosis, and late lumen loss (LLL). Random-effects models were employed to analyze outcomes within 1-year and beyond 1-year intervals. Meta-regression analysis was used to investigate the effect of age, sex, history of diabetes, hypertension, dyslipidemia, smoking, and ejection fraction on all outcomes by applying mixed-effect models. Results: We included 10 RCTs (1034 patients in the DCB group and 943 patients in the DES group). We found similar incidence of 1-year TLR (odds ratio [OR] 1.36; 95% confidence interval [CI] 0.86, 2.14; P 0.194; I 2 43.3%) and >1-year TLR (OR 0.94; 95% CI 0.57, 1.56; P 0.817; I 2 0%) with the use of DCB versus DES. The risks of all-cause mortality, MI, and stent thrombosis were comparable between DCB and DES in 1-year and beyond 1-year follow-ups. At 6-9 months angiographic follow-up, DCB was associated with non-significantly lower LLL compared to DES (standardized mean difference [SMD] -0.12 millimeters; 95% CI -0.29, 0.05; P 0.170; I 2 71.7%). Meta-regression indicated that higher prevalence of diabetes was associated with an increased risk of 1-year revascularization after DCB compared to DES (Estimate 0.07; P 0.003; I 2 0%). Additionally, male sex was associated with an increased LLL in DCB versus DES (Estimate 0.034; P 0.001; I 2 41.8%). No association was found between other baseline characteristics and measured clinical outcomes. Conclusion: DCB demonstrated comparable PCI outcomes compared to DES in patients with coronary ISR.

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). Endothelium-independent CMD has been subclassified into structural and functional groups based on hyperemic microvascular resistance (hMR, mmHg/cm/s). We hypothesized that endothelium-dependent CMD also has these subtypes. Methods: Patients with non-obstructive coronary artery disease who underwent coronary catheterization of the left anterior descending artery were included (n=112). Pressure and flow were recorded at rest, with adenosine, and with acetylcholine. Patients were classified by endothelial type and functional CMD (hMR<2.5) or structural CMD (hMR>2.5). Wave intensity analysis was performed and cumulative separated wave intensity (Joules/m 2 ) was calculated by standard formulae. Three dominant waves were analyzed (forward compression wave, FCW; backward compression wave, BCW; backward expansion wave, BEW). Results: Seventy-four of 109 patients had CMD, of which 59 had endothelium-independent and 38 had endothelium-dependent CMD (23 had both). Functional and structural subgroups were identified (Figure 1). All CMD subtypes had significantly different wave intensities at rest, adenosine, and acetylcholine (p<0.05). Comparing subtypes, there was no difference in wave intensities at rest. However, wave intensities significantly differed between all CMD subtypes with adenosine and acetylcholine, with higher energy waves in the endothelium-independent and functional groups (p<0.05, Figure 2). Conclusions: CMD is a heterogenous condition with distinct subtypes. Functional and structural groups exist in both endothelium-dependent and endothelium-independent CMD. These subgroups have distinct hemodynamic profiles as measured by wave intensity. A patient-specific approach to first line medical therapy may be improved by subgroup classification.

Abstract Background Six percent of patients presenting with acute myocardial infarction (MI) have MI with non-obstructed coronary artery disease (MINOCA). Coronary microvascular disease (CMD) is common in angina with non-obstructive coronary artery disease (ANOCA), but its prevalence and severity in MINOCA is undefined. Purpose Patients with CMD may have elevated risk of myocardial infarction despite no significant stenosis. We tested the hypothesis that patients with MINOCA have more significant burden of CMD than patients with ANOCA. Methods A retrospective case-control study was performed on patients who underwent invasive testing for signs of coronary ischemia and found to have non-obstructive disease (stenoses&lt; 50%). Cases of MI were classified as MINOCA (n=87) and compared to patients with ANOCA (n=552). Patients with spontaneous coronary artery dissection, myocarditis, Takotsubo cardiomyopathy or prior atherothrombotic MI were excluded. Coronary catheterization was performed followed by invasive provocation testing with adenosine and acetylcholine using a Doppler flow wire. CMD was subdivided into endothelium-independent, defined as coronary flow reserve (CFR) &lt; 2.5 with intra-coronary adenosine, and endothelium dependent, defined as &lt; 50% increase in coronary blood flow with acetylcholine. Epicardial vasoconstriction &gt; 90% with typical anginal symptoms was classified as epicardial vasospasm. Results There was no difference in age, sex or traditional coronary risk factors between the MINOCA and ANOCA groups (Table 1). Fifty (57%) of patients with MINOCA had type 2 MI secondary to supply-demand mismatch. Both MINOCA and suspected ANOCA patients had a high prevalence of CMD (71% vs 67%) and endothelium-independent CMD is more prevalent in MINOCA (64.5% vs 50.4%). Although odds of endothelium-dependent CMD were similar, the CFR within this group and CMD overall was worse in MINOCA patients (Figure 1). There was no difference in epicardial spasm. Conclusion Coronary microvascular disease and vasomotor dysfunction are common in patients with MINOCA, with a higher prevalence of endothelium-independent CMD and more severe CMD overall compared to patients with ANOCA. Treatment of CMD in patients with MINOCA may help reduce recurrence and warrants further investigation.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression. METHODS: We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16 691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree. RESULTS: Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42–4.96]; P <0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93–2.28]; P =0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M 1 : 0.86–0.88). CONCLUSIONS: We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.