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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.

Lipid-independent effects of statins. Today, there is growing evidence that 3-hydroxy-3-methylglutaryl(HMG) CoA reductase inhibitors or statins are not only potent plasma lipid-lowering drugs, but also exert various effects upon the cardiovascular system which are independent of their impact on plasma lipid levels. Moreover, it has become clear that many of these so-called pleiotropic effects (e.g. anti-oxidant, anti-inflammatory, anti-proliferative, anti-thrombotic, and endothelial-protective) are unrelated to the statinmediated lowering of intracellular cholesterol. Because most of these nonlipid effects of statins have been demonstrated in vitro or in animal models, they cannot be directly translated to the situation in humans. Thus, the clinical relevance of the variety of lipid-independent effects of these compounds is still unclear. However, several recently published articles demonstrated the existence of such lipid-independent statin effects in humans. This article, by reviewing the current literature about the presence of nonlipid effects of statins in humans, tries to determine how relevant these properties are in clinical practice. Furthermore, the current evidence regarding possible new indications for this interesting class of drugs is discussed. Viele dieser in letzter Zeit nachgewiesenen sogenannten pleiotropen Effekte (z.B. antioxidative, antiinflammatorische, antiproliferative und antithrombotische Wirkungen sowie Verbesserung der Endothelfunktion) scheinen unabhiingig vom Einfluss der Statine auf die zelluliire Cholesterin-Synthese zu sein. Aufgrund der Tatsache, dass diese lipidunabhiingigen Effekte mehrheitlich in vitro bzw. in Tiermodellen nachgewiesen wurden, stellt sichjedoch die Frage nach der klinischen Relevanz dieser Eigenschaften. Einige in letzter Zeit publizierte Studien haben aber gezeigt, dass zumindest gewisse der experimentell nachgewiesenen lipidunabhiingigen Effekte auch beim Menschen vorhanden sind. Die vorliegende Ubersichtsarbeit versucht anhand der derzeit vorliegenden Resultate klinischer Studien die Frage zu beantworten, wie relevant lipidunabhiingige Statin-Effekte im klinischen Alltag sind und ob bereits genug Evidenz vorhanden ist, um die Indikationsstellung for Sta tine uber die Therapie der Hyperlipidiimie hinaus auszuweiten. . Today, there is growing evidence that 3-hydroxy-3-methylglutaryl(HMG) CoA reductase inhibitors or statins are not only potent plasma lipid-lowering drugs, but also exert various effects upon the cardiovascular system which are independent of their impact on plasma lipid levels. Moreover, it has become clear that many of these so-called pleiotropic effects (e.g. anti-oxidant, anti-inflammatory, anti-proliferative, anti-thrombotic, and endothelial-protective) are unrelated to the statinmediated lowering of intracellular cholesterol. Because most of these nonlipid effects of statins have been demonstrated in vitro or in animal models, they cannot be directly translated to the situation in humans. Thus, the clinical relevance of the variety of lipid-independent effects of these compounds is still unclear. However, several recently published articles demonstrated the existence of such lipid-independent statin effects in humans. This article, by reviewing the current literature about the presence of nonlipid effects of statins in humans, tries to determine how relevant these properties are in clinical practice. Furthermore, the current evidence regarding possible new indications for this interesting class of drugs is discussed. Viele dieser in letzter Zeit nachgewiesenen sogenannten pleiotropen Effekte (z.B. antioxidative, antiinflammatorische, antiproliferative und antithrombotische Wirkungen sowie Verbesserung der Endothelfunktion) scheinen unabhiingig vom Einfluss der Statine auf die zelluliire Cholesterin-Synthese zu sein. Aufgrund der Tatsache, dass diese lipidunabhiingigen Effekte mehrheitlich in vitro bzw. in Tiermodellen nachgewiesen wurden, stellt sichjedoch die Frage nach der klinischen Relevanz dieser Eigenschaften. Einige in letzter Zeit publizierte Studien haben aber gezeigt, dass zumindest gewisse der experimentell nachgewiesenen lipidunabhiingigen Effekte auch beim Menschen vorhanden sind. Die vorliegende Ubersichtsarbeit versucht anhand der derzeit vorliegenden Resultate klinischer Studien die Frage zu beantworten, wie relevant lipidunabhiingige Statin-Effekte im klinischen Alltag sind und ob bereits genug Evidenz vorhanden ist, um die Indikationsstellung for Sta tine uber die Therapie der Hyperlipidiimie hinaus auszuweiten.

Introduction: Co-stimulatory proteins are master regulators of the immune system. We identified the co-stimulatory CD40-CD40L dyad as a key driver of inflammation during atherosclerosis and have shown that CD40 and CD40L exert cell-type divergent functions. Hypothesis: CD40 is abundantly expressed on endothelial cells (EC) undergoing endothelial mesenchymal transition (EndMT). We hypothesize that EC CD40 drives atherosclerosis via EndMT. Methods: We analyzed scRNAseq data from human carotid plaques, performed multiplex IHC, and used human aortic endothelial cells (HAECs) for in vitro studies. A tamoxifen-inducible EC specific CD40 deficient atherosclerotic mouse model (cadherin5 (cdh5)ERT2-CD40 flfl -ApoE -/- ) was generated. Results: Besides its presence on immune cells, CD40 is expressed on endothelial cells in both human and mouse atherosclerotic plaques. Analysis of scRNAseq data of human carotid atherosclerotic plaques showed that CD40 is highly expressed in COL1A2/FN1 expressing endothelial cells (ECs), a subset undergoing EndMT. Multiplex staining revealed that CD40 colocalized with the EndMT markers αSMA, NOTCH3, TWIST and VCAM1 in human plaques. In vitro , stimulation of human arterial endothelial cells (HAECs) with CD40L resulted in an increase in the EndMT markers markers fibronectin, vimentin, sm22α, FSP1 and snail. Using phosphoproteomics, CD40L was found to decrease phosphorylation of the junctional integrity proteins CTNNA1 [S652; S655] and ARHGAP21 [S1383]. To investigate the endothelial-specific effects of CD40 in atherosclerosis, 8-week-old cdh5ERT2-CD40 flfl -ApoE -/- mice and their CD40 flfl -ApoE -/- littermate controls were treated with tamoxifen and fed a high cholesterol diet for 10 wks. Deletion of EC-CD40 resulted in a significant reduction in plaque size. This reduction was accompanied by a shift from fibrous cap atheromas (FCA) towards intimal xanthoma (IX) and pathological intimal thickening (PIT). Flow cytometry analysis of the spleen showed that CD40 deletion in ECs results in a significant decrease in CD8 and CD4 effector T cells. This decrease in CD8 and CD4 effector T cells was accompanied by a diminished activation status, shown by a decrease in CD69 + CD8 + CD62 - CD44 + T cells, CD40L + CD8 + CD62 - CD44 + T cells and CD40L + CD4 + CD62 - CD44 + T cells. These findings demonstrate that endothelial CD40 drives atherosclerosis by inducing EndMT-driven plaque inflammation.

Abstract Aims Social isolation (SI) is associated with a higher risk of cardiovascular disease (CVD). One mechanism linking SI and CVD is accelerated biological ageing, which can be assessed using artificial intelligence-enabled electrocardiography (AI-ECG). We investigated whether longitudinal changes in SI status are associated with changes in biological ageing patterns. Methods and results A retrospective longitudinal cohort study including 17 663 individuals without significant CVD who completed ≥2 Berkman and Syme Social Network Index and had paired ECGs within 1 year of each questionnaire. Longitudinal SI status was defined by comparing baseline and follow-up SI status. Ageing trends were assessed using Δage-gap, defined as the change in the gap between AI-ECG-predicted age and chronological age from baseline to follow-up. Linear regression models predicting Δage-gap and survival analyses with Kaplan–Meier and multivariable Cox regression for all-cause mortality were performed. Persistently connected individuals were older [63.1 (52.1, 70.6) years] and had a higher prevalence of hyperlipidaemia and hypertension, yet demonstrated more favourable ageing trajectories. Similarly, those who became connected showed a non-significant attenuation of accelerated ageing. In multivariable linear regression, being persistently isolated [β = +0.412 years, P &lt; 0.001] or becoming isolated [β = +0.438 years, P = 0.012] was associated with accelerated ageing compared to being persistently connected. In survival analyses, becoming isolated (aHR = 1.94, 95% CI = 1.53–2.46, P &lt; 0.001) and being persistently isolated (aHR = 1.66, 95% CI = 1.40–1.96, P &lt; 0.001) were associated with significantly higher all-cause mortality, independent of chronological age and comorbidities. Conclusion Persistent social connection is associated with slower biological ageing and lower mortality. The effects of SI on ageing and survival appear to be potentially reversible, calling for a prospective study to evaluate interventions aimed at improving both the social and biological burden of SI.

Abstract Background and Aims A simple diagnostic method able to reliably exclude left main (LM) coronary artery disease (CAD) or LMCAD-equivalent would expand implementation of an initial non-invasive strategy in patients with chronic coronary syndrome (CCS). This study assessed the diagnostic utility of an approach using clinical and ECG stress testing (EST) variables in excluding LMCAD/LMCAD-equivalent in CCS patients. Methods In a multicentre case-control study, CCS patients undergoing invasive coronary angiography (CAG) after a maximal EST were evaluated. Cases were patients with angiographic ≥ 50% LM stenosis or ≥70% stenosis of both proximal left anterior descending and proximal circumflex arteries, matched with similar patients without them (controls) in a 1:3 ratio. A risk model developed through logistic regression was internally and externally validated. Results Three hundred and thirty-five cases were matched with 797 controls. The model area under the curve (AUC) was .78. Assuming LMCAD prevalence of 5% and a misclassification cost ratio of 1:100 (ratio of cost of performing CAG in a control to cost of not performing CAG in a case), negative predictive value was 98.2%. Thus, CAG could be safely avoided in 41% of patients, missing one LMCAD/LMCAD-equivalent diagnosis for every 58 CAGs safely spared in patients without them. Conclusions Among CCS patients, LMCAD/LMCAD-equivalent can be excluded with high negative predictive value through a model based on clinical and EST parameters, allowing initial non-invasive management of most patients able to exercise. This approach is potentially useful particularly in communities where access to computed tomography coronary angiography is limited.

Background Coronary flow reserve reflects microvascular function, whereas filling pressure indicates myocardial hemodynamic burden. In angina with nonobstructive coronary arteries, abnormalities in either could contribute to a supply–demand mismatch; however, their combined prognostic significance remains unclear. Methods Patients with angina with nonobstructive coronary arteries who underwent invasive coronary reactivity tests were studied retrospectively. Coronary microvascular dysfunction (CMD) was coronary flow reserve <2.5. An artificial intelligence–enabled ECG marker of elevated filling pressure (AIEFP) was applied as a scalable prognostic marker of myocardial hemodynamic stress. Associations with major adverse cardiovascular events were evaluated using Cox regression and propensity score overlap weighting. Results Among 1957 patients with angina with nonobstructive coronary arteries (median age, 51.8 years; 67.2% women), CMD+ was identified in 26.4% and AIEFP+ in 6.6%. Over 8 years, 204 patients (10.4%) experienced major adverse cardiovascular events. In nested models, both CMD (hazard ratio [HR]=1.42 [95% CI=1.13–1.78]; P =0.002) and AIEFP (HR=2.28 [95% CI=1.67–3.11]; P <0.001) remained associated with major adverse cardiovascular events after adjustment. Adding AIEFP to the base model improved model fitness (Δχ 2 =23.65, P <0.001; ΔAkaike Information Criterion=−21.7) and modestly improved discrimination (ΔHarrell concordance index=0.02, P =0.02). In a 4‐group model, adjusted risks increased in a graded manner. Overlap‐weighted analysis after covariate balance demonstrated distinct temporal risk trajectories: CMD+/AIEFP+ had the highest 1‐year risk (12.7%), and AIEFP+ had the highest cumulative 8‐year risk (57% in CMD− and 51.8% in CMD+). Conclusions CMD and AIEFP provide complementary prognostic information, with AIEFP remaining significantly associated with outcomes after multivariable adjustment. A dual‐axis framework integrating myocardial hemodynamic stress (AIEFP) and microvascular function (coronary flow reserve) may enhance risk stratification and enable identification of clinically distinct angina with nonobstructive coronary arteries phenotypes with divergent trajectories.

Poststenotic dilatation in renal artery stenosis, evaluated at abdominal CT, might be related to stenotic kidney damage and inflammation, particularly to monocyte chemoattractant protein-1 release.

Background Studies have demonstrated an association between endothelial dysfunction and major depressive disorder (MDD). However, the link between coronary endothelial dysfunction (CED) and an incident diagnosis of MDD across sexes is unclear. Methods Patients with nonobstructive coronary artery disease (stenosis <40%) underwent an invasive assessment of CED. Macrovascular CED was defined as a percentage change in coronary diameter in response to acetylcholine of ≤−10% compared with baseline. Microvascular CED was defined as a percentage change in coronary blood flow in response to acetylcholine of ≤−50% compared with baseline. In the period after the index procedure, patients were followed up for developing a diagnosis of MDD, and logistic regression was performed to assess the association between baseline CED and incident MDD. Results In total, 2280 patients underwent invasive testing for CED. A total of 516 patients (23%) underwent an evaluation for MDD at a date after the index procedure (mean±SD age, 53±12 years; 72% women). A total of 160 (31%) were diagnosed with MDD. The percentage change in coronary diameter in response to acetylcholine was lower in those diagnosed with MDD in all patients (−10.8% versus −5.3%; P =0.008), and in men (−19.0% versus −4.8%; P =0.001). In men, a higher proportion of those with macrovascular CED were diagnosed with MDD compared with those not diagnosed with MDD (59% versus 38%; P =0.035). In multivariable analyses, macrovascular CED was associated with MDD in men (odds ratio: 2.99 [95% CI, 1.26–7.45]; P =0.015). Conclusions Macrovascular CED is significantly associated with incident MDD in men with nonobstructive coronary artery disease. Endothelial dysfunction in the coronary arteries could thus be a helpful biomarker to identify patients at risk of MDD.

Background Uncontrolled hypertension is common in chronic kidney disease (CKD) patients. Electro-hydraulic acoustic therapy (eHAT) is a non-invasive treatment that may lower blood pressure (BP), but its safety and efficacy in CKD remain unclear. This study aimed to evaluate eHAT's feasibility and safety in this population. Methods In this single-arm, prospective, single-center proof-of-concept study, CKD patients received six eHAT treatments over three weeks. BP was assessed in-office (attended and unattended) at baseline and at 4-, 12-, 24-, and 48-weeks post-treatment. Ambulatory BP monitoring (ABPM) was performed at baseline, 12, and 48 weeks. The primary endpoint was change in systolic office BP (OBP) from baseline to 12 weeks. Secondary endpoints included additional BP measurements, kidney function, and safety. Results Fifteen patients completed all follow-ups. At 12 weeks, mean systolic OBP decreased by 9.73 mmHg (SD 14.77; p = 0.0032) and remained significantly lower at 24 weeks (−7.67 mmHg; p = 0.0335) and 48 weeks (−19.40 mmHg; p &lt; 0.0001). Diastolic OBP reductions were significant at 12 ( p = 0.0413) and 48 weeks ( p = 0.0022). By 12 weeks, 26% of participants reduced the number or dose of antihypertensive medications. Kidney function remained stable throughout. No safety signals were detected. Conclusion Our study highlights the feasibility and tolerability of eHAT in patients with CKD and HTN. Nonetheless, due to the small sample size and lack of a control group, these findings should be considered preliminary.