Age-stratified profiles and outcomes of patients with heart failure with preserved ejection fraction.

AIMS: This study aimed to elucidate age-stratified clinical profiles and outcomes in patients with heart failure (HF) with preserved left ventricular ejection fraction (LVEF) (HFpEF). METHODS AND RESULTS: The Chronic Heart Failure Registry and Analysis in the Tohoku District-2 (CHART-2) Study included 2824 consecutive HFpEF patients with LVEF ≥ 50% (mean age 69.0 ± 12.3 years; 67.7% male) with a median follow-up of 9.8 years. We stratified them into five age groups: ≤54 (N = 349, 12.4%), 55-64 (N = 529, 18.7%), 65-74 (N = 891, 31.6%), 75-84 (N = 853, 30.2%), and ≥85 years (N = 202, 7.2%), and we categorized these age groups into younger (≤64 years) and older (≥65 years) groups. We compared the clinical profiles and outcomes of HFpEF patients across age groups. Younger HFpEF groups exhibited a male predominance, elevated body mass index (BMI), and poorly controlled diabetes (haemoglobin A1c > 7.0%). Older HFpEF groups were more likely to be female with multiple comorbidities, including coronary artery disease, hypertension, renal impairment, and atrial fibrillation. The positive association between elevated BMI and HFpEF was more pronounced with lower classes of age from ≥85 to ≤54 years, especially in males. With higher classes of age from ≤54 to ≥85 years, mortality rates increased, and HF death became proportionally more prevalent (Ptrend < 0.001), whereas sudden cardiac death (SCD) exhibited the opposite trend (Ptrend = 0.002). Poorly controlled diabetes emerged as the only predictor of SCD in the younger groups (adjusted hazard ratio 4.26; 95% confidence interval 1.45-12.5; P = 0.008). Multiple comorbidities were significantly associated with an increased risk of HF-related mortality in the older groups. CONCLUSIONS: Younger HFpEF patients (≤64 years) exhibit a male predominance, elevated BMI, and poorly controlled diabetes, highlighting the importance of glycaemic control in reducing SCD risk. Older HFpEF patients (≥65 years) are more likely to be female, with multiple comorbidities linked to an increased risk of HF-related mortality. These findings underscore the need for physicians to recognize age-related, distinct HFpEF phenotypes for personalized patient management.

Prognostic significance of growth differentiation factor-15 across age in chronic heart failure.

AIMS: Growth differentiation factor-15 (GDF15), a cytokine in the transforming growth factor family, is up-regulated in stress and inflammatory conditions and is elevated in patients with heart failure (HF). However, the age-specific attributes and prognostic significance of GDF15 across age remain unknown in chronic HF (CHF). METHODS AND RESULTS: Serum levels of GDF15 were examined in 942 hypertensive patients (median 68 years) with CHF from the SUPPORT trial across the four age groups [under 50 (n = 73), 51-59 (n = 158), 60-69 (n = 296), and 70-79 years (n = 415)] and in the continuous spectrum. Clinical correlates of GDF15 were explored using the classic stepwise and LASSO (least absolute shrinkage and selection operator) regression approaches. Interaction terms with age were tested in the LASSO regression approach. The associations with the composite outcome of HF hospitalization or all-cause death were investigated across ages. Median GDF15 levels (pg/mL) increased along with aging, from 691 in under 50 years to 855 in 51-59 years, 1114 in 60-69 years, and 1516 in 70-79 years (trend P < 0.001). Age, sex, systolic blood pressure, history of diabetes, ischaemic heart disease, left ventricular (LV) end-systolic dimension, LV ejection fraction, estimated glomerular filtration rate, haemoglobin, N-terminal pro-brain natriuretic peptide (NT-proBNP), troponin, C-reactive protein, and the use of angiotensin-converting enzyme inhibitors, diuretics, and statins were mutually selected as clinical covariates of GDF15. The LASSO regression analysis identified significant interactions between age and the history of diabetes and NT-proBNP, with particularly robust associations in patients aged between 60 and 70 years. During the mean follow-up of 8.6 years, 474 composite endpoints of HF hospitalization or death occurred. GDF15 was associated with a higher risk of HF hospitalization or all-cause death [adjusted hazard ratio 1.84 (95% confidence interval 1.45-2.33)], with a particularly heightened risk in patients aged around 70 years (Pinteraction  = 0.0008). The model with GDF15 on top of other established risk factors yielded marginally higher C-statistics compared with the model without GDF15 (0.803 and 0.796, P = 0.045). The additive value of GDF15 on top of other established risk factors appeared similar across ages. A universal cut-off value of 1400 pg/mL performed well in discriminating between those with and without HF hospitalization or death. CONCLUSIONS: Some clinical correlates of GDF15 have an interaction with age. GDF15 is an important determinant of cardiovascular endpoints, particularly in patients aged around 70 years. The additive value of GDF15 appeared consistent across ages, suggesting the use of a universal cut-off value.

Underuse of heart failure medications and poor long-term prognosis in chronic heart failure patients with polypharmacy - A report from the CHART-2 study.

Background: In patients with chronic heart failure (CHF), comorbidities are often managed with multiple medications, characterized by polypharmacy, leading to increased risk of potentially inappropriate medication and adverse effects. Methods: We studied 4,876 consecutive patients with CHF (Stage C/D, age 69.0 ± 12.3 years) in the CHART-2 study to evaluate the association among polypharmacy, underuse of HF medications, and all-cause death. Polypharmacy was defined as the daily use of ≥ 8 medications for the survival classification and regression tree analysis. Results: The average number of medications was 10 in the polypharmacy group and 5 in the non-polypharmacy group, respectively. Over a median of 8.3 (4.1-11.7) years, the incidence rate of all-cause death was significantly higher in the polypharmacy group (n = 2,108) than in the non-polypharmacy group (57.3 % vs. 40.6 %; adjusted hazard ratio [aHR] 1.34 (95 %CI, 1.22-1.48), P < 0.001), even in age < 55 years (26.6 % vs. 14.3 %; adjusted hazard ratio [aHR] 1.61 (95 %CI, 1.04-2.50), P = 0.033). In patients with polypharmacy, those without renin-angiotensin system inhibitors (RAS-I) and/or beta-blockers (N = 1,023) were associated with increased incidence of all-cause death as compared with those with both medications (aHR 1.18; 95 %CI 1.04-1.35, P = 0.012). Conclusions: Polypharmacy was associated with poor long-term prognosis, even in younger patients with CHF. Among 4,876 patients with CHF, 1023 (20.9%) with polypharmacy and underuse of RAS-I and/or beta-blocker were associated with increased risk of all-cause death.

A Surgical Case of Partially Unroofed Coronary Sinus Atrial Septal Defect in an Elderly Patient Diagnosed by Preoperative Contrast-Enhanced Computed Tomography.

Unroofed coronary sinus syndrome is a rare congenital cardiac anomaly, involving some anatomical variations. Approximately 60% of patients with unroofed coronary sinus syndrome have a concomitant atrial septal defect, which is termed unroofed coronary sinus atrial septal defect (CSASD). The precise detection of these abnormalities has been usually difficult with conventional echocardiography, mostly due to its small and complex structures. Herein, we report a case with unroofed coronary sinus atrial septal defect, in which preoperative contrast-enhanced computed tomography (CT) was useful in the operative decision making. We successfully repaired the defective roof of the coronary sinus with a bovine patch, while eliminating the inter-atrial shunt. The patient's postoperative course was uneventful with no residual shunt.

von Willebrand factor Ristocetin co-factor activity to von Willebrand factor antigen level ratio for diagnosis of acquired von Willebrand syndrome caused by aortic stenosis.

Background: Severe aortic stenosis (AS) causes acquired von Willebrand syndrome by the excessive shear stress-dependent cleavage of high molecular weight multimers of von Willebrand factor (VWF). While the current standard diagnostic method is so-called VWF multimer analysis that is western blotting under nonreducing conditions, it remains unclear whether a ratio of VWF Ristocetin co-factor activity (VWF:RCo) to VWF antigen levels (VWF:Ag) of <0.7, which can be measured with an automated coagulation analyzer in clinical laboratories and is used for the diagnosis of hereditary von Willebrand disease. Objectives: To evaluated whether the VWF:RCo/VWF:Ag is useful for the diagnosis of AS-induced acquired von Willebrand syndrome. Methods: VWF:RCo and VWF:Ag were evaluated with the VWF large multimer index as a reference, which represents the percentage of a patient's VWF high molecular weight multimer ratio to that of standard plasma in the VWF multimer analysis. Results: We analyzed 382 patients with AS having transaortic valve maximal pressure gradients of >30 mmHg, 27 patients with peripheral artery disease, and 46 control patients free of cardiovascular disease with osteoarthritis, diabetes, and so on. We assumed a large multimer index of <80% as loss of VWF large multimers since 59.0% of patients with severe AS had the indices of <80%, while no control patients or patients with peripheral artery disease, except for 2 patients, exhibited the indices of <80%. The VWF:RCo/VWF:Ag ratios, measured using an automated blood coagulation analyzer, were correlated with the indices (rs = 0.470, P < .001). When the ratio of <0.7 was used as a cut-off point, the sensitivity and specificity to VWF large multimer indices of <80% were 0.437 and 0.826, respectively. Conclusion: VWF:RCo/VWF:Ag ratios of <0.7 may indicate loss of VWF large multimers with high specificity, but low sensitivity. VWF:RCo/VWF:Ag ratios in patients with AS having a ratio of <0.7 may be useful for monitoring the loss of VWF large multimers during their clinical courses.

Efficacy and Safety of Warfarin for the Treatment of Venous Thromboembolism　- A Multicenter Prospective Observational Cohort Study in Japan (AKAFUJI Study).

BACKGROUND: A large-scale prospective study of the efficacy and safety of warfarin for the treatment of venous thromboembolism (VTE) has not been conducted in Japan. Therefore, we conducted a real-world prospective multicenter observational cohort study (AKAFUJI Study; UMIN000014132) to investigate the efficacy and safety of warfarin for VTE.Methods and Results: Between May 2014 and March 2017, 352 patients (mean [±SD] age 67.7±14.8 years; 57% female) with acute symptomatic/asymptomatic VTE were enrolled; 284 were treated with warfarin. The cumulative incidence of recurrent symptomatic VTE was higher in patients without warfarin than in those treated with warfarin (8.7 vs. 2.2 per 100 person-years, respectively; P=0.018). The cumulative incidence of bleeding complications was not significantly different between the 2 groups. The mean prothrombin time-international normalized ratio (PT-INR) during warfarin on-treatment was <1.5 in 180 patients, 1.5-2.5 in 97 patients, and >2.5 in 6 patients. The incidence of bleeding complications was significantly higher in patients with PT-INR >2.5, whereas the incidence of recurrent VTE was not significantly different between the 3 PT-INR groups. The cumulative incidence of recurrent VTE and bleeding complications did not differ significantly among those in whom VTE was provoked by a transient risk factor, was unprovoked, or was associated with cancer. CONCLUSIONS: Warfarin therapy with an appropriate PT-INR according to Japanese guidelines is effective without increasing bleeding complications, regardless of patient characteristics.

Alleviated cerebral infarction in male mice lacking all nitric oxide synthase isoforms after middle cerebral artery occlusion.

PURPOSE: The role of the nitric oxide synthases (NOSs) system in cerebral infarction has been examined in pharmacological studies with non-selective NOSs inhibitors. However, due to the non-specificity of the non-selective NOSs inhibitors, its role remains to be fully elucidated. We addressed this issue in mice in which neuronal, inducible, and endothelial NOS isoforms were completely disrupted. METHODS AND RESULTS: We newly generated mice lacking all three NOSs by crossbreeding each single NOS-/- mouse. In the male, cerebral infarct size at 24 h after middle cerebral artery occlusion (MCAO) was significantly smaller in the triple n/i/eNOSs-/- genotype as compared with wild-type genotype. Neurological deficit score and mortality rate were also significantly lower in the triple n/i/eNOSs-/- than in the WT genotype. In contrast, in the female, there was no significant difference in the cerebral infarct size in the two genotypes. In the male triple n/i/eNOSs-/- genotype, orchiectomy significantly increased the cerebral infarct size, and in the orchiectomized male triple n/i/eNOSs-/- genotype, treatment with testosterone significantly reduced it. Cyclopaedic and quantitative comparisons of mRNA expression levels in cerebral infarct lesions between the male wild-type and triple n/i/eNOSs-/- genotypes at 1 h after MCAO revealed significant involvements of decreased oxidative stress and mitigated mitochondrial dysfunction in the alleviated cerebral infarction in the male triple n/i/eNOSs-/- genotype. CONCLUSIONS: These results provide the first evidence that the NOSs system exerts a deleterious effect against acute ischemic brain injury in the male.

Association between Non-Lipid Residual Risk Factors and Cardiovascular Events in Patients with Stable Coronary Artery Disease Treated with Pitavastatin: An Observation from the REAL-CAD Study.

AIMS: We aimed to investigate the association between non-lipid residual risk factors and cardiovascular events in patients with stable coronary artery disease (CAD) who achieved low-density lipoprotein cholesterol (LDL-C) ＜100 mg/dL from the Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study. METHODS: The REAL-CAD study was a prospective, multicenter, open-label trial. As a sub-study, we examined the prognostic impact of non-lipid residual risk factors, including blood pressure, glucose level, and renal function, in patients who achieved LDL-C ＜100 mg/dL at 6 months after pitavastatin therapy. Each risk factor was classified according to severity. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, and unstable angina requiring emergency hospitalization. RESULTS: Among 8,743 patients, the mean age was 68±8.2 years, and the mean LDL-C level was 84.4±18 mg/dL. After adjusting for the effects of confounders, an estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73 m2 showed the highest risk of the primary outcome (hazard ratio [HR] 1.92; 95% confidence interval [CI] 1.45-2.53). The combination of eGFR ≤ 60 and hemoglobin A1c (HbA1c) ≥ 6.0% also showed the highest risk of all-cause death (HR, 2.42; 95% CI, 1.72-3.41). CONCLUSIONS: In patients with stable CAD treated with pitavastatin and who achieved guidelines-directed levels of LDL-C, eGFR and HbA1c were independently associated with adverse events, suggesting that renal function and glycemic control could be residual non-lipid therapeutic targets after statin therapy.

Optimizing irradiation conditions for low-intensity pulsed ultrasound to upregulate endothelial nitric oxide synthase.

PURPOSE: Here we aimed to develop a minimally invasive treatment for ischemic heart disease and demonstrate that low-intensity pulsed ultrasound (LIPUS) therapy improves myocardial ischemia by promoting myocardial angiogenesis in a porcine model of chronic myocardial ischemia. Studies to date determined the optimal treatment conditions within the range of settings available with existing ultrasound equipment and did not investigate a wider range of conditions. METHODS: We investigated a broad range of five parameters associated with ultrasound irradiation conditions that promote expression of endothelial nitric oxide synthase (eNOS), a key molecule that promotes angiogenesis in human coronary artery endothelial cells (HCAEC). RESULTS: Suboptimal irradiation conditions included 1-MHz ultrasound frequency, 500-kPa sound pressure, 20-min total irradiation time, 32-48-[Formula: see text] pulse duration, and 320-[Formula: see text] pulse repetition time. Furthermore, a proposed index, [Formula: see text], calculated as the product of power and the total number of irradiation cycles applied to cells using LIPUS, uniformly revealed the experimental eNOS expression associated with the various values of five parameters under different irradiation conditions. CONCLUSION: We determined the suboptimal ultrasound irradiation conditions for promoting eNOS expression in HCAEC.

Long-term prognostic significance of history of cancer and atrial fibrillation in coronary artery disease.

Background: Limited data exist on the prognostic significance of a history of cancer and atrial fibrillation (AF) in patients with coronary artery disease (CAD). This study aimed to evaluate the associations among a history of cancer, AF, and long-term prognosis in patients with CAD. Methods: We studied 3,233 patients with CAD (69 ± 11 years; women, 23%) in a multicenter hospital-based cohort study, the CHART-2 and related a history of cancer and AF to cardiovascular outcomes with a median follow-up of 10.8 years. Results: Of the 3,233 patients enrolled, 10.7% and 11.2% had a history of cancer and AF, respectively, while 2.8% had both. Patients with AF and a history of cancer were characterized by older age, male sex, and higher BNP levels. Anticoagulant use with warfarin or direct oral anticoagulants increased from 43% at baseline to 56% at 10 years in patients with CAD with AF and no history of cancer and increased from 49% to 83% in those with both. Patients with CAD with both comorbidities had a higher risk of a composite outcome including stroke, thrombosis, and major bleeding (Hazard Ratio [HRadjusted], 2.26; 1.50-3.40, P < 0.001). Furthermore, patients with both comorbidities had a higher risk of all-cause death (1.55; 95% confidence interval [CI] 1.12-2.12, P = 0.007) including cancer death (2.62; 1.51-4.54, P = 0.001), and new-onset heart failure (HF) requiring hospitalization (2.47; 1.54-3.96, P < 0.001). Conclusions: These results demonstrate that CAD patients with a history of cancer and AF have an increased risk of composite outcomes, including stroke, systemic thrombosis, major bleeding, all-cause death, cancer-related death, and new-onset HF.

Clinical and Sociodemographic Factors Associated With Health-Related Quality of Life in Patients With Adult Congenital Heart Disease　- A Nationwide Cross-Sectional Multicenter Study.

BACKGROUND: Little is known about clinical or sociodemographic factors that influence health-related quality of life (HRQoL) in patients with adult congenital heart disease (ACHD).Methods and Results: We conducted a nationwide prospective cross-sectional multicenter study at 4 large ACHD centers in Japan. From November 2016 to June 2018, we enrolled 1,223 ACHD patients; 1,025 patients had an HRQoL score. Patients completed a questionnaire survey, including sociodemographic characteristics, and the 36-Item Short-Form Health Survey (SF-36). To determine factors associated with HRQoL, correlations between 2 SF-36 summary scores (i.e., physical component score [PCS] and mental component score [MCS]) and other clinical or sociodemographic variables were examined using linear regression analysis. In multivariable analysis, poorer PCS was significantly associated with 11 variables, including older age, higher New York Heart Association class, previous cerebral infarction, being unemployed, and limited participation in physical education classes and sports clubs. Poorer MCS was associated with congenital heart disease of great complexity, being part of a non-sports club, current smoking, and social drinking. Student status and a higher number of family members were positively correlated with MCS. CONCLUSIONS: This study demonstrates that HRQoL in ACHD patients is associated with various clinical and sociodemographic factors. Further studies are needed to clarify whether some of these factors could be targets for future intervention programs to improve HRQoL outcomes.

Roles of endothelial and smooth muscle cell dysfunction and vasa vasorum in vasomotor disorders in ischemia with no obstructive coronary artery disease.

Recently, the importance has emerged of ischemia with no obstructive coronary artery disease (INOCA), for which endothelial and vascular smooth muscle cell (VSMC) dysfunctions and alterations in coronary vasa vasorum are involved. Regarding endothelial vasodilator functions, both endothelium-derived nitric oxide and endothelium-derived hyperpolarizing factor play important roles in modulating vascular tone, especially in the microcirculation. Recent studies have suggested systemic endothelial dysfunction in INOCA. Regarding VSMC dysfunction, Rho-kinase has been identified as a key molecular mechanism of VSMC hyperconstriction in INOCA. Finally, recent advances of coronary imaging have demonstrated the important role of altered adventitial vasa vasorum functions in INOCA.

Effectiveness and safety of reduced-dose rivaroxaban for elderly patients with non-valvular atrial fibrillation: A subanalysis of the EXPAND study.

BACKGROUND: Establishing the appropriate rivaroxaban dose in older patients with non-valvular atrial fibrillation (NVAF) is important because of the high risk of adverse events. In this EXPAND study subanalysis, we examined the safety and efficacy of standard-dose (15 mg/day) and non-recommended reduced-dose (10 mg/day) rivaroxaban in patients aged ≥65 years with NVAF and preserved renal function. METHODS: The entire analysis population (ALL cohort [n = 3982]; ≥65 years) was divided into early elderly (ELD) (65-74 years [n = 1444]) and late ELD (≥75 years [n = 2386]) sub-cohorts. Each sub-cohort was divided into reduced-dose and standard-dose groups. Kaplan-Meier survival curves with adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were used to assess efficacy (thromboembolic events) and safety (hemorrhagic events) outcomes. RESULTS: The aHR for major bleeding did not differ between the dosages in any of the cohorts (aHRs: 0.86-0.93). There were no significant differences in the occurrence of stroke + systemic embolism (SE) or stroke + SE + myocardial infarction (MI) + cardiovascular (CV) death among the cohorts. The aHR for MI/unstable angina + interventional/CV surgery + CV death was higher with 10-mg/day rivaroxaban than 15-mg/day rivaroxaban in the ALL cohort (aHR: 1.56 [95% CI 1.02-2.37], p = 0.039) and the late ELD sub-cohort (aHR: 1.86 [95% CI 1.01-3.42], p = 0.045). CONCLUSIONS: Reduced-dose rivaroxaban may increase the risk of coronary artery events. The use of rivaroxaban 15 mg/day in patients with NVAF aged ≥75 years with preserved renal function was supported.

Residual Coronary Risk Factors Associated With Long-Term Clinical Outcomes in Patients With Coronary Artery Disease Treated With High- vs. Low-Dose Statin Therapy　- REAL-CAD Substudy.

BACKGROUND: It remains unclear which comorbidities, other than lipid parameters, or combination of comorbidities, best predicts cardiovascular events in patients with known coronary artery disease (CAD) treated with statins. Therefore, we aimed to identify the nonlipid-related prognostic factors and risk stratification of patients with stable CAD enrolled in the REAL-CAD study.Methods and Results: Blood pressure, glucose level, and renal function were considered as risk factors in the 11,141 enrolled patients. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, and unstable angina. The secondary composite endpoint was the primary endpoint and/or coronary revascularization. A significantly worse prognosis at the primary endpoint was observed in the estimated glomerular filtration rate (eGFR) ≤60 group, and the combination of eGFR ≤60 and HbA1c ≥6.0 was the worst (hazard ratio (HR) 1.66; P<0.001). However, even in the eGFR >60 group, systolic blood pressure (SBP) ≥140 mmHg met the secondary endpoint (HR 1.33; P=0.006), and the combination of eGFR ≤60 and HbA1c ≥6.0 was also the worst at the secondary endpoint (HR 1.35; P=0.002). CONCLUSIONS: Regarding nonlipid prognostic factors contributing to the incidence of cardiovascular events in statin-treated CAD patients, renal dysfunction was the most significant, followed by poor glucose control and high SBP.

Management of Coronary Artery Spasm.

Calcium channel blockers (CCBs) are the first-line treatment for coronary artery spasm (CAS). When CAS-related angina symptoms are not well controlled by CCB therapy, long-acting nitrates or (where available) nicorandil can be added as second-line medications. In the case of CAS refractory to standard treatments, several other alternative drugs and interventions have been proposed, including the Rho-kinase inhibitor fasudil, anti-adrenergic drugs, neural therapies and percutaneous coronary interventions. In patients with syncope or cardiac arrest caused by CAS-related tachyarrhythmias, or even bradyarrhythmias, implantation of an ICD or pacemaker, respectively, should be considered according to the risk of recurrence and efficacy of vasodilator therapy.

Mechanisms of Coronary Artery Spasm.

Recent clinical trials have highlighted that percutaneous coronary intervention in patients with stable angina provides limited additional benefits on top of optimal medical therapy. This has led to much more attention being paid to coronary vasomotion abnormalities regardless of obstructive or non-obstructive arterial segments. Coronary vasomotion is regulated by multiple mechanisms that include the endothelium, vascular smooth muscle cells (VSMCs), myocardial metabolic demand, autonomic nervous system and inflammation. Over the years, several animal models have been developed to explore the central mechanism of coronary artery spasm. This review summarises the landmark studies on the mechanisms of coronary vasospasm demonstrating the central role of Rho-kinase as a molecular switch of VSMC hypercontraction and the important role of coronary adventitial inflammation for Rho-kinase upregulation in VSMCs.

Coronary Microvascular Spasm: Clinical Presentation and Diagnosis.

Professor Maseri pioneered the research and treatment of coronary vasomotion abnormalities represented by coronary vasospasm and coronary microvascular dysfunction (CMD). These mechanisms can cause myocardial ischaemia even in the absence of obstructive coronary artery disease, and have been appreciated as an important aetiology and therapeutic target with major clinical implications in patients with ischaemia with non-obstructive coronary artery disease (INOCA). Coronary microvascular spasm is one of the key mechanisms responsible for myocardial ischaemia in patients with INOCA. Comprehensive assessment of coronary vasomotor reactivity by invasive functional coronary angiography or interventional diagnostic procedure is recommended to identify the underlying mechanisms of myocardial ischaemia and to tailor the best treatment and management based on the endotype of INOCA. This review highlights the pioneering works of Professor Maseri and contemporary research on coronary vasospasm and CMD with reference to endothelial dysfunction, Rho-kinase activation and inflammation.