Epicardial Coronary Stenosis Research Articles

Fractional flow reserve measurement using dynamic CT perfusion imaging in patients with coronary artery disease

Fractional flow reserve measurement using dynamic CT perfusion imaging in patients with coronary artery disease

Prognostic implications of microvascular resistance reserve in symptomatic patients with intermediate coronary stenosis

Abstract Background Microvascular resistance reserve (MRR) is a novel index reflecting coronary microcirculatory function, irrespective of epicardial coronary artery stenosis. There is limited evidence regarding whether MRR can be an independent prognostic tool in patients with stable ischemic heart disease (IHD). Objective To evaluate clinical outcomes according to MRR in patients with stable IHD accompanied with or without significant epicardial coronary artery stenosis. Methods The current study included 547 consecutive patients undergoing systematic echocardiographic and invasive physiologic assessment for suspected stable IHD. Significant epicardial coronary artery stenosis was defined as fractional flow reserve (FFR)≤0.80. Coronary microvascular dysfunction (CMD) was defined as MRR≤3.0. Primary outcome was major adverse cardiovascular event (MACE), a composite of cardiovascular death, myocardial infarction, repeat revascularization, and admission for heart failure. Results Among the total patients, 172 patients (31.4%) had FFR≤0.80 and 200 patients (36.6%) had CMD defined by MRR≤3.0. MRR showed no significant correlation with FFR (R=-0.031, P=0.469), however, it was significantly correlated with index of microcirculatory resistance (R=-0.353, P<0.001), NT-proBNP (R=-0.296, P<0.001), left ventricular filling pressure (E/e’) (R=-0.224, P<0.001), and diastolic dysfunction grade (P<0.001). During median follow-up of 3.3 years (interquartile range from 2.0 to 4.5 years), MRR was significantly associated with MACE risk (HR 1.23 per-1 decrease, 95% CI 1.12-1.36, P<0.001). CMD defined by MRR≤3.0 was associated with an increased MACE risk in both FFR>0.80 (41.0% vs. 26.0%; HRadj 1.59, 95% CI 1.07-2.35, P=0.021) and FFR≤0.80 (34.7% vs. 14.8%; HRadj 2.32, 95% CI 1.12-4.82, P=0.024) groups. Conclusion Decreased MRR was associated with the presence of cardiac diastolic dysfunction as well as with increased left ventricular filling pressure. The presence of CMD defined by MRR was independently associated with the risk of a composite of cardiovascular death, myocardial infarction, repeat revascularization, and admission for heart failure in patients with stable IHD, irrespective of significant epicardial coronary artery stenosis.

The relationship between coronary microvascular dysfunction and left ventricular longitudinal systolic function in patients with diabetes mellitus

Abstract Background Coronary microvascular dysfunction (CMD) often accompanies diabetes mellitus (DM), leading to myocardial ischemia despite normal or mildly narrowed coronary arteries (<50% stenosis). CMD causes myocardial hypoperfusion, resulting in impaired systolic function. Coronary flow reserve (CFR) serves as a marker of microvascular function, particularly in the absence of significant epicardial coronary stenosis. Myocardial contrast echocardiography (MCE) is a key tool for clinically assessing CFR. Global longitudinal strain (GLS) derived from two-dimensional speckle tracking echocardiography (2D-STE) offers early insights into left ventricular systolic dysfunction during subclinical stages but is underexplored in diabetic CMD patients. Objective This study aimed to assess myocardial microcirculatory dysfunction in diabetic patients using stress myocardial ultrasound enhancement imaging, investigate its relationship with left ventricular longitudinal systolic function, and evaluate the utility of 2D-STE in assessing left ventricular systolic function in CMD patients. The findings provide insights for early detection and prevention of left ventricular longitudinal systolic dysfunction in diabetic patients with myocardial microcirculatorydysfunction. Methods Seventy type 2 diabetic patients who underwent coronary CT or angiography within the past three months without obstructive coronary artery disease were included. Clinical data, biochemical parameters, and blood glucose levels were collected. Left ventricular longitudinal strain indices were obtained using 2D-STE, and microvascular function was assessed based on CFR measured via transthoracic stress MCE. Patients were categorized into CMD (CFR<2) and control (CFR≧2) groups, with clinical and echocardiographic parameters compared. Strain parameters included GLS at rest, GLS under stress, and ∆GLS. Correlations between these indices and CFR were analyzed. Results 1. Seventy patients, with 41 males (41.4%) and 58 females (58.6%), averaging 56.14±10.84 years, were included. The mean BMI was 25.53±3.40. Among them, 23 patients were smokers (32.8%), 41 had hypertension (58.6%), and 36 had hyperlipidemia (51.4%). 2. Patients in the CMD group had significantly shorter diabetes duration (6.59±2.18 years vs. 8.13±2.17 years) and lower glycosylated hemoglobin (7.99±1.52% vs. 8.78±1.55%) (P<0.05). No significant differences were observed in other parameters. 3. GLS and ∆GLS differed significantly between groups, while other echocardiographic parameters did not. 4. Logistic regression analysis identified GLS as an independent predictor of CMD in diabetic patients under stress. Conclusions 1. Diabetic patients with CMD exhibit lower GLS and ∆GLS under stress, indicating early reductions in left ventricular systolic function reserve. 2. 2D-STE can detect early left ventricular systolic impairment in diabetic patients.MCE quantitative analysisGLS in normal and CMD group

Comparative study of myocardial perfusion and coronary flow velocity reserve derived from adenosine triphosphate stress myocardial contrast echocardiography in coronary lesions with no/mild stenosis.

Qualitative myocardial perfusion (QMP) derived from myocardial contrast echocardiography reflects the capillary flow, while coronary flow velocity reserve from Doppler spectrum (D-CFVR) of the left anterior descending coronary artery (LAD) is used to assess coronary microvascular function, particularly after excluding severe epicardial coronary stenosis. The present study aimed to assess the relationship of QMP and D-CFVR in detecting coronary microvascular disease (CMVD) by using adenosine triphosphate stress myocardial contrast echocardiography (ATP stress MCE). Seventy-two patients (mean age: 54.22 ± 12.78 years) with chest pain and <50% coronary stenosis diagnosed by quantitative coronary angiography or dual-source CT underwent ATP stress MCE. The distribution of myocardial perfusion and CFVR value was estimated by experienced physicians. Of the 72 LAD with 0%-50% diameter stenosis, 15 (21%) exhibited abnormal CFVR and 31 (43%) displayed abnormal perfusion with ATP stress MCE. Eleven of the 15 LAD territories (73%) with abnormal CFVR values showed abnormal perfusion. However, CFVR was considered normal in 20 LAD territories (35%), despite the presence of perfusion defect in the territory. Abnormal myocardial perfusion during ATP stress MCE was found in a sizable percentage of patients in whom CFVR of the supplying vessel was considered normal.

Age-related structural remodelling of the coronary circulation.

While it is broadly accepted that ageing is associated with impairment of coronary microvascular function, little is known about the underlying mechanisms. We investigated age-related changes in coronary microvascular structure in patients with stable angina without epicardial coronary stenoses. In an analysis of the IDEAL registry, a total of 165 vessels without coronary stenosis were interrogated with combined pressure/Doppler guidewires. We calculated diastolic microvascular conductance (DMVC) and backward expansion wave (BEW), and compared them between age tertiles. We calculated the prevalence of CMD, defined by reduced coronary flow reserve (CFR), and the prevalence of low BEW and low DMVC in each group. The three study groups were defined as having 37-53, 54-66, and 67-77 years of age, respectively. Oldest (3rd tertile) patients showed lower hyperemic flow velocity (46.7 ± 14.4 vs. 45.1 ± 12.4 vs. 38.4 ± 11.5 cm s-1, p = 0.019), lower DMVC (1.90 ± 0.71 vs. 1.44 ± 0.56 vs. 1.37 ± 0.67 cm s-1 mmHg-1, p < 0.001) and lower BEW intensity (5.9 [2.9-8.4] vs. 4.8 [2.9-6.8] vs. 4.4 [3.4-6.3] × 106 W m-2 s-1, p = 0.094). Older age was independently associated with lower BEW intensity (B: -0.10, 95% confidence interval [CI]: -0.17 to -0.09, p = 0.021) and DMVC (B: -0.25 95% CI: -0.45 to -0.09, p = 0.027). In patients with CFR < 2.5, the prevalence of BEW intensity and DMVC below the 25th percentile increased with age (25.0% vs. 52.0% vs. 72.7%, p = 0.010). Ageing is independently associated with structural microcirculatory remodeling that is reflected in BEW intensity and DMVC measurements, and with an increased prevalence of structural CMD. These results are important to understand non-obstructive mechanisms of myocardial ischemia in the elderly.

Future of invasive and non-invasive hemodynamic assessment for coronary artery disease management.

Coronary artery disease represents a global health challenge. Accurate diagnosis and evaluation of hemodynamic parameters are crucial for optimizing patient management and outcomes. Nowadays a wide range of both non-invasive and invasive methods are available to assess the hemodynamic impact of both epicardial coronary stenosis and vasomotor disorders. In fact, over the years, important developments have reshaped the nature of both invasive and non-invasive diagnostic techniques, and the future holds promises for further innovation and integration. Non-invasive techniques have progressively evolved and currently a broad spectrum of methods are available, from cardiac magnetic resonance imaging with pharmacological stress and coronary computed tomography (CT) to the newer application of FFR-CT and perfusion CT. Invasive methods, on the contrary, have developed to a full-physiology approach, able not only to identify functionally significant lesions but also to evaluate microcirculation and vasospastic disease. The aim of this review is to summarize the current state-of-the-art of invasive and non-invasive hemodynamic assessment for CAD management.

Microcirculatory dysfunction in hypertrophic cardiomyopathy with chest pain assessed by angiography-derived microcirculatory resistance

Chest pain, a common initial symptom in hypertrophic cardiomyopathy (HCM) patients, is closely linked to myocardial ischemia, despite the absence of significant coronary artery stenosis. This study explored microvascular dysfunction in HCM patients by employing angiography-derived microcirculatory resistance (AMR) as a novel tool for comprehensive assessment. This retrospective analysis included HCM patients with chest pain as the primary symptom and control patients without cardiac hypertrophy during the same period. The AMR was computed through angiography, providing a wire-free and adenosine-free index for evaluating microcirculatory function. Propensity score matching ensured balanced demographics between groups. This study also investigated the correlation between the AMR and clinical outcomes by utilizing echocardiography and follow-up data. After matching, 76 HCM patients and 152 controls were analyzed. While there was no significant difference in the incidence of epicardial coronary stenosis, the AMR of three epicardial coronary arteries was markedly greater in HCM patients. The criterion of an AMR ≥ 250 mmHg*s/m was that 65.7% of HCM patients experienced coronary microvascular dysfunction (CMD). Independent risk factors for CMD included increased left ventricular (LV) wall thickness (OR = 1.209, 95% CI 1.013–1.443, p = 0.036). Furthermore, an AMR_LAD ≥ 250 mmHg*s/m had an increased cumulative risk of the endpoint (log-rank p = 0.023) and was an independent risk factor for the endpoint (HR = 11.64, 95% CI 1.13–120.03, p = 0.039), providing valuable prognostic insights.

Visual Estimates of Coronary Slow Flow Are Not Associated With Invasive Wire-Based Diagnoses of Coronary Microvascular Dysfunction.

Coronary slow flow (CSF) by invasive coronary angiography is frequently understood to be an indicator of coronary microvascular dysfunction (CMD) in patients with ischemia with nonobstructive coronary arteries. However, the relationship between visual estimates of CSF and quantitative wire-based invasive diagnosis of CMD is uncertain. We prospectively enrolled adults aged ≥18 years with stable ischemic heart disease who were referred for invasive coronary angiography. Individuals with ≥50% epicardial coronary artery stenosis were excluded. Invasive coronary angiography was reviewed for CSF, defined as ≥3 cardiac cycles to opacify distal vessels with contrast. Coronary function testing was performed in the left anterior descending coronary artery using bolus coronary thermodilution techniques to measure coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR). Invasively determined CMD was defined as abnormal CFR (<2.5), abnormal IMR (≥25), or both. Among 104 participants, the median age was 61.5 years and 79% were female. The median CFR was 3.6 (interquartile range, 2.5-4.7) and the median IMR was 21 (interquartile range, 13.3-28.0). Overall, 24.0% of participants had abnormal CFR, 34.6% had abnormal IMR, and 48.1% had a final diagnosis of invasively determined CMD. CSF was present in 23 participants (22.1%). The proportions of patients with CMD (56.5% versus 45.7%; P=0.36), abnormal CFR (17.4% versus 25.9%; P=0.40), and abnormal IMR (43.5% versus 32.1%; P=0.31) were not different in patients with versus without CSF. Among patients with ischemia with nonobstructive coronary artery, CSF was not associated with abnormal CFR, IMR, or either abnormal CFR or IMR. CSF is not a reliable angiographic surrogate of abnormal CFR or IMR as determined by invasive, wire-based physiology testing. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03537586.

Ten questions about myocardial infarction with non-obstructed coronary arteries

The term "MINOCA" refers to myocardial infarction with non-obstructed coronary arteries and has been used to define acute myocardial infarction with no angiographic evidence of significant epicardial coronary artery stenosis. Patients with MINOCA represent a rather heterogeneous group of acute coronary syndrome, and this may account for the wide variation in the incidence of MINOCA in different studies. Several pathogenic mechanisms have been suggested to underlie MINOCA, but the condition continues to represent a diagnostic and therapeutic challenge for the cardiologist. Therefore, an adequate diagnostic assessment, carefully characterizing the pathogenic mechanisms, and a selection of more targeted treatments are needed to improve clinical outcomes. In this focused review, we will try to provide answers to the most common questions on the causes, diagnosis, treatment, and outcomes of MINOCA.

Prognostic Implications of Microvascular Resistance Reserve in Symptomatic Patients With Intermediate Coronary Stenosis

BackgroundMicrovascular resistance reserve (MRR) is a novel index reflecting coronary microcirculatory function, irrespective of epicardial coronary artery stenosis. There is limited evidence regarding whether MRR can be an independent prognostic tool in patients with stable ischemic heart disease (IHD). ObjectivesThe aim of this study was to evaluate clinical outcomes according to MRR in patients with stable IHD accompanied with or without significant epicardial coronary artery stenosis. MethodsThe present study included 547 consecutive patients undergoing systematic echocardiographic and invasive physiological assessment for suspected stable IHD. Significant epicardial coronary artery stenosis was defined as fractional flow reserve (FFR) ≤0.80. Coronary microvascular dysfunction (CMD) was defined as MRR ≤3.0. The primary outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, repeat revascularization, and admission for heart failure. ResultsAmong the study group, 172 patients (31.4%) had FFR ≤0.80, and 200 patients (36.6%) had CMD defined by MRR ≤3.0. MRR showed no significant correlation with FFR (R = −0.031; P = 0.469), but it was significantly correlated with the index of microcirculatory resistance (R = −0.353; P < 0.001), N-terminal pro–B-type natriuretic peptide (R = −0.296; P < 0.001), left ventricular filling pressure (E/e′ ratio) (R = −0.224; P < 0.001), and diastolic dysfunction grade (P < 0.001). During a median follow-up period of 3.3 years (Q1-Q3: 2.0-4.5 years), MRR was significantly associated with MACE risk (HR: 1.23 per 1-U decrease; 95% CI: 1.12-1.36; P < 0.001). CMD defined by MRR ≤3.0 was associated with an increased MACE risk for both FFR >0.80 (41.0% vs 26.0%; adjusted HR: 1.59; 95% CI: 1.07-2.35; P = 0.021) and FFR ≤0.80 (34.7% vs 14.8%; adjusted HR: 2.32; 95% CI: 1.12-4.82; P = 0.024). ConclusionsDecreased MRR was associated with the presence of cardiac diastolic dysfunction as well as increased left ventricular filling pressure. The presence of CMD defined by MRR was independently associated with the risk for a composite of cardiovascular death, myocardial infarction, repeat revascularization, and admission for heart failure in patients with stable IHD, irrespective of significant epicardial coronary artery stenosis. (Prognostic Impact of Cardiac Diastolic Function and Coronary Microvascular Function [DIAST-CMD]; NCT05058833)

Noninvasive transthoracic doppler flow velocity and invasive thermodilution to assess coronary flow reserve.

Coronary flow reserve (CFR) provides prognostication and coronary physiological information, including epicardial coronary stenosis and microvascular function. The relationship between stress transthoracic Doppler echocardiography (TDE)-derived coronary flow velocity reserve (CFRS-TDE) and thermodilution-derived coronary flow reserve (CFRthermo) before and after elective percutaneous coronary intervention (PCI) remains unclear. This single-center prospective registry study evaluated patients who underwent fractional flow reserve (FFR)-guided elective PCI for left anterior descending artery (LAD) lesions with wire-based invasive physiological measurements and pre- and post-PCI stress TDE examinations. A total of 174 LAD lesions from 174 patients were included in the final analysis. A modest correlation was detected between the pre-PCI CFRS-TDE and the pre-PCI CFRthermo (r=0.383, P<0.001). The frequently used CFRS-TDE threshold of 2.0 corresponded to a pre-PCI CFRthermo of 2.18. Pre-PCI CFRS-TDE underestimated pre-PCI CFRthermo [1.89 (1.44-2.31) vs. 2.05 (1.38-2.93), P<0.001]. Both CFRS-TDE and CFRthermo increased significantly post-PCI [pre-PCI CFRS-TDE 1.89 vs. post-PCI CFRS-TDE 2.33, P<0.001; pre-PCI CFRthermo 2.05 (1.38-2.93) vs. post-PCI CFRthermo 2.59 (1.63-3.55), P<0.001]. In contrast, there was no significant relationship between changes in CFRS-TDE and changes in CFRthermo after PCI (r=0.008, P=0.915) or between post-PCI CFRS-TDE and post-PCI CFRthermo (r=0.054, P=0.482). Pre-PCI CFRS-TDE and CFRthermo are modestly correlated, but post-PCI CFRS-TDE and CFRthermo have no correlation. CFRS-TDE and CFRthermo are not interchangeable, particularly post-PCI, suggesting that the two metrics represent different coronary physiologies after PCI.

Diagnostic value of computed tomography myocardial perfusion imaging to detect coexisting microvascular dysfunction in patients with obstructive epicardial coronary artery disease.

Computed tomography myocardial perfusion (CT-MP) has reported usefulness in assessing hemodynamically significant epicardial coronary artery lesions. However, the diagnostic ability of the absolute coronary flow using CT-MP to detect coronary microvascular dysfunction (CMD) remains elusive. This prospective cohort study aimed to assess the diagnostic value of CT-MP in evaluating coexisting CMD in patients with functionally significant epicardial coronary stenosis and to analyze the predictive factors of lesions with CMD. Sixty-eight patients with chronic coronary syndrome (CCS) and de novo single functionally significant stenosis [fractional flow reserve (FFR) ≤0.80] were studied. CMD was defined as an index of microcirculatory resistance ≥25. We compare clinical background and CT-MP findings between patients with and without CMD (CMD, n=29; non-CMD, n=39). CT-MP, and quantitative and qualitative plaque assessments were included in computed tomography angiography assessment. Logistic regression analysis was performed to predict CMD. FFR, invasive wire-derived coronary flow reserve (CFRwire) and index of microcirculatory resistance were 0.68 [interquartile range (IQR), 0.59-0.74], 1.71 (IQR, 1.24-2.88), and 22.6 (IQR, 15.1-34.5), respectively. The rest and hyperemic-myocardial blood flow (MBF) and CT-MP-derived CFR (CFRCT-MP) were 0.83 (0.64-1.03) mL/min/g, 2.14 (1.30-2.92) mL/min/g, and 2.19 (1.44-3.37), respectively. In the territories with CMD, hyperemic-MBF was significantly lower than in those without [1.68 (IQR, 0.84-2.44) vs. 2.31 (IQR, 1.67-3.34) mL/min/g, P=0.015] and the prevalence of CFRCT-MP <2.0 was higher in the lesions with CMD than in those without (62.1% vs. 28.2%, P=0.011), while FFR values were similar. Fibrofatty and necrotic core component volume was greater in the vessels with CMD than in those without [31.8 (IQR, 19.0-48.9) vs. 25.1 (IQR, 17.2-32.1) mm3, P=0.045]. Multivariable logistic regression analysis showed that hyperemic-MBF and fibrofatty and necrotic core component volume were independent predictors of CMD territories [odds ratio (OR) =0.583; 95% confidence interval (CI): 0.355-0.958; P=0.033 and OR =1.040; 95% CI: 1.010-1.070; P=0.011]. Quantitative assessment of absolute coronary flow using pre-percutaneous coronary intervention (PCI) CT-MP, and comprehensive plaque analysis using computed tomography angiography may help detect coexisting subtended microvascular dysfunction in territories with functionally significant epicardial coronary lesions. Further studies are required to elucidate the clinical significance of coexisting CMD in patients with CCS undergoing PCI.

In vivo validation of intra-coronary absolute flow measurements and comparison of reliability between different microvascular indices and the microvascular resistance reserve

Abstract Background Coronary microvascular dysfunction plays a major role in patients with cardiac ischemia without flow limiting epicardial coronary stenosis, takotsubo cardiomyopathy, aortic valve stenosis and heart failure with preserved ejection fraction. In clinical practice, the index of microvascular resistance (IMR) and coronary flow reserve (CFR), and more recently the absolute coronary blood flow (ABF), absolute coronary resistance (ACR) and the microvascular resistance reserve (MRR) are used as parameters to measure resistance and flow using continuous coronary thermodilution. Purpose Firstly, to validate ABF measured with continuous coronary thermodilution in vivo against epicardial doppler-measured flow. Secondly, to assess reliability and reproducibility in-vivo of different microvascular indices. Methods For the purpose of this study coronary measurements were conducted in two large animal models and in patients, all with the appropriate ethical committee approval. For the first part of the study, fourteen sheep underwent repeated paired measurements of ABF and ACR (with use of continuous thermodilution) with different saline infusion speeds, as well as IMR, CFR and MRR in multiple coronary vessels. Seven additional sheep underwent these measurements while having simultaneous measurements with epicardial coronary flow probes (gold standard) in an open-chest model. The epicardial flow probes were placed on the proximal left anterior descending and circumflex artery. Maximal hyperemia was induced with adenosine (CFR and IMR) or infusion of saline at a rate of 30ml/min (ABF, ACR and MRR). For the second part of the study, in 41 patients receiving routine microvascular assessment, IMR and CFR measurements were duplicated by a single operator, after re-calibration, to assess the reproducibility of the measurement. The combined animal and human data resulted in the analysis of 408 coronary measurements made in 88 coronary vessels during 65 heart catheterizations. Results In sheep, ABF measured with continuous thermodilution (with saline infusion speeds from 5ml/min to 30ml/min) was accurate when compared with epicardial flow measurements. (Table 1, Fig 1A) Notably, the continuous thermodilution measurement had the tendency to slightly overestimate ABF. (Table 1, Fig 1B) The two methods were equivalent within 15% (Two one-sided test: mean difference: -8.73%; 95% CI: -14.40 to -3.06%, p= 0.016). When comparing test-retest reproducibility between the indices, CFR performed the worst while ACR and MRR performed the best. MRR had a significantly better reproducibility than the IMR. (Table 1, Fig 1C). Conclusion ABF can accurately be determined by continuous coronary thermodilution. MRR and ACR have a significantly superior reliability and reproducibility compared to IMR and CFR. Unlike ACR, MRR is not vessel or territory-size dependent and is therefore the index of choice for future research and clinical assessment of the microcirculation.

Coronary artery tortuosity and mid-term all-cause mortality of patients with ischemia and non-obstructive coronary arteries.

Background: Coronary artery tortuosity (CAT) is a frequently encountered angiographic feature of patients with ischemia and non-obstructive coronary arteries (INOCA). However, there is limited data regarding the possible correlation between CAT and all-cause mortality in these patients. Aim: To assess the survival prognostic implications of CAT in INOCA patients and the predictors of all-cause mid-term mortality of these patients. Methods: All consecutive INOCA patients, with preserved ejection fraction evaluated for clinical ischemia by coronary angiography in our department between January 2014 and December 2020 were considered for inclusion. Patients with epicardial coronary artery stenosis ≥ 50%, severe pulmonary hypertension, or decompensated extra cardiac disease were excluded. Eleid classification was used for CAT severity characterization. We assessed all-cause mortality in January 2023. Results: Our sample included 328 INOCA patients. 15.54% died during the mean follow-up of 3.75 ± 1.32 years. 79.88% had CAT. CAT patients were older (65.10±9.09 versus 61.24±10.02 years, p=0.002), and more often female (67.18% versus 31.82%, p<0.001). CAT was inversely correlated with all-cause mid-term mortality (OR 0.35, 95%CI 0.16 - 0.77, p=0.01). CAT severity had no impact on survival. In CAT patients the initial multivariable analysis identified NT-proBNP levels (HR 3.96, p=0.01), diabetes mellitus (DM) (HR 4.76, p=0.003), and atrial fibrillation (HR 2.68, p=0.06) as independent predictors of all-cause mortality. In the final analysis, NT-proBNP and DM were the main independent predictors of survival. Conclusions : In our INOCA cohort, CAT patients were older and more likely female. CAT was inversely correlated with mid-term all-cause mortality. NT-proBNP and DM were the main independent predictors of mortality of CAT patients.

Cardioprotective and anti-anginal efficacy of Nicorandil: A Comprehensive Review.

Angina pectoris remains a significant burden despite advances in medical therapy and coronary revascularization. Many patients (up to 30%) with angina have normal coronary arteries, with coronary microvascular disease (CMD) and/or coronary artery vasospasm (CAVS) being major drivers of the myocardial demand-supply mismatch. Even among patients revascularized for symptomatic epicardial coronary stenosis, recurrent angina remains highly prevalent. Medical therapy for angina currently centers around two disparate goals, viz secondary prevention of hard clinical outcomes and symptom control. Vasodilators such as nitrates have been first-line anti-anginal agents for decades, along with beta-blockers and calcium channel blockers. However, efficacy in terms of symptoms control is heterogenous, depending on underlying mechanism(s) of angina in an individual patient, often necessitating multiple agents. Nicorandil (NCO) is an anti-anginal first discovered in the late 1970s with a uniquely dual mechanism of action. Like a typical nitrate, it mediates medium-large vessel vasodilation via nitric oxide. Additionally, NCO has ATP-dependent potassium channel-agonist activity (KATP), mediating microvascular dilatation. Hence, it has proven effective in both CAVS and CMD, typically challenging patient populations. Moreover, emerging evidence suggests cardiomyocyte protection against ischemia via ischemic preconditioning (IPC) may be mediated via KATP-agonism. Finally, there is now fairly firm evidence in favor of NCO in terms of hard event reduction among patients with stable coronary artery disease (CAD), following myocardial infarction, and perhaps even among patients with congestive heart failure (CHF). This review aims to summarize the mechanism of action of NCO, its efficacy as an anti-anginal, and current evidence behind its impact on hard outcomes. Finally, we review other cardiac and emerging non-cardiac indications for NCO use.Keywords: angina, stable ischemic heart disease, anti-anginal, efficacy, cardioprotective.

Coronary "Microvascular Dysfunction": Evolving Understanding of Pathophysiology, Clinical Implications, and Potential Therapeutics.

Until recently, it has been generally held that stable angina pectoris (SAP) primarily reflects the presence of epicardial coronary artery stenoses due to atheromatous plaque(s), while acute myocardial infarction (AMI) results from thrombus formation on ruptured plaques. This concept is now challenged, especially by results of the ORBITA and ISCHEMIA trials, which showed that angioplasty/stenting does not substantially relieve SAP symptoms or prevent AMI or death in such patients. These disappointing outcomes serve to redirect attention towards anomalies of small coronary physiology. Recent studies suggest that coronary microvasculature is often both structurally and physiologically abnormal irrespective of the presence or absence of large coronary artery stenoses. Structural remodelling of the coronary microvasculature appears to be induced primarily by inflammation initiated by mast cell, platelet, and neutrophil activation, leading to erosion of the endothelial glycocalyx. This leads to the disruption of laminar flow and the facilitation of endothelial platelet interaction. Glycocalyx shedding has been implicated in the pathophysiology of coronary artery spasm, cardiovascular ageing, AMI, and viral vasculitis. Physiological dysfunction is closely linked to structural remodelling and occurs in most patients with myocardial ischemia, irrespective of the presence or absence of large-vessel stenoses. Dysfunction includes the impairment of platelet and vascular responsiveness to autocidal coronary vasodilators, such as nitric oxide, prostacyclin, and hydrogen sulphide, and predisposes both to coronary vasoconstriction and to a propensity for microthrombus formation. These findings emphasise the need for new directions in medical therapeutics for patients with SAP, as well as a wide range of other cardiovascular disorders.

The imPAct of Trimetazidine on MicrOcirculation after Stenting for stable coronary artery disease (PATMOS study).

Myocardial ischemia is caused by epicardial coronary artery stenosis or atherosclerotic disease affecting microcirculation. Trimetazidine (TMZ), promotes glucose oxidation which optimizes cellular energy processes in ischemic conditions. Small studies demonstrated protective effects of TMZ in terms of reducing myocardial injury after percutaneous coronary intervention (PCI), its effect on microcirculation using contemporary investigative methods has not been studied. The aim of the study was to examine effects of trimetazidine, given before elective PCI, on microcirculation using invasively measured index of microcirculatory resistance (IMR). This was prospective, single blinded, randomized study performed in a single university hospital. It included consecutive patients with an indication for PCI of a single, de novo, native coronary artery lesion. Patients were randomly assigned to receive either TMZ plus standard therapy (TMZ group) or just standard therapy. Coronary physiology indices fractional flow reserve (FFR), coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) were measured before and after PCI using coronary pressure wire. We randomized 71 patients with similar clinical characteristics and risk profile, previous medications and coronary angiograms. Patientshad similar values of Pd/Pa, FFR and CFR prior to PCI procedure. After PCI, FFR values were higher in TMZ group, while IMR values were lower in this group respectively (FFR TMZ + 0.89 ± 0.05 vs. TMZ - 0.85 ± 0.06, p = 0.007; CFR TMZ + 2.1 ± 0.8 vs. TMZ- 2.3 ± 1.3, p = 0.469; IMR TMZ + 18 ± 9 vs. TMZ- 24 ± 12, p = 0.028). In two-way repeated measures ANOVA PCI was associated with change in FFR values (TMZ p = 0.050; PCI p < 0.001; p for interaction 0.577) and TMZ with change in IMR values (TMZ p = 0.034, PCI p = 0.129, p for interaction 0.344). Adding trimetazidine on top of medical treatment prior to elective PCI reduces microvascular dysfunction by lowering postprocedural IMR values when compared to standard therapy alone.

Characteristic cardiac capillary pericytes in a Fabry disease patient receiving enzyme replacement therapy

Fabry disease, a lysosomal disorder caused by deficiency in α-galactosidase A, patients report chest pain in the absence of epicardial coronary artery stenosis. Although it is conceivable that coronary microvascular dysfunction due to globotriaosylceramide (GL-3) accumulation within the vasculature causes angina, the precise histology was unknown. A 34-year-old male patient diagnosed with Fabry disease [NM_000169.3:c.1089_1090insTCGC (p.Tyr365Lysfs*11)] and treated for 6 years with enzyme replacement therapy (ERT) was referred to our cardiology department because of palpitations and precordial discomfort. He was diagnosed for paroxysmal atrial fibrillation and subsequently underwent catheter ablation therapy. The procedure resolved his palpitations, but his precordial discomfort remained. Again, coronary angiography showed no organic stenosis. A 24-hour Holter electrocardiogram detected neither arrhythmia nor ischemic changes. Echocardiography showed normal wall motion with diffuse left ventricular hypertrophy. Endomyocardial biopsy revealed severe vacuolated hypertrophied myocytes appearing transparent, like a lace curtain, which is characteristic of Fabry disease (Figure A, A’ and B). Electron microscopic examination revealed abundant lamellar bodies with a myelin-like configuration within cardiomyocytes and interstitial macrophages, indicating GL-3 deposition (Figure C, D and E). We also detected numerous interstitial microcapillaries showing abundant lamellar body deposits within the capillary pericytes but not the endothelial cells (Figure F, F’-1 and F’-2. Pericytes surrounding the endothelial cells can regulate capillary blood flow in microvascular beds. Our pathological findings suggest progressive lamellar body accumulation caused angina by disrupting microvascular circulation. This case highlights progression of microvascular Fabry disease especially in capillary pericytes and also a need for develop therapies targeting capillary circulation.

Investigation of the Relationship Between Triglycerides-Glucose İndex and Coronary Slow Flow: A Retrospective Case-Control Study.

Coronary slow flow (CSF) refers to delayed distal vessel opacification in the absence of epicardial coronary artery stenosis. The etiopathogenic mechanism of CSF is still unclear. This study investigates the relationship between CSF and the triglyceride-glucose (TyG) index. The study sample consisted of 118 CSF patients and 105 patients with normal coronary flow (NCF). The coronary flow rate was measured via the Thrombolysis in Myocardial Infarction (TIMI) frame count (TFC) method in all patients. The TyG index was calculated as the logarithm of the [fasting triglyceride (mg/dL)×fasting glucose (mg/dL)]/2 value. A significance level of < 0.05 was adopted as statistically significant. The TyG index, low-density lipoprotein (LDL), body mass index (BMI), neutrophil-to-lymphocyte ratio (NLR) and TFC values, male ratio, and the ratio of smokers were higher, whereas high-density lipoprotein (HDL) levels were significantly lower in the CSF group compared to the NCF group (p<0,05). The correlation analysis revealed that CSF was significantly correlated with TyG index, BMI, NLR, and HDL values. The strongest of these correlations was between CSF and TyG index (r= 0.57, p<0.001). Additionally, the multivariate analysis revealed that TyG index, BMI, NLR ratio, and male gender were independent predictors for CSF (p<0.05). Receiver operating characteristic (ROC) curve analysis indicated that a cut-off value of ≥ 9.28 for the TyG index predicted CSF with a sensitivity of 78% and a specificity of 78.1% [Area under the curve (AUC): 0.868 and 95% Confidence Interval (CI): 0.823-0.914]. The findings of this study revealed a very strong relationship between CSF and TyG index.

Association between coronary flow and aortic stenosis during transcatheter aortic valve implantation.

In patients with aortic stenosis (AS), the coronary flow reserve decreases even in the absence of epicardial coronary artery stenosis. Systolic coronary flow reversal (SFR) reflecting reduced coronary microcirculation, often seen in patients with severe AS, has a potential negative impact on the pathogenesis of cardiac dysfunction. However, there are limited data on the relationship between the severity of AS and SFR, as well as on the benefits of transcatheter aortic valve implantation (TAVI). The aim of this study was to evaluate the relationship between the severity of AS and efficacy of TAVI in improving SFR. Consecutive patients with AS who had undergone TAVI using transoesophageal echocardiography (TEE) from November 2020 to February 2022 were prospectively enrolled. Coronary flow in the left anterior descending artery as well as the aortic valve peak velocities, and the mean aortic valve pressure gradients (AVPGs), indicating the severity of AS, were measured using intraprocedural TEE before and after TAVI. The following parameters were measured as coronary flow: systolic and diastolic peak velocity (cm/s) and systolic and diastolic velocity-time integral (VTI) (cm). SFR was defined as the presence of a reversal coronary flow component in systole. The enrolled patients were classified into two groups according to the presence or absence of SFR before TAVI. A total of 25 patients were included: 13 had SFR and 12 who had no SFR, before TAVI. Patients with SFR had significantly higher aortic valve peak velocities (451.1±45.9 vs. 372.1±52.1cm/s; P<0.001) and mean AVPGs (49.2±14.5 vs. 30.3±11.6mmHg; P=0.002) than those without. The optimal binary cut-off aortic valve peak velocity values and the mean AVPG associated with the presence of SFR before TAVI were >410.0cm/s (specificity, 75.0%; sensitivity, 92.3%) and >37.4mmHg (specificity, 83.3%; sensitivity, 92.3%), respectively. After TAVI, SFR immediately disappeared in 11 of 13 patients with SFR (84.6%). Overall, the systolic coronary VTI significantly increased after TAVI (2.0±4.7 vs. 6.4±3.2cm, P<0.001), and this increase was greater in patients with SFR than in those without SFR before TAVI (interaction P=0.035). SFR was found to be associated with the severity of AS and with a greater increase in systolic coronary flow immediately after TAVI.