Coronary Flow Reserve Research Articles

Association between CZT‑SPECT myocardial blood flow and coronary stenosis: A cross‑sectional study.

The association between the quantitative and semi-quantitative parameters of myocardial blood flow obtained using cadmium-zinc-telluride single photon emission computed tomography (CZT-SPECT) and coronary stenosis remains unclear. Therefore, the objective of the present study was to evaluate the diagnostic value of two parameters obtained using CZT-SPECT in patients with suspected or known coronary artery disease. A total of 24 consecutive patients who underwent CZT-SPECT and coronary angiography within 3 months of each other were included in the study. To evaluate the predictive ability of the regional difference score (DS), coronary flow reserve (CFR), and the combination thereof for positive coronary stenosis at the vascular level, receiver operating characteristic (ROC) curves were plotted and the area under the curves (AUCs) were calculated. Comparisons of the reclassification ability for coronary stenosis between different parameters were assessed by calculating the net reclassification index (NRI) and the integrated discrimination improvement (IDI). The 24 participants (median age: 65 years; range: 46-79 years; 79.2% male) included in this study had a total of 72 major coronary arteries. When stenosis ≥50% was defined as the criteria for positive coronary stenosis, the AUCs and the 95% confidence interval (CI) for regional DS, CFR, and the combination of the two indices were 0.653 (CI, 0.541-0.766), 0.731 (CI, 0.610-0.852) and 0.757 (CI, 0.645-0.869), respectively. Compared with single DS, the combination of DS and CFR increased the predictive ability for positive stenosis, with an NRI of 0.197-1.060 (P<0.01) and an IDI of 0.0150-0.1391 (P<0.05). When stenosis ≥75% was considered as the criteria, the AUCs were 0.760 (CI, 0.614-0.906), 0.703 (CI, 0.550-0.855), and 0.811 (CI, 0.676-0.947), respectively. Compared with DS, CFR had an IDI of -0.3392 to -02860 (P<0.05) and the combination of DS and CFR also enhanced the predictive ability, with an NRI of 0.0313-1.0758 (P<0.01). In conclusion, both regional DS and CFR had diagnostic values for coronary stenosis, but the diagnostic abilities differed in distinguishing between different degrees of stenosis, and the efficiency was improved with a combination of DS and CFR.

Randomized Placebo-Controlled Trial to Evaluate Effects of Eplerenone on Myocardial Perfusion and Function Among Persons With Human Immunodeficiency Virus (HIV)-Results From the MIRACLE HIV Study.

Increased renin angiotensin aldosterone system (RAAS) activity may contribute to excess cardiovascular disease in people with HIV (PWH). We investigated how RAAS blockade may improve myocardial perfusion, injury, and function among well-treated PWH. Forty PWH, on stable ART, without known heart disease were randomized to eplerenone 50 mg PO BID (n = 20) or identical placebo (n = 20) for 12 months. The primary endpoints were (1) myocardial perfusion assessed by coronary flow reserve (CFR) on cardiac PET or stress myocardial blood flow (sMBF) on cardiac MRI or (2) myocardial inflammation by extracellular mass index (ECMi) on cardiac MRI. Beneficial effects on myocardial perfusion were seen for sMBF by cardiac MRI (mean [SD]: 0.09 [0.56] vs -0.53 [0.68] mL/min/g; P = .03) but not CFR by cardiac PET (0.01 [0.64] vs -0.07 [0.48]; P = .72, eplerenone vs placebo). Eplerenone improved parameters of myocardial function on cardiac MRI including left ventricular end diastolic volume (-13 [28] vs 10 [26] mL; P = .03) and global circumferential strain (GCS; median [interquartile range 25th-75th]: -1.3% [-2.9%-1.0%] vs 2.3% [-0.4%-4.1%]; P = .03), eplerenone versus placebo respectively. On cardiac MRI, improvement in sMBF related to improvement in global circumferential strain (ρ = -0.65, P = .057) among those treated with eplerenone. Selecting for those with impaired myocardial perfusion (CFR <2.5 and/or sMBF <1.8), there was a treatment effect of eplerenone versus placebo to improve CFR (0.28 [0.27] vs -0.05 [0.36]; P = .04). Eplerenone prevented a small increase in troponin (0.00 [-0.13-0.00] vs 0.00 [0.00-0.74] ng/L; P = .03) without effects on ECMi (0.9 [-2.3-4.3] vs -0.7 [-2.2--0.1] g/m2; P = .38). CD4+ T-cell count (127 [-38-286] vs -6 [-168-53] cells/μL; P = .02) increased in the eplerenone- versus placebo-treated groups. RAAS blockade with eplerenone benefitted key indices and prevented worsening of myocardial perfusion, injury, and function among PWH with subclinical cardiac disease when compared with placebo. NCT02740179 (https://clinicaltrials.gov/ct2/show/NCT02740179?term=NCT02740179&draw=2&rank=1).

Coronary microcirculation and left ventricular diastolic function but not myocardial deformation indices are impaired early in patients with chronic kidney disease.

To investigate abnormalities in myocardial strain and classic echocardiographic indices and coronary flow reserve (CFR), in younger versus older CKD patients. Sixty consecutive CKD patients (<60 years old n=30, ≥60 years old n=30) and 30 healthy controls (age- and gender-matched with younger CKD patients) were recruited. An echocardiographic assessment including myocardial strain indices (i.e. global longitudinal strain -GLS -, TWIST, UNTWIST rate) was performed at baseline and following dipyridamole administration in all participants. Younger CKD patients had higher E/e', left ventricular mass index and relative wall thickness and lower E' (p< .005 for all) compared to healthy controls. Older CKD patients had lower E/A and E' (p< .05 for both) compared to younger CKD patients; these differences did not remain significant after adjustment for age. CFR was higher in healthy controls compared to younger and older CKD patients (p< .05 for both) without a significant difference between CKD groups. There were no significant differences in GLS, TWIST or UNTWIST values among the three groups of patients. Dipyridamole-induced changes did not differ significantly among the three groups. Compared to healthy controls, impaired coronary microcirculation and left ventricular diastolic function, but not myocardial strain abnormalities, are found in young CKD patients and deteriorate with aging.

Relationship of OCT-defined plaque characteristics with CCTA-derived coronary inflammation and CMR-derived global coronary flow reserve in patients with acute coronary syndrome.

The relationship of layered plaque detected by optical coherence tomography (OCT) with coronary inflammation and coronary flow reserve (CFR) remains elusive. We aimed to investigate the association of OCT-defined layered plaque with pericoronary adipose tissue (PCAT) inflammation assessed by coronary computed tomography angiography (CCTA) and global (G)-CFR assessed by cardiac magnetic resonance imaging (CMR) in patients with acute coronary syndrome (ACS). We retrospectively investigated 88 patients with first ACS who underwent preprocedural CCTA, OCT imaging of the culprit lesion prior to primary/urgent percutaneous coronary intervention (PCI), and postprocedural CMR. All patients were divided into two groups according to the presence and absence of OCT-defined layered plaque at the culprit lesion. Coronary inflammation was assessed by the mean value of PCAT attenuation (-190 to -30 HU) of the three major coronary vessels. G-CFR was obtained by quantifying absolute coronary sinus flow at rest and during maximum hyperemia. CCTA and CMR findings were compared between the groups. In a total of 88 patients, layered plaque was detected in 51 patients (58.0%). The patients with layered plaque had higher three-vessel-PCAT attenuation value (-68.58 ± 6.41 vs. -71.60 ± 5.21 HU, P = 0.021) and culprit vessel-PCAT attenuation value (-67.69 ± 7.76 vs. -72.07 ± 6.57 HU, P = 0.007) than those with non-layered plaque. The patients with layered plaque had lower G-CFR value (median, 2.26 [interquartile range, 1.78, 2.89] vs. 3.06 [2.41, 3.90], P = 0.003) than those with non-layered plaque. The presence of OCT-defined layered plaque at the culprit lesion was associated with high PCAT attenuation and low G-CFR after primary/urgent PCI in patients with ACS. OCT assessment of culprit plaque morphology and detection of layered plaque may help identify increased pericoronary inflammation and impaired CFR, potentially providing the risk stratification in patients with ACS and residual microvascular dysfunction after PCI.

The impact of cardiac SPECT in risk stratification for women with suspected coronary artery disease in a very high cardiovascular risk country

Abstract Funding Acknowledgements Type of funding sources: None. Background Risk stratification has become increasingly important in the management of women with coronary artery disease (CAD). Population based cross-sectional study of cardiovascular risk (CVR) factors in Latvia revealed that women in age 25 -74 are in a very high CVR group: more than 60% of women have dyslipidemia, 30% have arterial hypertension (AH) and are overweight. Purpose To evaluate CVR factor profile in women with suspected CAD and performed cardiac single photon emission computed tomography (SPECT) and to prove the need of perfusion imaging for women in a very high cardiovascular risk population. Methods Cardiac SPECT for women with suspected CAD and positive or non-informative exercise test was performed in a single center from 2018 till 2022. The patients were analyzed by risk factors and perfusion test result, divided into 2 groups: normal myocardial perfusion or true myocardial perfusion defect. Results 466 patients without known CAD were analyzed. The mean age of cohort patients was 59.3±10.9 years. 28 (6.0%) patients had no CVR factors, 90 (19.3%) women had only 1, but the rest of them (348, 74.7%) had 2 or more CVR factors. Dyslipidemia was present in 358 (76.8%), AH in 282 (60.5%) and type 2 Diabetes mellitus (T2DM) in 27 (5.8%) patients. More than half of patients (n=303, 65.0%) were overweight (BMI&amp;gt;25.0 kg/m2). 65 (13.9%) women were current or ex-smokers. True myocardial perfusion defect was detected in 96 patients (20.6%). There was no statistically significant difference between CVR risk factor count and cardiac SPECT result (p=0.229), although there were patients with significant perfusion defect without any risk factor present. However, significant correlation between risk factors and detection of obstructive coronary artery disease (CAD) after positive cardiac SPECT was found (p&amp;lt;0.001). Totally in study was detected 71 patients with suspected ischemia with non-obstructive CAD (INOCA), but further investigation with intracoronary physiology measurements – coronary flow reserve (CFR), index of microvascular resistance (IMR) and acetylcholine provocation test is required to define INOCA endotype. Conclusions The cardiac SPECT is an appropriate diagnostic method for women patients with suspected CAD. Even in patients with no CVR factors, but with positive or non-informative exercise test, the CAD is present, therefore they should be referred to cardiac SPECT in a very high CVR country. In patients with significant perfusion defect and absence of obstructive CAD, the performance of intracoronary physiology measurements is required.

Coronary microvascular dysfunction in Takotsubo syndrome and associations with left ventricular function.

Coronary microvascular dysfunction (CMD) has been proposed as an important pathophysiological mechanism in Takotsubo syndrome (TTS). Our aims were (i) to evaluate and compare levels of CMD in patients with TTS and patients with ischaemia and no obstructive coronary arteries (INOCA) and (ii) to investigate associations between CMD and clinical parameters, left ventricular function, and coronary atherosclerosis in TTS. We conducted a prospective study of 27 female TTS patients and an equally sized, age- and gender-matched, cohort of INOCA patients. Coronary microvascular function was quantified invasively using the index of microcirculatory resistance (IMR), coronary flow reserve (CFR), and resistive reserve ratio (RRR). CMD was defined as IMR≥25 and/or CFR≤2. In the TTS patients, left ventricular function was assessed with echocardiography and cardiovascular magnetic resonance (CMR) imaging, and coronary atherosclerosis was visualized with intravascular ultrasound with near-infrared spectroscopy (IVUS-NIRS). The incidence of CMD was higher in the TTS patients than in the INOCA cohort (78% vs. 44%, P=0.01), with higher IMR (30 vs. 14, P=0.002), lower CFR (1.8 vs. 2.8, P=0.009), and lower RRR (2.1 vs. 3.5, P=0.003). In apical compared with midventricular TTS, IMR was numerically higher (50 vs. 28, P=0.20), whereas CFR and RRR were lower (1.5 vs. 2.5, P=0.003 and 1.6 vs. 2.7, P=0.01, respectively). Global longitudinal strain and global circumferential strain, assessed with CMR imaging, were more impaired in apical than in midventricular TTS (-11 vs. -14, P<0.001 and -12 vs. -15, P=0.049, respectively). In the TTS patients, CFR and RRR correlated with echocardiography-derived (R2 =0.15, P=0.002 and R2 =0.18, P=0.007, respectively) and CMR-derived (R2 =0.09, P=0.025 and R2 =0.10, P=0.038, respectively) ejection fraction. CFR and RRR correlated inversely with CMR-derived end-diastolic volume index, end-systolic volume index, and left ventricular mass index. IMR, CFR, and RRR were not associated with measures of coronary atherosclerosis derived by IVUS-NIRS. Coronary microvascular dysfunction is common in patients with TTS and more frequent than in patients with INOCA. CMD in TTS is more severe in the apical compared with the midventricular phenotype of the syndrome, is associated with left ventricular function, but is unrelated to coronary atherosclerosis. Our results support the notion of CMD as a key mediator in TTS.

Ticagrelor vs. clopidogrel for coronary microvascular dysfunction in patients with STEMI: a meta-analysis of randomized controlled trials.

Approximately half of ST-segment elevation myocardial infarction (STEMI) patients who undergo revascularization present with coronary microvascular dysfunction. Dual antiplatelet therapy, consisting of aspirin and a P2Y12 inhibitor (e.g., clopidogrel or ticagrelor), is recommended to reduce rates of cardiovascular events after STEMI. The present study performed a pooled analysis of randomized controlled trials (RCTs) to compare effects of ticagrelor and clopidogrel on coronary microcirculation dysfunction in STEMI patients who underwent the primary percutaneous coronary intervention. The PubMed, Embase, Cochrane Library, and Web of Science databases were searched for eligible RCTs up to September 2022, with no language restriction. Coronary microcirculation indicators included the corrected thrombolysis in myocardial infarction (TIMI) frame count (cTFC), myocardial blush grade (MBG), TIMI myocardial perfusion grade (TMPG), coronary flow reserve (CFR), and index of microcirculatory resistance (IMR). Seven RCTs that included a total of 957 patients (476 who were treated with ticagrelor and 481 who were treated with clopidogrel) were included. Compared with clopidogrel, ticagrelor better accelerated microcirculation blood flow [cTFC = -2.40, 95% confidence interval (CI): -3.38 to -1.41, p < 0.001] and improved myocardial perfusion [MBG = 3, odds ratio (OR) = 1.99, 95% CI: 1.35 to 2.93, p < 0.001; MBG ≥ 2, OR = 2.57, 95% CI: 1.61 to 4.12, p < 0.001]. Ticagrelor has more benefits for coronary microcirculation than clopidogrel in STEMI patients who undergo the primary percutaneous coronary intervention. However, recommendations for which P2Y12 receptor inhibitor should be used in STEMI patients should be provided according to results of studies that investigate clinical outcomes.

P106 AN INTRIGUING CASE OF INOCA IN THE CATH–LAB

Abstract A 63–year–old woman presented to our Center for a longstanding history of typically radiating oppressive chest pain, with both resting and exertional episodes,mostly occurring early in the morning and exacerbated by cold.Two years before for a treadmill test positive for electrocardiographic (EKG) criteria of exercise–induced ischemia, she underwent coronary angiography which was found negative for epicardial obstructive coronary artery disease.Given the suspicion of coronary microvascular disease,empirical antianginal therapy with Ranolazine was started at that time,with transient improvement of symptoms. She presented to our Center for a 6 month history of recurrence of symptoms. Her antianginal therapy with Ranolazine was up titrated to 750 mg BID and Verapamil (40 mg TID) was added to her usual therapy given the suspicion of coronary vasospasm as additional component in the pathogenesis of her symptoms,as suggested by the anamnestic recall.Moreover a 24–hour–Holter monitoring was performed with subsequent finding of several episodes of horizontal ST–segment depression(up to 3 mm),mainly on awakening,in the absence of significant arrhythmias.The patient underwent coronary angiography for the assessment of coronary physiology. On angiography, the absence of epicardial obstructive coronary artery disease was confirmed, with the finding of extensive coronary fistulas originating from the left coronary system and communicating with the left ventricular cavity.After induction of maximal hyperemia, the clinical suspicion of coronary microvascular disease was confirmed (CFR 1.9).In addition, reduced coronary flow reserve in the left anterior descending (LAD) territory compatible with both microvascular dysfunction and coronary steal was documented (RFR 0.91;baseline FFR:0.94,after systemic adenosine:0.79).Given the clinical suspicion, vasoreactivity test with intracoronary acetylcholine (2–20–100–200 mcg) was also performed,which was positive for epicardial spasm at mid–distal LAD and concomitant onset of chest pain and ischemic EKG changes(diffuse ST–segment depression) with prompt regression after intracoronary nitrate administration.Taken together,clinical and instrumental findings suggested the diagnosis of mixed angina by combination of three mechanisms:microvascular disease,epicardial spasm and coronary steal due to extensive coronary artery fistulas.The patient was discharged with Ranolazine and Diltiazem at maximum tolerated dose with clinical benefit.

Home-Based Exercise Training in the Recovery of Multisystem Inflammatory Syndrome in Children: A Case Series Study.

To assess the potential therapeutic role of exercise on health-related quality of life, assessed by the Pediatric Outcomes Data Collection Instrument (PODCI), coronary flow reserve (CFR), cardiac function, cardiorespiratory fitness, and inflammatory and cardiac blood markers in multisystemic inflammatory syndrome in children (MIS-C) patients. This is a case series study of a 12-wk, home-based exercise intervention in children and adolescents after MIS-C diagnosis. From 16 MIS-C patients followed at our clinic, 6 were included (age: 7-16 years; 3 females). Three of them withdrew before the intervention and served as controls. The primary outcome was health-related quality of life, assessed PODCI. Secondary outcomes were CFR assessed by 13N-ammonia PET-CT imaging, cardiac function by echocardiography, cardiorespiratory fitness, and inflammatory and cardiac blood markers. In general, patients showed poor health-related quality of life, which seemed to be improved with exercise. Additionally, exercised patients showed improvements in coronary flow reserve, cardiac function, and aerobic conditioning. Non-exercised patients exhibited a slower pattern of recovery, particularly in relation to health-related quality of life and aerobic conditioning. Our results suggest that exercise may play a therapeutic role in the treatment of post-discharge MIS-C patients. As our design does not allow inferring causality, randomized controlled trials are necessary to confirm these preliminary findings.

Fibrotic Plaque and Microvascular Dysfunction Predict Early Cardiac Allograft Vasculopathy Progression After Heart Transplantation: The Early Post Transplant Cardiac Allograft Vasculopathy Study.

Early cardiac allograft vasculopathy (CAV) prognostication is needed to improve long-term outcomes after heart transplantation. We characterized first year posttransplant coronary anatomic-physiologic alterations to determine predictors of early CAV progression. Heart transplant recipients at 2 institutions (enrolled January 2018 to March 2021) underwent prospective evaluation 3 and 12-month posttransplant with angiography and left anterior descending artery intravascular ultrasound, optical coherence tomography, fractional flow reserve, coronary flow reserve, and index of microcirculatory resistance measurements. CAV progression was assessed by intravascular ultrasound change in percentage intimal volume from baseline to 12-month follow-up. Eighty-two patients (mean age, 51 years; 60% men) completed evaluation at mean 13.8 and 56.3 weeks posttransplant. Donor atherosclerosis (baseline intravascular ultrasound maximal intimal thickness, ≥0.5 mm) was evident in 50%. De novo (follow-up maximal intimal thickness, ≥0.5 mm) and rapidly progressive CAV (maximal intimal thickness, ≥0.5-mm increase from baseline) developed in 24% and 13%, respectively. On optical coherence tomography, baseline to follow-up median intimal volume increased 42% (0.58 mm3/mm), percentage intimal volume increased 44% (4.6%), vessel volume decreased 4% (-0.50 mm3/mm) and lumen volume decreased 9% (-1.02 mm3/mm); P<0.05 for all. Fibrotic plaque was the predominant morphology: baseline, 29% and follow-up, 50%. Coronary physiology was abnormal in 41% at baseline and 45% at follow-up, with 1 in 5 patients having microvascular dysfunction (index of microcirculatory resistance, ≥25). On multivariable linear regression analysis, recipient male sex, fibrotic plaque, and index of microcirculatory resistance were independent predictors of coronary disease progression. Fibrotic plaque on optical coherence tomography and index of microcirculatory resistance early posttransplant predict CAV progression in the first year of transplantation. URL: https://www. gov; Unique identifier: NCT03217786.

Development of artificial intelligence tools for invasive Doppler-based coronary microvascular assessment.

Coronary flow reserve (CFR) assessment has proven clinical utility, but Doppler-based methods are sensitive to noise and operator bias, limiting their clinical applicability. The objective of the study is to expand the adoption of invasive Doppler CFR, through the development of artificial intelligence (AI) algorithms to automatically quantify coronary Doppler quality and track flow velocity. A neural network was trained on images extracted from coronary Doppler flow recordings to score signal quality and derive values for coronary flow velocity and CFR. The outputs were independently validated against expert consensus. Artificial intelligence successfully quantified Doppler signal quality, with high agreement with expert consensus (Spearman's rho: 0.94), and within individual experts. Artificial intelligence automatically tracked flow velocity with superior numerical agreement against experts, when compared with the current console algorithm [AI flow vs. expert flow bias -1.68 cm/s, 95% confidence interval (CI) -2.13 to -1.23 cm/s, P < 0.001 with limits of agreement (LOA) -4.03 to 0.68 cm/s; console flow vs. expert flow bias -2.63 cm/s, 95% CI -3.74 to -1.52, P < 0.001, 95% LOA -8.45 to -3.19 cm/s]. Artificial intelligence yielded more precise CFR values [median absolute difference (MAD) against expert CFR: 4.0% for AI and 7.4% for console]. Artificial intelligence tracked lower-quality Doppler signals with lower variability (MAD against expert CFR 8.3% for AI and 16.7% for console). An AI-based system, trained by experts and independently validated, could assign a quality score to Doppler traces and derive coronary flow velocity and CFR. By making Doppler CFR more automated, precise, and operator-independent, AI could expand the clinical applicability of coronary microvascular assessment.

Coronary microvascular disease is associated with arterial stiffness in patients with ischemia and no obstructive coronary arteries

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Existing data suggest that stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. There is a gap in the current literature regarding the possible association between higher aortic stiffness and myocardial ischemia in this special population. Arterial Stiffness (AS) is an independent risk factor for cardiovascular disease, directly related to increased coronary atherosclerosis, an entity frequently encountered in hypertensive patients. Purpose The aim of this study is to determine whether arterial stiffness is increased in patients with Coronary Microvascular Dysfunction (CMD) compared to hypertensives controls. Methods We examined 21 hypertensive patients [9 female, 39%, mean age: 61.2±9.9 years, mean office blood pressure (BP) : 139/86±18/10 mmHg] and 25 CMD patients (16 female, 64%, mean age : 57.9±4.8 years, average office BP: 127/77±18/10 mmHg). In the group of patients with chronic angina pectoris, CMD was defined by a standardized systematic protocol in which coronary flow reserve (CFR) and index of microvascular resistance (IMR) were measured in the left anterior descending coronary artery using a temperature/pressure sensor-tipped guidewire. CMD patients were classified into 2 groups, structural and functional endotype, based on commonly used cut-offs (impaired CFR &amp;lt; 2.5, increased IMR ≥ 25). Functional CMD was defined as abnormal CFR in combination with normal IMR and structural CMD as abnormal CFR with abnormal IMR. In addition, in all participants, arterial stiffness was assessed using aortic augmentation index (AIx), derived from the analysis of central pulse waveforms, recorded by applanation tonometry directly from the radial artery. Results In CMD group, mean CFR and IMR were 1.6 ± 0.9 and 43.9± 30 IU, respectively. Of the 25 patients with abnormal CFR, 8 (32%) had normal IMR consistent with functional CMD endotype, and 17 (68%) had abnormal IMR consistent with structural endotype. AIx was found increased in CMD patients compared to asymptomatic hypertensives (36.44±11.1 vs 25.4±11.6%, p=0.024). This difference in AIx between the CMD and asymptomatic hypertensive controls was found to be statistically significant after adjustment for gender and age (p&amp;lt;0.05). No statistically significant difference was found in body mass index, renal function, history of dyslipidemia, diabetes mellitus and smoking between the two groups (p=NS). Conclusion Arterial stiffness was found increased in patients with CMD compared to hypertensives. These results suggest that therapies targeting vascular stiffening could provide additional clinical benefit in this special category of patients with impaired coronary microvasculature.

Coronary microvascular disease is associated with decreased nailfold capillary density in patients with ischemia and no obstructive coronary arteries

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Existing data support that coronary microcirculation impairment is common in patients with angina pectoris without obstructive coronary artery disease. There are insufficient data in the literature regarding possible generalized microangiopathy in the above population. Purpose The aim of this study is to evaluate whether patients with coronary microvascular dysfunction (CMD) compared to individuals without angina are characterized by a different level of capillary density in the nailfold capillary microscopy. Methods We examined 21 patients [9 female, 39%, mean age: 61.2±9.9 years, mean office blood pressure (BP) : 139/86±18/10 mmHg] and 25 CMD patients (16 female, 64%, mean age : 57.9±4.8 years, average office BP: 127/77±18/10 mmHg). In the group of patients with chronic angina pectoris CMD was defined by a standardized systematic protocol in which coronary flow reserve (CFR) and index of microvascular resistance (IMR) were measured in the left anterior descending coronary artery using a temperature/pressure sensor-tipped guidewire. CMD patients were classified into 2 groups, the structural and the functional endotype, based on commonly used cut-offs (impaired CFR &amp;lt; 2.5, increased IMR ≥ 25). Functional CMD was defined as abnormal CFR in combination with normal IMR and structural CMD as abnormal CFR with abnormal IMR. In addition, the assessment of skin microcirculation was performed by capillaroscopy, a non-invasive technique to evaluate small vessels of the microcirculation in the nailfold, using stereomicroscope in all patients. Results In CMD group, mean CFR and IMR were 1.6 ± 0.9 and 43.9± 30 IU, respectively. Of the 25 patients with abnormal CFR, 8 (32%) had normal IMR consistent with functional CMD endotype, and 17 (68%) had abnormal IMR consistent with structural endotype. Capillary density in patients with CMD was significantly decreased compared to that of asymptomatic participants (9 vs 10.86 vessels/mm, p=0.04). The difference in capillary density between the two groups was statistically significant after adjustment for multiple comparisons (p&amp;lt;0.05). No significant difference was found in body mass index, renal function, medical history of dyslipidemia, diabetes mellitus and smoking status between the two groups (p&amp;lt;0.05). Conclusion Patients with CMD compared to individuals without angina are characterized by decreased nailfold capillary density. These results suggest that there is a correlation between microcirculatory impairment at the level of the coronary microcirculation and the peripheral vascular beds.

Diagnostic performance of angiography-derived fractional flow reserve analysis based on bifurcation fractal law for assessing hemodynamic significance of coronary stenosis.

Blood flow into the side branch affects the calculation of coronary angiography-derived fractional flow reserve (FFR), called Angio-FFR. Neglecting or improperly compensating for the side branch flow may decrease the diagnostic accuracy of Angio-FFR. This study aims to evaluate the diagnostic accuracy of a novel Angio-FFR analysis that considers the side branch flow based on the bifurcation fractal law. A one-dimensional reduced-order model based on the vessel segment was used to perform Angio-FFR analysis. The main epicardial coronary artery was divided into several segments according to the bifurcation nodes. Side branch flow was quantified using the bifurcation fractal law to correct the blood flow in each vessel segment. In order to verify the diagnostic performance of our Angio-FFR analysis, two other computational methods were taken as control groups: (i) FFR_s: FFR calculated by delineating the coronary artery tree to consider side branch flow, (ii) FFR_n: FFR calculated by just delineating the main epicardial coronary artery and neglecting the side branch flow. The analysis of 159 vessels from 119 patients showed that our Anio-FFR calculation method had comparable diagnostic accuracy to FFR_s and provided significantly higher diagnostic accuracy than that of FFR_n. In addition, using invasive FFR as a reference, the Pearson correlation coefficients of Angio-FFR and FFRs were 0.92 and 0.91, respectively, while that of FFR_n was only 0.85. Our Angio-FFR analysis has demonstrated good diagnostic performance in assessing the hemodynamic significance of coronary stenosis by using the bifurcation fractal law to compensate for side branch flow. Bifurcation fractal law can be used to compensate for side branch flow during the Angio-FFR calculation of the main epicardial vessel. Compensating for side branch flow can improve the ability of Angio-FFR to diagnose stenosis functional severity. • The bifurcation fractal law could accurately estimate the blood flow from the proximal main vessel into the main branch, thus compensating for the side branch flow. • Angiography-derived FFR based on the bifurcation fractal law is feasible to evaluate the target diseased coronary artery without delineating the side branch.

Sex differences in the development of coronary microvascular diseases in type-2 diabetes: possible role of gap junction protein connexin-40

Type-2 diabetes (T2D) increases the risk of cardiovascular diseases 2-4 folds in both sexes compared to non-diabetic individuals. However, more than 50% of female patients who experience chest pain have coronary microvascular disease (CMD) instead of obstructive CAD. On the other hand, 20% of men with chest pain have CMD. CMD is characterized by reduced coronary flow reserve, and coronary flow is regulated by the change in capillary density and vessel diameter. Gap junction protein connexin-40 (Cx40) plays a significant role in coronary microvascular function by controlling endothelium-dependent relaxation (EDR), cardiac endothelial cell (CEC) migration and capillary density. We hypothesized that T2D differentially affects the CX-40 expression and function in male and female coronary artery (CA) and causes CMD. The objective of this study is to identify the molecular mechanisms underlining the development of T2D-induced CMD in male and female mice.T2D mice were generated by a combination of high-fat diet feeding and a low-dose of streptozotocin (75 mg/kg, i.p.). The oral glucose tolerance was conducted at 4-, 8-, 12-, and 16 weeks after diabetes induction. Coronary flow velocity reserve (CFVR) was used to assess coronary microvascular function in mice. Coronary endothelial function was determined by 1) capillary density measurement in the left ventricle and 2) isometric tension experiment in small CAs (3rd order). CECs from male and female mice were isolated to conduct molecular biological experiments.There was no significant difference in CFVR and capillary density between control male and female mice. However, T2D mice of both sexes showed significant differences in the properties of EDR, CFVR and capillary density. T2D male mice exhibited a significant attenuation of EDR accompanied by impaired endothelium-derived nitric oxide(EDNO)-dependent relaxation and endothelium-dependent hyperpolarization (EDH)-mediated relaxation. On the contrary, there is no difference in EDR between control and diabetic female mice. Capillary density was reduced in T2D mice of both sexes compared to the respective controls. Our RNA sequencing data in CECs revealed that Cx40 is one of the genes which contributes to diabetes-mediated CMD. Systemic Cx40-KO male mice showed reduced EDR, EDH-mediated relaxation and capillary density compared to wild type control. T2D reduced the expression of Cx40 and overexpression of Cx40 restored EDR in CAs and increased capillary density in T2D male mice.T2D impaired coronary microvascular function in both sexes. However, the cause of reduced CFVR was different between diabetic male and female mice. In T2D females, capillary rarefaction was a primary cause of reduced CFVR. In contrast, attenuated EDNO- and EDH-mediated relaxation, reduced capillary density and downregulation of Cx40 contributed to decreased CFVR in T2D male mice. Future studies are required to establish the role of Cx40 in the development of CMD in T2D females. Supported by NIH R01HL142214 and DOD W81XWH2110472 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Impact of Trimethylamine N-Oxide and Coronary Microcirculatory Dysfunction on Outcomes following ST-Elevation Myocardial Infarction

Persistent coronary microcirculatory dysfunction (CMD) and elevated trimethylamine N-oxide (TMAO) levels after ST-elevation myocardial infarction (STEMI) may drive negative structural and electrical cardiac remodeling, resulting in new-onset atrial fibrillation (AF) and a decrease in left ventricular ejection fraction (LVEF). TMAO and CMD are investigated as potential predictors of new-onset AF and left ventricular remodeling following STEMI. This prospective study included STEMI patients who had primary percutaneous coronary intervention (PCI) followed by staged PCI three months later. Cardiac ultrasound images were obtained at baseline and after 12 months to assess LVEF. Coronary flow reserve (CFR), and index of microvascular resistance (IMR) were assessed using the coronary pressure wire during the staged PCI. Microcirculatory dysfunction was defined as having an IMR value ≥25 U and CFR value <2.5 U. A total of 200 patients were included in the study. Patients were categorized according to whether or not they had CMD. Neither group differed from the other with regards to known risk factors. Despite making up only 40.5% of the study population, females represented 67.4% of the CMD group p < 0.001. Similarly, CMD patients had a much higher prevalence of diabetes than those without CMD (45.7% vs. 18.2%; p < 0.001). At the one-year follow-up, the LVEF in the CMD group had decreased to significantly lower levels than those in the non-CMD group (40% vs. 50%; p < 0.001), whereas it had been higher in the CMD group at baseline (45% vs. 40%; p = 0.019). Similarly, during the follow-up, the CMD group had a greater incidence of AF (32.6% vs. 4.5%; p < 0.001). In the adjusted multivariable analysis, the IMR and TMAO were associated with increased odds of AF development (OR: 1.066, 95% CI: 1.018-1.117, p = 0.007), and (OR: 1.290, 95% CI: 1.002-1.660, p = 0.048), respectively. Similarly, elevated levels of IMR and TMAO were linked with decreased odds of LVEF improvement, while higher CFR values are related to a greater likelihood of LVEF improvement. CMD and elevated TMAO levels were highly prevalent three months after STEMI. Patients with CMD had an increased incidence of AF and a lower LVEF 12 months after STEMI.

Non-invasive Evaluation of Coronary Flow Reserve in Cardiac Syndrome X Patients.

Non-invasive Evaluation of Coronary Flow Reserve in Cardiac Syndrome X Patients.

Adverse cardiovascular events in patients with coronary microvascular dysfunction: results of a 12-month follow-up with a control group

Aim. To assess the development of adverse cardiovascular events in patients with non-obstructive coronary artery disease (CAD) and coronary microvascular dysfunction (CMD), identified by dynamic myocardial single-photon emission computed tomography (SPECT), during 12-month follow-up compared with patients without CMD.Material and methods. The study included 118 patients (70 men, mean age, 62,0 [58,0; 69,0] years) with preserved ejection fraction (62 [59; 64] %) and non-obstructive CAD. Serum levels of the N-terminal pro-brain natriuretic peptide were assessed at baseline by enzyme immunoassay. Coronary flow reserve (CFR) was assessed by dynamic SPECT. CFR ≤2 was a CMD marker.Results. Six patients discontinued participation in the study due to loss of contact with them, while the rest were divided into groups depending on CMD presence: group 1 included patients with CMD (CFR ≤2; n=42), and group 2 was the control group and included patients without CMD (CFR &gt;2; n=70). Within 12-month follow-up, 25 patients reported adverse events. According to Kaplan-Meier analysis, the prevalence of adverse cardiovascular events was higher in patients with CMD (45,2%, n=19) than in patients without it (8,6%, n=6) (p&lt;0,001). Multivariate regression analysis showed that the presence of CMD (odds ratio (OR), 2,42; 95% confidence interval (CI), 1,26-5,85; p&lt;0,001) and diastolic dysfunction (OR, 3,27; 95% CI, 2,26-5,64; p&lt;0,001) were independent predictors of poor outcomes. The combination of CMD with diastolic dysfunction more than 5 times increased the risk of adverse events (OR, 5,18; 95% CI, 3,61-11,84; p&lt;0,001).Conclusion. We found that in patients with non-obstructive CAD, the presence of CMD, identified by dynamic myocardial SPECT, was associated with a higher risk of adverse cardiovascular events within 12-month follow-up period than in patients without CMD. At the same time, the combination of CMD with diastolic dysfunction more than 5 times increased the risk of adverse outcomes.

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.

The value of myocardial work in the estimation of left ventricular systolic function in patients with coronary microvascular disease: A study based on adenosine stress echocardiography.

Coronary microvascular dysfunction (CMD) is associated with increased cardiovascular events in patients with angina with non-obstructive coronary (ANOCA), especially heart failure. Conventional echocardiography is difficult to identify early alterations in cardiac function due to CMD. We recruited 78 ANOCA patients. All patients underwent conventional echocardiography examination, adenosine stress echocardiography and examination of coronary flow reserve (CFR) by transthoracic echocardiography. Based on the CFR results, patients were divided into the CMD group (CFR < 2.5) and the non-CMD group (CFVR ≥ 2.5). Demographic data, conventional echocardiographic parameters, two-dimensional speckle-tracking echocardiography (2D-STE) parameters and myocardial work (MW) were compared between the two groups at rest and at stress. Logistic regression was used to analyze the factors associated with CMD. There was no significant difference in conventional echocardiography parameters, 2D-STE related indices or MW at rest between the two groups. Global work index (GWI), global contractive work (GCW), and global work efficiency (GWE) were lower in the CMD group than in the non-CMD group at stress (p = 0.040, 0.044, <0.001, respectively), but global waste work (GWW) and peak strain dispersion (PSD) were higher (both p < 0.001). GWI and GCW were associated with systolic blood pressure, diastolic blood pressure, product of heart rate and blood pressure, GLS and coronary flow velocity. While GWW was mainly correlated with PSD, GWE was correlated with PSD and GLS. In the non-CMD group, the responses to adenosine was mainly manifested as an increase in GWI, GCW and GWE (p = 0.001, 0.001, 0.009, respectively) and a decrease in PSD and GWW (p = 0.001, 0.015, respectively). In the CMD group, the response to adenosine was mainly manifested as an increase in GWW and a decrease in GWE (p = 0.002, and 0.006, respectively). In the multivariate regression analysis, we found that ΔGWW (difference in GWW before vs. after adenosine stress) and ΔPSD (difference in PSD before vs. after adenosine stress) were independent factors associated with CMD. The ROC curves showed that the composite prediction model consisting of ΔGWW and ΔPSD had excellent diagnostic value for CMD (area under the curve = 0.913). In the present study, we found that CMD caused deterioration of myocardial work in ANOCA patients under adenosine stress, and that increased cardiac contraction asynchrony and wasted work may be the main changes caused by CMD.