Microangiopathy Research Articles

Feasibility and Improved Diagnostic Yield of Intracoronary Adenosine to Assess Microvascular Dysfunction With Bolus Thermodilution.

Bolus thermodilution and intravenous adenosine are established methods for coronary microcirculatory assessment. Yet, its adoption remains low, partly due to procedural time and patient discomfort associated with intravenous adenosine. We investigated differences between intracoronary and intravenous adenosine using bolus thermodilution in terms of microcirculatory indices, procedural time, and side effects associated with adenosine in patients with myocardial ischemia and nonobstructive coronary arteries. In this prospective, observational study, 102 patients with suspected myocardial ischemia and nonobstructive coronary arteries underwent measurements of mean transit time, coronary flow reserve, index of microcirculatory resistance, procedure time and patient tolerability with low-dose intracoronary adenosine, high-dose intracoronary adenosine (HDIC), and intravenous adenosine. HDIC induced greater hyperemia compared with low-dose intracoronary IC adenosine and intravenous adenosine with a shorter hyperemic mean transit time, P<0.0001. Coronary flow reserve was higher and index of microcirculatory resistance lowest with HDIC, compared with low-dose intracoronary IC adenosine and intravenous adenosine, P<0.05. Low coronary flow reserve was downgraded from 21% with intravenous adenosine to 10% with HDIC adenosine (P=0.031); high index of microcirculatory resistance was downgraded from 23% with intravenous adenosine to 14% with HDIC (P=0.098). Intracoronary adenosine was associated with lower procedural times (P<0.0001). More patients experienced chest pain with intravenous adenosine (P<0.01) and the chest pain intensity was higher compared with intracoronary adenosine (P<0.0001). In patients with suspected myocardial ischemia and nonobstructive coronary arteries undergoing coronary microcirculatory assessment with bolus thermodilution, the use of HDIC compared with intravenous adenosine was associated with enhanced induction of hyperemia. The use of intracoronary adenosine allowed for a shorter procedure time and was better tolerated. URL: clinicaltrials.gov; Unique Identifier: NCT04827498.

Developing a Women's Heart Center With a Specialization in Coronary Microvascular and Vasomotor Dysfunction: If You Build It, They Will Come.

Women's Heart Centers (WHC) are comprehensive, multidisciplinary care centers designed to close the existing gap in women's cardiovascular care. The WHC at The Christ Hospital Heart and Vascular Institute (TCH-WHC) in Cincinnati, Ohio was established in October of 2020, and is a specialized coronary microvascular and vasomotor dysfunction (CMVD) program. The TCH-WHC focuses its efforts across five pillars: patient care, research, education, community outreach and advocacy, and grants and philanthropy. These areas, centered around providing specalized CMVD care and treatment have allowed for substantial growth. From October 2020-December 2023, TCH-WHC saw a total of 3219 patients, 42% of which were apart of the CMVD program. Since establishment, patient volume has consistently increased year over year. The CMVD program at TCH-WHC is one of the fastest growing in the U. S. and is nationally recognized for specialized clinical care, diagnostics, and research. The goal of this review is to provide an overview of the TCH-WHC structure that allows for the establishment and growth of a CMVD program and to outline core activities supporting the TCH-WHC approach.

Microvascular insulin resistance with enhanced muscle glucose disposal in CD36 deficiency.

Microvascular dysfunction contributes to insulin resistance. CD36, a fatty acid transporter and modulator of insulin signalling, is abundant in microvascular endothelial cells. Humans carrying the minor allele (G) of CD36 coding variant rs3211938 have 50% reduced CD36 expression and show endothelial dysfunction. We aimed to determine whether G allele carriers have microvascular resistance to insulin and, if so, how this affects glucose disposal. Our multi-disciplinary approach included hyperinsulinaemic-euglycaemic clamps in Cd36-/- and wild-type mice, and in individuals with 50% CD36 deficiency, together with control counterparts, in addition to primary human-derived microvascular endothelial cells with/without CD36 depletion. Insulin clamps showed that Cd36-/- mice have enhanced insulin-stimulated glucose disposal but reduced vascular compliance and capillary perfusion. Intravital microscopy of the gastrocnemius showed unaltered transcapillary insulin flux. CD36-deficient humans had better insulin-stimulated glucose disposal but insulin-unresponsive microvascular blood volume (MBV). Human microvascular cells depleted of CD36 showed impaired insulin activation of Akt, endothelial NO synthase and NO generation. Thus, in CD36 deficiency, microvascular insulin resistance paradoxically associated with enhanced insulin sensitivity of glucose disposal. CD36 deficiency was previously shown to reduce muscle/heart fatty acid uptake, whereas here we showed that it reduced vascular compliance and the ability of insulin to increase MBV for optimising glucose and oxygen delivery. The muscle and heart respond to these energy challenges by transcriptional remodelling priming the tissue for insulin-stimulated glycolytic flux. Reduced oxygen delivery activating hypoxia-induced factors, endothelial release of growth factors or small intracellular vesicles might mediate this adaptation. Targeting NO bioavailability in CD36 deficiency could benefit the microvasculature and muscle/heart metabolism. Clinicaltrials.gov NCT03012386 DATA AVAILABILITY: The RNAseq data generated in this study have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/ ) under accession code GSE235988 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235988 ).

GLCCI1 alleviates GRP78-initiated endoplasmic reticulum stress-induced apoptosis of retinal ganglion cells in diabetic retinopathy by upregulating and interacting with HSP90AB1

Retinal ganglion cells (RGCs) are among the first neurons to undergo apoptosis in diabetic retinopathy (DR), with their relationship to endoplasmic reticulum stress (ERS)-induced apoptosis still unclear. While glucocorticoid-induced transcript 1 (GLCCI1) has been shown to inhibit apoptosis, its role in ERS-induced apoptosis and its mechanisms in DR remain unclarified. Our findings indicated that GLCCI1 is predominantly localized in the ganglion cell layer and is downregulated in DR. GLCCI1 overexpression mitigated the apoptosis of RGCs and the swelling of endoplasmic reticulum and mitochondria under hyperglycemia, and downregulated ERS-induced apoptosis related markers (GRP78, CHOP and cleaved CASP3), whereas GLCCI1 knockdown has the opposite effect. In vivo, GLCCI1 overexpression not only prevents structural lesions but also protects against microvascular dysfunctions in the retinas of DR mice. We found that GLCCI1 directly interacts with HSP90AB1, which in turn interacts with GRP78. Additionally, GLCCI1 is an upstream regulator of HSP90AB1, which regulates GRP78. Thus, the impact of GLCCI1 on the ERS-induced apoptosis is mainly through the regulation of HSP90AB1, and subsequently inhibiting GRP78-initiated ERS-induced apoptosis. These findings offer a promising avenue for further treatment of DR.

Association between the plasma ceramide and coronary microvascular resistance

BackgroundPlasma ceramide plays a potentially significant role in the pathogenesis of coronary microvascular dysfunction. However, the relationship between plasma ceramide and coronary microvascular resistance in patients remains unclear. This study aimed to evaluate the association between plasma ceramide levels, as well as their distinct ratios, and coronary microvascular resistance.MethodsThis single-center observational study retrospectively enrolled patients who underwent both ceramide measurement and coronary angiography during hospitalization. The microvascular resistance of the coronary arteries was assessed in all patients using the angiography-derived index of microcirculatory resistance (Angio-IMR). The cumulative coronary microvascular resistance was calculated by summing the microvascular resistance of the three main coronary arteries. Multiple linear and logistic regression analyses were employed to evaluate the relationship between plasma ceramide and cumulative coronary microvascular resistance. Restricted cubic spline (RCS) analysis was conducted to investigate the association between plasma ceramide levels and cumulative coronary microvascular resistance. Receiver operating characteristic (ROC) curves were employed to evaluate the predictive value of plasma ceramide for coronary microvascular resistance. Additionally, subgroup analyses and interaction tests were performed.ResultsA total of 225 patients were included in this study, with a median cumulative coronary microvascular resistance of 48.04 (40.32–56.73). After adjusting for potential confounding factors, both plasma 16:0 ceramide and the 16:0/24:0 ceramide ratio were positively associated with cumulative coronary microvascular resistance [standardized β ± standard error: 75.05 ± 8.46 (P < 0.001) and 91.72 ± 20.41 (P < 0.001), respectively]. Similar independent associations were observed in predicting high cumulative microvascular resistance [β = 8.03 ± 1.91 (P < 0.001) and 9.98 ± 3.88 (P = 0.010), respectively]. Additionally, a significant nonlinear relationship was observed between plasma 16:0 ceramide, the 16:0/24:0 ceramide ratio, and cumulative coronary microvascular resistance (P for nonlinear < 0.05). The ROC analysis revealed that the optimal cut-off for plasma 16:0 ceramide is 0.178 µmol/L, with a specificity of 57.1% and a sensitivity of 91.2%. For the 16:0/24:0 ceramide ratio, the optimal cut-off is 0.072, yielding a specificity of 73.2% and a sensitivity of 54.9%. Subgroup analysis indicated that the association between plasma ceramide and coronary microvascular resistance was trending toward non-significance in patients with acute coronary syndrome (ACS).ConclusionsA significant nonlinear relationship exists between plasma ceramide and coronary microvascular resistance, which holds important clinical implications for the risk stratification of coronary microvascular disease. New insights into the potential effects of ceramides enhance our understanding of the complex mechanisms underlying coronary microvascular disease and warrant further investigation in a broader population.Graphical abstract

Coronary Sinus Reducer Improves Angina, Quality of Life, and Coronary Flow Reserve in Microvascular Dysfunction

Coronary Sinus Reducer Improves Angina, Quality of Life, and Coronary Flow Reserve in Microvascular Dysfunction

The Coronary Sinus Reducer as a Game-Changer for the Treatment of Coronary Microvascular Dysfunction

The Coronary Sinus Reducer as a Game-Changer for the Treatment of Coronary Microvascular Dysfunction

Coronary Microvascular Dysfunction: Searching the Strongest Imaging Modality in Different Scenarios.

Coronary microvascular dysfunction is a clinical condition very diffuse in many different settings. Often the diagnosis can be very tricky, and choosing the proper diagnostic strategy can be fundamental for reaching the goal. The aim of this review is to evaluate the properties and the feasibility of our tests in specific scenarios by looking at the performances of each methodology reported in the literature.

Paradigm shift from glucocentric to organ protection for the management of hyperglycemia in patients with type 2 diabetes

The UK Prospective Diabetes Study was the first study to investigate the effectiveness of glycemic control in patients with type 2 diabetes. Since then, many studies have evaluated the impact of intensive glycemic control on diabetes-related morbidities and mortality. The results of these studies were intended to change the paradigm for controlling glycated hemoglobin and preventing diabetes-related complications, but the beneficial outcomes were limited to microvascular diseases rather than diabetes-related cardiorenal diseases and deaths. This has emphasized the need for comprehensive management of other risk factors (hypertension, dyslipidemia, renal failure, etc.) in addition to hyperglycemia to prevent atherosclerotic cardiovascular diseases and end-stage renal disease in type 2 diabetes. Since 2008, clinical trials to demonstrate cardiovascular safety have shown a beneficial effect of sodium-glucose transporter 2 inhibitors or glucagon-like peptide-1 receptor agonists on macrovascular or renal complications in patients with type 2 diabetes. Recently, major societies around the world including the Korean Diabetes Association, have shifted the goals of diabetes management from the typical glucocentric view to cardiorenal outcome-oriented (organ protection) care, which has been widely accepted and is gradually applied to primary care.

Інфаркт міокарда з необструктивними коронарними артеріями: патогенетичні патерни та діагностичний пошук

The term MINOCA (Myocardial Infarction with Non-Obstructive Coronary Arteries) refers to pathological conditions where there is evidence of myocardial necrosis due to a lack of blood flow but no significant coronary lesions are seen on angiography. This is working diagnosis, which requires careful investigation to identify specific causes: plaque rupture, coronary dissection, vasospasm, microvascular dysfunction, thromboembolism, etc. Angiography alone, in most cases, does not lead to an etiological diagnosis. So additional techniques like intracoronary imaging and vasomotor function tests are important, especially in younger patients. This literature review demonstrates the main pathogenic patterns and diagnostic approachs for MINOCA patients.

Endogen microvascular dysfunction is associated with worse outcomes in heart transplantation

Abstract Background Cardiac allograft vasculopathy (CAV) affects the health of both epicardial and microvascular blood vessels in heart transplants. Coronary microvascular dysfunction (CMD) has been associated with poor outcomes in the non-transplant population. Two patterns of microvascular dysfunction have been characterized, classical (low stress flow) and endogen (high rest flow). Whether these patterns of microvascular dysfunction are associated with outcomes in the transplant population has not been thoroughly evaluated. Purpose The purpose of the study was to assess the relationship between microvascular dysfunction and adverse outcomes in patients with heart transplants. Methods Patients with no history of angiographic CAV who underwent positron emission tomography myocardial perfusion imaging and were found to have normal perfusion (summed stress score = 0) were included in the study. Patients were then classified by microvascular dysfunction: normal (flow reserve ≥ 2.0) versus abnormal (flow reserve &amp;lt;2.0). Patients were further subclassified based on pattern of microvascular dysfunction, classical (stress myocardial flow &amp;lt;1.7 mL/min/g) and endogen (stress myocardial flow ≥1.7 mL/min/g). The two primary outcomes were all-cause mortality and a composite of death, heart failure hospitalization, acute coronary syndrome, and revascularization. Kaplan-Meier survival and Cox proportional regression were used to assess the relationship between microvascular function and outcomes. Results In total, 359 patients were enrolled in the study, of which 29 (8%) had classical CMD and 78 (22%) had endogen CMD. Patients with endogen CMD were more likely to be women (46%) compared to 31% for normal microvascular function and 24% for classical CMD. During a median follow up period of 2.0 years (Q1 1.7, Q3 2.3), 36 patients had an adverse event and 19 patients died. Endogen CMD was associated with a significantly higher risk of both the composite outcome, HR 2.30 (1.15 – 4.61), and all-cause mortality, 4.19 (1.64 – 10.73). Classical CMD was not associated with either the composite outcome, HR 0.88 (0.20 – 3.84) or death, HR 1.02 (0.12 – 8.33), however assessment of classical CMD was limited by small sample size. Conclusions Endogen-type CMD is associated with worse intermediate-term outcomes in transplant patients compared to normal microvascular function and classical-type CMD, although comparison to classical-type CMD was limited by small sample size.Table 1:DemographicsFigure 1:KM Survival Curves

Traditional cardiovascular risk factors and coronary microvascular disease in women and men- a single center study

Abstract Introduction Coronary microvascular dysfunction (CMD) is a common, often missed, cause for effort intolerance and angina symptoms, and is associated with adverse clinical outcomes. Risk factors for the development of CMD have not been fully elucidated, and studies examining sex associated differences in traditional cardiovascular risk factors (TCRs) for obstructive coronary artery disease (CAD) in patients with CMD have yielded conflicting results. Although several non-invasive methods for the evaluation of CMD exist, currently, catheter-based invasive assessment is the gold standard for the diagnosis of coronary microvascular dysfunction. Purpose To examine the association between TCR and CMD and sex associated differences in TCR, in a prospective cohort of patients undergoing invasive microvascular function evaluation in a large tertiary medical center. Methods In this single center, prospective registry, we enrolled patients with non-obstructive CAD undergoing clinically indicated invasive assessment of coronary microvascular function between November 2019 and March 2023. Measurements of microvascular function included CFR, IMR, RRR as well as FFR. Pathologic CFR was defined as &amp;lt;2.5 or &amp;lt;2. Associations between coronary microvascular dysfunction, traditional cardiovascular risk factors, and sex were assessed using univariate and multivariate regression models. Results Overall, 245 patients with non-obstructive CAD were included in the analysis (62.9% female; median age 68 (interquartile range [IQR]: 59,75). Microvascular dysfunction was diagnosed in 141 patients (57.5%). The prevalence of microvascular dysfunction was similar in women and men in the entire cohort (59.0% vs. 57.0%; p=0.77). In 41 patients diagnosed with functional microvascular dysfunction there were more women than men (70.7% vs. 29%). When using a threshold of CFR&amp;lt;2.5 no association was found between traditional risk factors for coronary atherosclerosis and CMD regardless of whether CMD was structural or functional. In women, but not in men, older age and the presence of previous ischemic heart disease were associated with lower coronary flow reserve (CFR) (β=-0.29; p&amp;lt;0.01 and β=-0.15; p=0.05, respectively) and lower resistive reserve ratio (RRR) (β=-0.28; p&amp;lt;0.01 and β=-0.17; p=0.04, respectively). When using a threshold of &amp;lt;2.0 for CFR similar results were found. Conclusion The prevalence of TCRs was similar in patients with and without CMD. In women, older age and previous IHD were associated with lower CFR and RRR values while no association between TCRs and indices of CMD was found in men. It is likely that there are other, currently unknown risk factors for CMD as well as unique risk factors for each of its endotypes, beyond TCRs. It is unclear which parameter of microvascular dysfunction is the most accurate, and whether different parameters should be used in women and men. Large-scale multi-center studies to further evaluate these issues are needed.Variables associated with CMDStudy inclusion process

Assessment of structural and functional microvascular dysfunction using microvascular resistance reserve versus invasive exercise stress testing

Abstract Background Coronary microvascular dysfunction is an heterogenous entity with structural dysfunction present in about 60% of cases. Although Coronary Flow Reserve (CFR) is commonly used for diagnosis, this index is nonspecific to the microvasculature. The effectiveness of the recently introduced Microvascular Resistance Reserve (MRR) and absolute microvascular resistance (Rµ) in identifying microvascular dysfunction endotypes remains uncertain. Objective To evaluate whether MRR and hyperemic Rµ assessment are effective in dichotomizing functional and structural microvascular dysfunction as compared with Rµ and coronary blood flow (Q) monitoring during exercise. Methods Rµ and MRR were first assessed using continuous thermodilution with saline infusion at 10 mL/min (rest) and 20 mL/min (hyperemia) in the left anterior descending artery of consecutive patients with Angina and Non-Obstructive Coronary Arteries. An MRR&amp;lt;2.3 was considered the cutoff for coronary microvascular dysfunction. Q and Rµ were assessed during subsequent stress testing with an incremental workload of 30 watts every two minutes, using a dedicated supine cycling ergometer. Results Coronary microvascular dysfunction was observed in 36.6% of the participants with suspected Angina with Non-Obstructive Coronary Artery disease (11 out of 30). Median hyperemic Rµ was 561 [381; 684] Wood Unit (WU) among patients with microvascular dysfunction. Participants with structural dysfunction (MRR&amp;lt;2.3 and hyperemic Rµ&amp;gt;561WU), had a resting Rµ similar to participants without CMD (1286±410 versus 1231±291 WU) but exhibited both impaired reduction of Rµ (139 [64; 288] versus 191 [74; 317] WU per 30 watts) and increase of Q during exercise (20 [1; 37.5] versus 52 [15.5; 92.0] mL/min per 30 watts). Patients with functional dysfunction (MRR&amp;lt;2.3 and hyperemic Rµ&amp;lt;561WU) had lower resting Rµ (672±219 WU) and higher resting Q (152±39 versus 84±24 mL/min) with a similar increase of Q during exercise (55 [30.5; 103.0] than participants without CMD. Mean N-terminal pro B-type natriuretic peptide level was higher in the structural group (425±563 ng/L) as compared to the functional and normal groups (86±10 ng/L and 50±80 ng/L respectively). Conclusion The use of MRR combined to hyperemic Rµ, derived from continuous intracoronary thermodilution, enables the assessment of coronary microvascular dysfunction with an accurate distinction between functional and structural endotypes.Microvascular hemodynamic adaptationNTpBNP level

Coronary physiology: no complete diagnosis without acteylcholine

Abstract Introduction In up to 40% of patients with pectanginous symptoms, no obstructive coronary artery disease (NOCAD, no stenosis &amp;gt; 50%) can be detected as the cause, so that the terms ANOCA (angina with no obstructive CAD) or INOCA (ischemia with no obstructive CAD) have been defined. In patients with acute myocardial infarction, 5-20% are diagnosed with MINOCA (myocardial infarction with no obstructive CAD). Microvascular dysfunction (CMD) or coronary spasm has been identified as one of the leading causes of these entities. Further clarification by determining the coronary flow reserve (CFR) an microvascular resistance (IMR) is used to diagnose CMD and is also included in the ESC guidelines. The indices can be determined using thermodilution or ultrasound/doppler wires methods. According to current recommendations, the acteylcholine provocation test is administered in cases of suspected coronary spasm. Despite extensive studies on the safety of ACh testing, many clinics refrain from testing for vasoconstriction disorder although microvascular coronary spasm has been shown to be the leading subgroup of CMD in registry studies. Purpose We want to investigate the necessity of a complete coronary physiological examination, consisting of CRF/IMR and ACh provocation test, when compared to testing without ACh. Methods All 299 patients who underwent complete physiological testing in our clinic between 2021 and 2024 due to ANOCA, INOCA or MINOCA were evaluated retrospectively. Patients completed a coronary physiological examination using thermodilution and an acetylcholine provocation test. The IMR, CFR, fractional flow reserve (FFR), resting full-cycle ratio (RFR) and the ACh test (defined as epicardial spasm &amp;gt;90% reduction in coronary diameter with symptoms and/or ischemic electrocardiographic changes, respectively no epicardial spasm &amp;gt;90% reduction in coronary diameter with symptoms and and ischemic electrocardiographic changes for microvascular spasm) are thus routinely measured. Results Of the total of 299 patients included, 244 (81%) were found to have impaired vasoconstriction with pathologic ACh testing, either alone or in combination with pathologic indices CFR/IMR. The leading finding of pathological spasms was microvascular coronary spasm (66%). 119 patients with normal CFR/IMR had a diagnosis of microvascular (72 patients) or macrovascular spasm (47 patients). 40% of the total patient cohort would have not had a compete diagnosis without the use of Ach testing. Conclusion Physiological testing without the systematic use of ACh testing will misdagnose a significant amout of patients with ANOCA/MINOCA/INOCA. ACh testing should be always performed to complete the diagnosis for these patients

ERBB4 activation prevents microvascular dysfunction in a large animal model of hypertensive heart disease

Abstract Background Coronary microvascular dysfunction (CMD) participates in the pathophysiology of multiple cardiovascular diseases, but treatment options are limited. A new treatment option may include ERBB4 stimulation by neuregulin-1 (NRG1), which has anti-inflammatory, antifibrotic, and cardioprotective effects in models of heart failure. Objectives To assess the effect NRG1/ERBB4 stimulation on CMD in hypertensive heart disease. Methods Hypertensive heart disease was induced in 12 Aachener minipigs by implantation of deoxycorticosterone acetate (DOCA) pellets for 8 weeks and compared to 6 controls. The DOCA pigs were randomized to a weekly infusion of JK07, a NRG1 fusion protein with improved pharmacokinetic and pharmacodynamic properties, or vehicle. Microvascular resistance was measured using the bolus thermodilution method. Results DOCA significantly increased microvascular resistance compared to controls (from 14.5 to 19.9 mmHg.s, p = 0.028). This increase was abrogated by JK07 (11.3 mmHg.s, p = 0.018 vs DOCA). dP/dtmax increased by DOCA compared to controls (from 2415.5 to 4455.5 mmHg/s, p = 0.011), which was also abrogated by JK07 (3107.3 mmHg/s, p = 0.055 vs DOCA). Interstitial left ventricular fibrosis was significantly lower in JK07-treated pigs compared to DOCA only (2.1 vs. 5.4 %, p = 0.026), but without difference in perivascular fibrosis (p = 0.48). JK07 did not affect myocyte cross-sectional area, capillary density, pericyte coverage, or microvascular vessel thickness. Conclusions ERBB4 activation by JK07 is capable to prevent CMD in a DOCA hypertensive pig model. Functional rather than structural alterations may explain the protective effects of JK07 on microvascular resistance.Visual summaryJK07 decreases microvascular resistance

Functional improvement of non-infarct related coronary artery stenosis by extensive LDL-C reduction with a PCSK9 antibody: the FITTER trial, microvascular function analysis

Abstract Background Atherosclerosis and microvascular dysfunction are closely linked. Moreover, impaired microvascular function is strongly associated with increased risk on major adverse cardiac events. In patients presenting with acute coronary syndrome (ACS), microvascular function is reduced. PCSK9-inhibitors have shown to reduce plaque burden and lipid load in epicardial vessels and might exhibit similar results on microvascular vessels, thereby improving microvascular function. The FITTER trial offers the unique opportunity to test this hypothesis. Methods The FITTER trial is a multi-center, randomized, double blind, placebo controlled clinical trial for patients presenting with ACS and multi-vessel disease (MVD). After treatment of the culprit lesion, fractional flow reserve (FFR) measurement of non-infarct related artery (non-IRA) lesions was performed. Patients with intermediate, non-critical lesions (FFR: 0.67-0.85) were included in this trial. For exploratory purpose, additional physiological assessment of the non-IRA included coronary flow reserve (CFR) and microvascular resistance index (IMR) measurements. Microvascular function was evaluated using a pressure- and temperature-sensitive guidewire and a bolus thermodilution method. Participants were randomized and treated for 12 weeks with either evolocumab or placebo in addition to high-intensity statin therapy. Staged reevaluation was done at 12 weeks. After repeated physiology testing, PCI was performed if deemed necessary. Pre-defined exploratory analysis includes the absolute and relative difference in change between CFR and IMR from baseline to follow up in the non-IRA. PCSK9 inhibition might result in a relatively larger increase of CFR and larger decrease of IMR. Results Between March 2020 and August 2023, a total of 150 patients were included in the trial. In 61 patients (88.5% male, age 65.3 ± 9.1 years, 23.0% STEMI, 70.5% non-STEMI, 6.6% UAP) successful baseline and follow-up measurements of microvascular function were performed. Complete results will be available at the beginning of March 2024. The primary- and secondary endpoints will be submitted for late-breaking clinical trials selection. The results of this abstract will include a per vessel analysis of coronary artery microvascular function. Conclusion The FITTER trial will provide new insights on the potential of extensive LDL-C reduction with a PCSK9 antibody on microvascular coronary artery function in patients presenting with ACS and MVD.

Relation of plasma neuropeptide-Y with myocardial function and infarct severity in acute ST-elevation myocardial infarction

Abstract Background Acute myocardial infarction is associated with high levels of cardiac sympathetic stimulation, which leads to the release of the co-transmitter neuropeptide-Y (NPY). NPY acts as a potent vasoconstrictor and an association with increased risk for heart failure and microvascular dysfunction after acute ST-elevation myocardial infarction (STEMI) has been suggested. Purpose This study aims to comprehensively evaluate the association of plasma NPY with myocardial function and infarct severity, visualized by cardiac magnetic resonance (CMR) imaging, in STEMI patients revascularized by primary percutaneous coronary intervention (PCI). Methods In this observational study, we included 260 STEMI patients treated with primary PCI. Plasma NPY concentrations were measured by an immunoassay 24h after PCI from peripheral venous blood samples. Left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), infarct size (IS) and microvascular obstruction (MVO) were determined using CMR imaging 4 days and 4 months after PCI. Results Median plasma concentrations of NPY were 70 [interquartile range (IQR): 35-115] pg/ml. NPY levels above median were significantly associated with lower LVEF (48% vs. 52%, p=0.004), decreased GLS (-8.8% vs. -12.6%, p&amp;lt;0.001) and larger IS (17% vs. 13%, p=0.041) in the acute phase after infarction as well as in the chronic stage (LVEF: 50% vs. 52%, p=0.030, GLS: -10.5 vs. -12.9, p&amp;lt;0.001, IS: 13% vs. 10%, p=0.011). In addition, NPY levels were significantly related to presence of MVO (58% vs. 52%, p=0.041). Moreover, in multivariable linear regression analysis, NPY remained significantly associated with all investigated CMR parameters (LVEF: p&amp;lt;0.001, GLS: p&amp;lt;0.001, IS: p=0.003, MVO: p=0.042) independent of other established clinical variables including high-sensitivity cardiac troponin T, pre-interventional TIMI flow 0 and left anterior descending artery as culprit lesion location. Conclusion High plasma levels of NPY, measured 24h after STEMI, were independently associated with lower LVEF, decreased GLS, larger IS as well as presence of MVO, indicating plasma NPY as a valuable biomarker for optimized risk stratification.

Cardioprotection with transcoronary saline infusion during primary angioplasty for ST-elevation myocardial infarction: design and rationale of the STEMI-Cool pilot study

Abstract Background Prompt restoration of blood flow in ST-segment elevation myocardial infarction (STEMI) with primary percutaneous coronary intervention (pPCI) improves outcomes, but is associated with myocardial stunning, increased infarct size, and microvascular dysfunction. To date, there is no effective therapy to reduce this ischaemia-reperfusion injury (IRI). Mild systemic hypothermia has demonstrated potential but is difficult to achieve and poorly tolerated. Transcoronary hypothermia delivers rapid and effective myocardial cooling, is well tolerated, but not effective when commenced after flow restoration. Coronary haemodilution during reperfusion has shown cardioprotective effects in preclinical studies but has not been fully assessed. Purpose STEMI-Cool is a pragmatic, registry-based randomised clinical trial to assess recruitment rate, feasibility, and safety of a simple protocol which we have reported in a proof-of-concept study. The study has commenced recruitment and aims to overcome the limitations of previous negative studies by combining the beneficial effects of transcoronary cooling and dilution, initiating the infusion prior to wire insertion - therefore avoiding initial unprotected reperfusion (likely to be the critical time for IRI), and avoiding significant delays in reperfusion. Moreover, we will explore mechanistic endpoints and an original method to quantify the intracoronary dilution (with a thermodilution-derived "haemodilution constant ratio"). Lastly, we will investigate ways to "engineer out" the thermistor wire so that the method could be applied to routine pPCI with conventional equipment. Methods Pragmatic broad eligibility criteria allow potential recruitment of all STEMI cases clinically eligible for pPCI. Sixty patients will be randomised 1:1 to standard of care or protected reperfusion with continuous infusion of room temperature saline through the guiding catheter, to achieve intracoronary temperature reduction of 6-8°C. The infusion commences prior to crossing the occlusion with a thermistor wire, which is used as guidewire, and continues for 10 minutes after flow restoration (i.e., TIMI flow≥2). Invasive coronary physiology studies are undertaken after pPCI. Novel and established biomarkers of myocardial damage and inflammation (including dipeptidyl peptidase 3, tumor necrosis factor α, and interleukins 1β, 6, 10) are measured in the preprocedural arterial blood. Cardiac imaging and clinical outcomes are assessed at 48h and 6-12 months. Nesting STEMI-Cool in our local registry Heart-ACS facilitates blood sampling and follow-up. Conclusions STEMI-Cool will primarily investigate recruitment rate, feasibility and safety of an innovative, simple cooling and diluting strategy for cardioprotection during pPCI. Mechanistic outcomes will explore inflammatory, microvascular, structural and functional changes. Finally, we will aim to simplify further the protocol for future research and potential clinical use.STEMI-Cool method schematicSTEMI-Cool protocol timeline

Impaired retinal micro-vascular function in patients with a systemic sclerosis

Abstract Background Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by widespread and progressive multi-organ fibrosis and vascular abnormalities. Endothelial dysfunction is an early manifestation of SSc and an important contributor to the progression and prognosis of the disease. Dynamic retinal vascular analysis (DVA) is a new method for non-invasive and precise determination of microvascular function. The primary aim was to assess micro- and macro-vascular function in patients with SSc. Methods In this study, vascular function was measured non-invasively with flicker-light induced vasodilation of retinal arterioles (FIDart) and branchial arterial flow-mediated vasodilation (FMD). Patients with SSc were prospectively enrolled in the study (n = 40; mean ± SD age 56±11 years, females 73 %) and compared with age- and sex-matched HC (n = 40; mean age 56±15 years, females 73%). Results Retinal microvascular function was significantly impaired in patients with SSc compared to matched HC (2.3±2.0% versus 3.1±1.9% respectively, p=0.04, figure 1). There was a trend for lower FMD in patients with SSc in comparison to HC (5.0± 3.2% versus 6.2±3.2% respectively, p=0.07). Conclusion Patients with SSc have severe impairment of retinal vascular function compared to matched HC. Thus, microvascular dysfunction in these patients is of systemic nature and retinal vessel analysis may serve as an important marker for SSc disease, severity and prognosis. These results set the stage for further studies on retinal function in SSc patients.Figure 1

Coronary sinus reducer device for the treatment of refractory angina: a single center experience

Abstract Introduction The coronary sinus Reducer emerged as a complementary therapy in patients with angina refractory to optimal medical therapy and not amenable to revascularization. Aim The aim of this study was to assess the safety and efficacy of the Reducer in a real-world cohort of patients presenting with refractory angina. Methods and population Twenty-six patients with refractory angina, objective evidence of myocardial ischemia attributable to the left coronary artery and deemed unsuitable for revascularization were treated with Reducer at a single center between April 2018 and January 2023. Safety endpoints were procedural success and complications. Efficacy endpoints, assessed at 6-month, were a reduction in Canadian Cardiovascular Society angina (CCS) class and a reduction in pharmacological antianginal therapy. Results Twenty-one (81%) patients had end-stage coronary artery disease without targets for further revascularization (13 had previous CABG ± PCI and 8 had only PCI) and 5 patients had microvascular disease without epicardial stenosis. All procedures were performed via right jugular vein. The mean procedure and fluoroscopy duration were 66±29 and 19±8 minutes. Procedural success was achieved in all patients, with no device related complications. There was one cardiac tamponade, promptly treated with pericardiocentesis. Regarding the efficacy endpoint, 21 patients (81%) had at least 1 grade reduction in CCS class, 13 patients (50%) had at least 2 class reductions, and 7 patients (28 %) became asymptomatic, with a mean reduction of CCS class of 1.4±0.9, from 2.6±0.5 to 1.2±0.9 (p=0.001) at 6-month follow-up. During this time frame, twelve patients (46%) withdrew or reduced the dose of at least one anti-anginal drug. The mean reduction of anti-anginal drugs was 0.54 ±0.86, from 3.5±1.02 to 2.9±1.07 (p=0.04). Conclusion In this real-world, single-center experience, implantation of Reducer was safe and associated with improvement of angina and reduction of anti-anginal drugs intake in patients with refractory angina unsuitable for revascularization.