Coronary Vascular Dysfunction Research Articles

The Relationship between the Systemic Immune-Inflammation Index and Ischemia with Non-Obstructive Coronary Arteries in Patients Undergoing Coronary Angiography.

Ischemia with the non-obstructive coronary artery (INOCA) is an ischemic heart disease that mostly includes coronary microvascular dysfunction and/or epicardial coronary vasospasm due to underlying coronary vascular dysfunction and can be seen more commonly in female patients. The systemic immune-inflammation index (SII, platelet × neutrophil/lymphocyte ratio) is a new marker that predicts adverse clinical outcomes in coronary artery disease (CAD). This study aims to investigate the relationship between INOCA and SII, a new marker associated with inflammation. A total of 424 patients (212 patients with INOCA and 212 normal controls) were included in the study. Peripheral venous blood samples were received from the entire study population prior to coronary angiography to measure SII and other hematological parameters. In our study, the value of p<0.05' was considered statistically significant. The optimal cut-off value of SII for predicting INOCA was 153.8 with a sensitivity of 44.8% and a specificity of 78.77% (Area under the curve [AUC]: 0.651 [95% CI: 0.603-0.696, p=0.0265]). Their ROC curves were compared to assess whether SII had an additional predictive value over components. The AUC value of SII was found to be significantly higher than that of lymphocyte (AUC: 0.607 [95% CI: 0.559-0.654, p = 0.0273]), neutrophil (AUC: 0.559 [95%CI: 0.511-0.607, p=0.028]) and platelet (AUC: 0.590 [95% CI: 0.541-0.637, p = 0.0276]) in INOCA patients. A high SII level was found to be independently associated with the existence of INOCA. The SII value can be used as an indicator to add to the traditional expensive methods commonly used in INOCA prediction.

Abstract 16706: Women With Coronary Vascular Dysfunction Have Heightened Emotional Responses to Mental Stress With Attenuated Recovery

Introduction: Coronary vascular dysfunction (CVaD) is associated with major adverse outcomes, recurrent chest pain, and can be triggered by mental stress. Hypothesis: We hypothesized that women with CVaD have heightened emotional response and attenuated recovery compared to reference control (RC) women. Methods: Women diagnosed with CVaD (cases, n=57, age: 57±1 years) by abnormal adenosine or acetylcholine response during invasive coronary function testing were enrolled in Cardiac Autonomic Nervous System Study and compared to age-matched, asymptomatic RCs women (n=25, age: 56±3 years), free of cardiac or risk factor history. All underwent two 4-minute standardized mental stress tests - anger recall and mental arithmetic - followed by 15 minutes of recovery. Emotional arousal (tension, anxious, depressed) and chest pain were assessed via self-reported Likert scale at baseline, after stress, and after recovery. The difference between post-stress or post-recovery and baseline scores was used to evaluate stress provocation and recovery. Increased differences indicate more provocation or recovery attenuation. We utilized multivariate models adjusted for anti-anginal medications, statins, and aspirin or traditional cardiovascular risk factors and chest pain to assess associations between CVaD and chest pain or emotional arousal, respectively. Results: The two groups did not differ in hemodynamic response to mental stress (p&gt;0.05). In multivariate models, CVaD status was associated with more stress-provoked chest pain (β 1.24 [0.1, 2.4], p=0.03) and more attenuated chest pain recovery (β 1.5 [0.6, 2.3], p=0.001) than RC. Similarly, after adjustment, cases were associated with more stress-provoked anxiety (β 1.2 [0.2, 2.2], p=0.02) and tension (β 1.2 [0.001, 2.4], p=0.05) while having more attenuated recovery of anxiety (β 1.1 [0.1, 2.0], p=0.02) and tension (β 1.1 [0.2, 2.0], p=0.02) compared to RC. There were no differences in feelings of depression between the two groups. Conclusions: Response to mental stress is heightened with attenuated recovery in women with CVaD. An improved understanding of mechanisms in stress response and CVaD is needed for potential therapeutic targets that may improve angina and quality of life.

Abstract 14700: Associations of Left Ventricular Structure With Cumulative Systolic Blood Pressure Load: A Report From Women’s Ischemia Syndrome Evaluation - Coronary Vascular Dysfunction Study

Background: Recent studies have identified cumulative systolic blood pressure load to be associated with increased risk of adverse cardiovascular disease (CVD) outcomes. Similarly, associations between left ventricular (LV) structure and CVD events have long been recognized. Purpose: The purpose of this study was to assess the association between cumulative systolic blood pressure (CuSBP) load and LV structure in women with suspected ischemia with no obstructive coronary arteries (INOCA). Methods: Women enrolled in the Women’s Ischemia Syndrome Evaluation - Coronary Vascular Dysfunction (WISE-CVD) study (NCT00832702) underwent cardiac magnetic resonance imaging (CMRI) for LV structure and those (n= 225) who had at least 2 blood pressure (BP) measures recorded at a single site before their baseline CMRI were included in this analysis. Cumulative systolic BP (CuSBP) was defined as systolic BP (SBP) ≥ 130 divided by all SBP readings and each mean value multiplied by the years. LV remodeling index was defined as the ratio between LV mass and LV end diastolic volume (LVEDV). Results: The mean age was 55±10 years, body mass index (BMI) 26.3 ± 5.5 kg/m 2 , 36% had a history of hypertension, number of BP medications was mean 2.7 ± 1.6 [median 2 (range 0, 8)], and SBP and DBP were 126 ± 15 and 66 ± 10 mmHg respectively. Age, BMI and history of hypertension were significantly associated with higher CuSBP load. In univariate analyses, LV end diastolic volume and LV end systolic volume decreased, and LV remodeling index increased across CuSBP quartiles while LV mass index did not significantly differ among the quartiles (Figure 1) . In multivariable regression analysis, the association between CuSBP and LV mass index and LV remodeling index remained significant. Conclusions: Among women with suspected INOCA, higher CuSBP load was associated with greater LV mass index and concentric LV remodeling independent of age. Changes in LV volumes may represent age-related changes in LV structure.

Coronary vascular dysfunction is associated with increased risk of death in patients with peripheral artery disease.

Peripheral artery disease (PAD) and coronary vascular dysfunction are common in patients with cardiometabolic disease. Neither the prevalence of coronary vascular dysfunction among patients with PAD nor the prognostic impact with these two conditions present together has been well studied. Consecutive patients who underwent PET MPI were analyzed for presence of coronary vascular dysfunction [myocardial blood flow reserve (MBFR)<2]. Cox regression was used to examine the association of reduced MBFR with mortality in patients with PAD, as well as the association of comorbid MBFR<2 and PAD with all-cause death. Among 13,940 patients, 1936 (14%) had PAD, 7782 (56%) had MBFR<2 and 1346 (10%) had both PAD and MBFR<2. Reduced MBFR was very common (69.5%) and was associated with increased risk of all-cause death (HR 1.69, 95%CI 1.32, 2.16, p<0.01) in patients with PAD. Patients with both PAD and MBFR<2, and those with either PAD or reduced MBFR had increased risk of death compared to those with neither condition: PAD+MBFR<2 [(HR 95%CI), 2.30; 1.97-2.68], PAD+MBFR≥2 (1.37; (1.08-1.72), PAD-MBFR<2 (1.98; 1.75-2.25), p<0.001 for all). Coronary vascular dysfunction was common in patients with PAD and was associated with increased risk of death.

Endothelial cell-specific roles for tetrahydrobiopterin in myocardial function, cardiac hypertrophy, and response to myocardial ischemia-reperfusion injury.

The cofactor tetrahydrobiopterin (BH4) is a critical regulator of nitric oxide synthase (NOS) function and redox signaling, with reduced BH4 implicated in multiple cardiovascular disease states. In the myocardium, augmentation of BH4 levels can impact on cardiomyocyte function, preventing hypertrophy and heart failure. However, the specific role of endothelial cell BH4 biosynthesis in the coronary circulation and its role in cardiac function and the response to ischemia has yet to be elucidated. Endothelial cell-specific Gch1 knockout mice were generated by crossing Gch1fl/fl with Tie2cre mice, generating Gch1fl/flTie2cre mice and littermate controls. GTP cyclohydrolase protein and BH4 levels were reduced in heart tissues from Gch1fl/flTie2cre mice, localized to endothelial cells, with normal cardiomyocyte BH4. Deficiency in coronary endothelial cell BH4 led to NOS uncoupling, decreased NO bioactivity, and increased superoxide and hydrogen peroxide productions in the hearts of Gch1fl/flTie2cre mice. Under physiological conditions, loss of endothelial cell-specific BH4 led to mild cardiac hypertrophy in Gch1fl/flTie2cre hearts. Endothelial cell BH4 loss was also associated with increased neuronal NOS protein, loss of endothelial NOS protein, and increased phospholamban phosphorylation at serine-17 in cardiomyocytes. Loss of cardiac endothelial cell BH4 led to coronary vascular dysfunction, reduced functional recovery, and increased myocardial infarct size following ischemia-reperfusion injury. Taken together, these studies reveal a specific role for endothelial cell Gch1/BH4 biosynthesis in cardiac function and the response to cardiac ischemia-reperfusion injury. Targeting endothelial cell Gch1 and BH4 biosynthesis may provide a novel therapeutic target for the prevention and treatment of cardiac dysfunction and ischemia-reperfusion injury.NEW & NOTEWORTHY We demonstrate a critical role for endothelial cell Gch1/BH4 biosynthesis in coronary vascular function and cardiac function. Loss of cardiac endothelial cell BH4 leads to coronary vascular dysfunction, reduced functional recovery, and increased myocardial infarct size following ischemia/reperfusion injury. Targeting endothelial cell Gch1 and BH4 biosynthesis may provide a novel therapeutic target for the prevention and treatment of cardiac dysfunction, ischemia injury, and heart failure.

INNOVATIONS IN DIAGNOSTIC METHODS: NUCLEAR MEDICINE — MYOCARDIAL PERFUSION, FLOW RESERVE AND MYOCARDIAL VIABILITY

Nuclear Medicine, by integrating information on relative myocardial perfusion, ventricular function and absolute quantitative data such as myocardial blood flow and coronary flow reserve, expands and modifies the scope of evaluation of patients with chronic coronary insufficiency. These measures are producing a paradigm shift in the assessment and management of patients with CAD, allowing the definition of a broad spectrum of coronary vascular dysfunction. These quantitative tools provide a measure of the integrated effects of focal coronary stenoses, diffuse atherosclerosis, and microvascular dysfunction on myocardial perfusion. This data set allows improving the diagnosis and assessment of the extent of epicardial disease, reclassifying the prognosis, demonstrated through robust literature data that confirm the incremental value over other variables in the risk stratification of patients with ischemic heart disease, and allow to identify coronary microcirculatory disease with or without epicardial CAD. A more accurate and sensitive assessment of myocardial tissue ischemia is then obtained. This chapter explores these possibilities, the assessment of myocardial viability, and the future perspectives of Nuclear Medicine, which include the development of new radiopharmaceuticals focused on molecular imaging and the creation of new hybrid devices that combine functional and anatomical information in a single test

Contemporary and future invasive coronary vasomotor function testing and treatment in patients with ischaemia with no obstructive coronary arteries.

In the current review, we emphasize the importance of diagnostics and therapy in patients with ischaemia with no obstructive coronary arteries (INOCA). The importance of the diagnostic coronary function test (CFT) procedure is described, including future components including angiography-derived physiology and invasive continuous thermodilution. Furthermore, the main components of treatment are discussed. Future directions include the national registration ensuring a high quality of INOCA care, besides a potential source to improve our understanding of pathophysiology in the various phenotypes of coronary vascular dysfunction, the diagnostic CFT procedure, and treatment.

Abstract 11380: Exercise Induced ST Segment Elevation Caused by Coronary Vasospasm

Case Presentation: A 52-year-old male with no known medical history was seen in the cardiology clinic for occasional pressure-like chest pain on exertion. Due to an intermediate pretest probability of CAD, ischemic workup with a nuclear perfusion exercise stress test was planned. Patient achieved maximum predicted heart rate after 12 minutes of exercising, with no anginal symptoms, ST segment changes or arrhythmias during the entire period. However, 3 minutes into the recovery phase, he developed chest pain and diaphoresis, with EKG now showing 7mm ST elevations in the inferior leads and BP falling to 77/56 mmHg. STEMI code was called, and patient was emergently taken to the cardiac cath lab for coronary angiogram and possible PCI. Angiogram found the coronary arteries to be non-obstructive but revealed vessels possibly having vasospasm. Intra coronary nitroglycerin was given with no further PCI. The patient’s symptoms subsided after the angiogram, and he remained asymptomatic thereupon and was eventually discharged on Verapamil and nitrate therapy. Discussion: Typically, vasospastic angina occurs at rest. Exercise induced and post-exercise recovery phase ST segment elevation on EKG is associated with severe atherosclerotic disease with significant coronary obstruction. However, exercise induced ST elevations in the post exercise recovery phase caused by non-obstructive, vasospastic coronary arteries, as seen in this patient, is a rare occurrence. The vasospasm is hypothesized to be due to coronary vascular smooth muscle hyperactivity and endothelial cell dysfunction. Treatment is usually with calcium channel blockers, nitrates and lifestyle modification such as smoking cessation and alcohol restriction. This case illustrates the importance of identifying the etiology of the angina, noting that post exercise ST segment elevations are not always associated with coronary vessel obstruction and vasospasm should be considered as a possible etiology.

Ventricular and vascular stiffening in ischemia with no obstructed coronary arteries: novel insight from pressure-volume analysis

Abstract Background Ischemia with no obstructed coronary arteries (INOCA) is prevalent among women and associated with an increased risk of developing heart failure with preserved ejection fraction (HFpEF), however the mechanism linking these conditions remains poorly understood. Coronary vascular dysfunction is common in INOCA, representing a putative mechanism driving heart failure progression. Purpose To evaluate the role of coronary vascular dysfunction on left ventricular (LV) function in women with INOCA. Methods Women with suspected INOCA, defined as having signs and symptoms of ischemia but no obstructive coronary artery disease, underwent LV pressure-volume assessment at rest and during 3 minutes of isometric handgrip stress at 30% of maximal voluntary contraction. Coronary function testing was performed by infusing standard doses of adenosine, acetylcholine, and nitroglycerine through a guiding catheter placed in the left main coronary artery, per our published protocols. Using standardized definitions of normal versus abnormal responses, cases with zero abnormal coronary pathways (n=12) were compared to cases with three abnormal coronary pathways (n=7). Results At rest, end-systolic pressure and end-systolic elastance were elevated in cases with abnormal coronary vascular function (Figure), while normalized peak filling rate was lower (0.45±0.15 s mmHg–1 vs 0.37±0.08 s mmHg–1). With isometric handgrip, end-systolic pressure and end-systolic elastance increased similarly between groups, remaining highest in those with abnormal coronary vascular function (Figure). End-diastolic pressure-volume declined with handgrip in those without coronary vascular dysfunction, while increasing (up and to the left) in those with coronary vascular dysfunction (Figure). Likewise, normalized peak filling rate improved with handgrip in those without coronary vascular dysfunction, but did not change in those with coronary vascular dysfunction (0.66±0.37 s mmHg–1 vs 0.38±0.15 s mmHg–1). Conclusions We show heightened ventricular and vascular stiffness in women with INOCA who have abnormal coronary vascular function. These preliminary data support the hypothesis that coronary vascular dysfunction may be a putative mechanistic pathway driving heart failure progression in INOCA. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health

Pericardial fat from a single horizontal long axis cardiac magnetic resonance cine image: a validation study against three-dimensional cardiac computed tomography

Abstract Background Excess fat accumulation around the heart (i.e., pericardial fat) is positively associated with cardiovascular disease. Pericardial fat is composed of two distinct depots: (1) epicardial fat, which is a metabolically active adipose tissue located between the heart and the pericardium, and (2) paracardial fat, which is the fat deposit in the mediastinum outside of the parietal pericardium. Both depots are visible on the horizontal long axis cardiac magnetic resonance (CMR) cine (i.e., four chamber view), offering an attractive opportunity to quantify pericardial fat from standard CMR cine images. Purpose To validate pericardial fat area measured from a single horizontal long axis CMR cine against whole-heart volumetric non-contrast cardiac computed tomography (CT) measurements. Methods To accomplish our goal, we leveraged 25 cases from the Women's Ischemia Syndrome Evaluation – Coronary Vascular Dysfunction Continuation cohort who underwent both cardiac MRI and cardiac CT within a median of 35 days apart. For MRI, pericardial fat area was measured from a single high resolution steady state free precession cine image in the horizontal long axis imaging plane using commercially available software (CVI42 V5.13.5, Circle Cardiovascular Imaging, Figure 1A). For CT, pericardial fat volume was measured using a fully automated deep learning algorithm (QFAT 2.0, Figure 1A). Results Fat area measured from a single horizontal long axis cine image was closely related to fat volume measured by three-dimensional cardiac CT, with strong correlations for epicardial fat (R2=0.72, p&amp;lt;0.01, Figure 1B), paracardial fat (R2=0.80, p&amp;lt;0.01, Figure 1C), and pericardial fat (R2=0.91, p&amp;lt;0.01, Figure 1D). Conclusions Measuring pericardial fat area, and its constituent parts, from a single horizontal long axis cine image is both feasible and strongly related to reference standard pericardial fat volume by cardiac CT. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National Institutes of Health

Analysis of Epidemiological Characteristics of New Cardiovascular Diseases in Cancer Patients with Cardiovascular Disease.

In cancer patients, a cardiovascular disease (CVD) is a prevalent occurrence. When a patient has both heart disease and cancer, the treatment can be complicated because treatment for one condition can have an adverse effect on the outcome of the other. A cardiovascular disease that involves heart failures, coronary artery disease (CAD), stroke, pericardial diseases, arrhythmias, and valve and vascular dysfunction is a serious worry for long-term cancer patients. Because preclinical research is limited, it is critical to comprehend the pathophysiology of CVD as a consequence of anticancerous therapies while taking into account the developing and expanding heart. As a result, in this research, we look at the epidemiological characteristics of cancer patients who also have cardiovascular illness. Low-dose chest computed tomography, cardiac CT, and cardiac magnetic resonance imaging (MRI) are used to acquire the data and perform the screening. Chemotherapeutic drugs such as anthracyclines and trastuzumab are used to treat the condition. Univariate analysis is used to examine risk factors and predict cardiovascular damage. Sensitivity, specificity, positive predictive value, negative predictive value, life expectancy, left ventricular ejection fraction (LVEF), and longitudinal strain are among the metrics examined.

Hangover after Side Branch Stenting: The Discomfort Comes Afterwards.

The authors report on a patient with recurrent angina at rest and on exertion 2 years after percutaneous revascularisation of the first diagonal branch (D1). Invasive coronary angiography with full functional testing was planned with the tentative diagnosis of coronary vascular dysfunction. Coronary angiography with functional testing revealed a haemodynamically significant intermediate stenosis at the D1–left anterior descending artery bifurcation. Optical coherence tomography demonstrated neointimal bridging and accelerated downstream atherosclerosis that was induced by protrusion of the previously implanted stent into the main branch. Although the overhanging stent was considered insignificant at first, it caused significant discomfort after 2 years. After provisional stenting of the main branch with crushing of the protruding stent and continuous medical treatment, the patient remained free of recurrent angina.

Hypoglycosylated Follistatin‐Like 1 Attenuates the Loss of Coronary and Cerebral Vascular Functional Capacity in Ossabaw Swine with Cardiometabolic Heart Failure with Reduced Ejection Fraction

Ischemic heart disease is a leading cause of death, often resulting from heart failure caused by myocardial infarction. Diabetic cardiomyopathy is increasingly problematic clinically, with the combination of metabolic syndrome and chronic inflammation greatly increasing the risk for both coronary and cerebral vascular disease. Follistatin‐like 1 (FSTL1) is a protein that, when non‐glycosylated, displays regenerative properties including pro‐angiogenic effects and prevention of abnormal vascular remodeling. Thus, the objective of the current study was to assess the therapeutic benefit of human recombinant non‐glycosylated FSTL1 protein on both coronary and cerebral vascular function in a pre‐clinical Ossabaw swine model of myocardial infarction (MI). We hypothesized FSTL1 would attenuate the development of coronary and cerebral vascular dysfunction in an experimental setting of cardiometabolic heart failure with reduced ejection fraction (HFrEF). Intact female Ossabaw swine (2 months old) were fed a Western Diet for 4 months to develop metabolic syndrome. At 6 months of age, animals were subjected to 90 minutes ischemia followed by reperfusion (I/R) to induce MI. One month post‐MI, ALZET osmotic pumps were implanted and either vehicle (MI group) or FSTL1 (MI+FSTL1 group) was delivered over two weeks, with terminal vascular experiments performed 2 months post‐MI. In vitroassessment of isolated coronary (n=5‐6 for infarct, border, and remote regions of the left ventricle; 139.5 ± 4.9 μm diameter) and cerebral (n=2‐6 for middle cerebral artery second order pial; 385.3 ± 18.7 μm diameter) arteriole function was examined using pressure myography. Dose response curves for: 1) U46619 (thromboxane A2 agonist); and 2) NS‐1619 (large‐conductance calcium‐activated potassium channel activator; BKCa) were conducted. A 2x2 ANOVA (Group X Dose) was used to determine significance at the p &lt; 0.05 level. Cardiometabolic HFrEF was indicated by a combined ejection fraction of 38 ± 2% and a fasting HOMA‐IR of 3.8 ± 0.4 (vs. 0.6 ± 0.1 historical control). In coronary arterioles, the NS‐1619 induced vasodilatory capacity was increased ~18‐fold in MI+FSTL1 animals relative to MI (100 ± 13% vs. 1832 ± 3% in MI and MI+FSTL1, respectively) in the remote region of the heart (interaction effect), but not the infarct nor border regions. In cerebral arterioles, the vasoconstrictor capacity in response to U46619 was increased ~2‐fold in MI+FSTL1 relative to MI animals (100 ± 19% vs. 213 ± 25% in MI and MI+FSTL1, respectively; interaction effect). In conclusion, FSTL1 partially attenuates the loss of functional capacity in both coronary and cerebral arterioles, demonstrating its potential to improve vascular function in an experimental setting of cardiometabolic HFrEF.

Purinergic signaling in myocardial ischemia-reperfusion injury.

Purines and their derivatives, extensively distributed in the body, act as a class of extracellular signaling molecules via a rich array of receptors, also known as purinoceptors (P1, P2X, and P2Y). They mediate multiple intracellular signal transduction pathways and participate in various physiological and pathological cell behaviors. Since the function in myocardial ischemia-reperfusion injury (MIRI), this review summarized the involvement of purinergic signal transduction in diversified pathological processes, including energy metabolism disorder, oxidative stress injury, calcium overload, inflammatory immune response, platelet aggregation, coronary vascular dysfunction, and cell necrosis and apoptosis. Moreover, increasing evidence suggests that purinergic signaling also mediates the prevention and treatment of MIRI, such as ischemic conditioning, pharmacological intervention, and some other therapies. In conclusion, this review exhibited that purinergic signaling mediates the complex processes of MIRI which shows its promising application and prospecting in the future.

Outpatient Management of Patients With Angina With No Obstructive Coronary Arteries: How to Come to a Proper Diagnosis and Therapy.

Two-thirds of women and one-third of men who undergo a clinically indicated coronary angiography for stable angina, have no obstructive coronary artery disease (CAD). Coronary vascular dysfunction is a highly prevalent underlying cause of angina in these so called “Angina with No Obstructive Coronary Arteries (ANOCA)” patients, foremost in middle aged women. Coronary vascular dysfunction encompasses various endotypes, namely epicardial and microvascular coronary spasms, impaired vasodilatation, and increased microvascular resistance. ANOCA patients, especially those with underlying coronary vascular dysfunction, have an adverse cardiovascular prognosis, poor physical functioning, and a reduced quality of life. Since standard ischemia detection tests and coronary angiograms are not designed to diagnose coronary vascular dysfunction, this ischemic heart disease is often overlooked and hence undertreated. But adequate diagnosis is vital, so that treatment can be started to reduce symptoms, reduce healthcare costs and improve quality of life and cardiovascular prognosis. The purpose of this review is to give a contemporary overview of ANOCA with focus on coronary vascular dysfunction. We will provide a possible work-up of patients suspected of coronary vascular dysfunction in the outpatient clinical setting, based on the latest scientific insights and international consensus documents. We will discuss the value of ischemia detection testing, and non-invasive and invasive methods to diagnose coronary vascular dysfunction. Furthermore, we will go into pharmacological and non-pharmacological therapeutic options including anti-anginal regimens and lifestyle interventions.

Sex Differences in Coronary Function Test Results in Patient With Angina and Nonobstructive Disease.

Introduction: Invasive coronary function testing (CFT) has become the recommended diagnostic tool to assess the various endotypes of coronary vasomotor dysfunction in patients with angina and no obstructive coronary artery disease (ANOCA), which has implications for therapy and prognosis. Although the expanding performance of CFT is leading to increased knowledge of coronary vasomotor dysfunction, little is known about sex-related differences in the results of comprehensive CFT.Methods: We conducted a prospective study of all consecutive patients with ANOCA that underwent clinically indicated CFT in a tertiary interventional from February 2019 to February 2021. CFT consisted of acetylcholine testing to diagnose epicardial or microvascular spasm, and adenosine testing to diagnose CMD. CMD was defined as an index of microvascular resistance (IMR) ≥ 25 and/or coronary flow reserve (CFR) < 2.0.Results: In total, 228 women and 38 men underwent CFT. No differences in traditional risk factors were seen, but women had a higher prevalence of migraine (45 vs. 14%, p = 0.001). Men more often had a history of percutaneous coronary intervention (12 vs. 49%, p = 0.001). We found no difference in clinical presentation. Coronary vasomotor dysfunction was present in 95% of men and 88% of women (p = 0.25), but males show more often epicardial spasm and less microvascular spasm than women (63 vs. 42% and 29 vs. 40% respectively, p = 0.039). Impaired CFR was more prevalent among females (6 vs 20%, p = 0.033). IMR [median of 23 (15–32) vs. 19 (13–25), p = 0.08] did not differ between the sexes.Conclusion: Men undergoing CFT show a comparable prevalence of coronary vascular dysfunction as women. However, men have a higher prevalence of epicardial spasm and a lower prevalence of microvascular spasm compared with women. An impaired CFR was more often present in women, with an equally impairment of IMR.

Management of Advanced Heart Failure in Children with Cancer Therapy-Related Cardiac Dysfunction.

The evolution of cancer therapies has led to marked improvement in survival of those affected by childhood malignancies, while also increasing the recognition of early and late toxicities associated with cancer therapies. Cardiotoxicity can include cardiomyopathy/heart failure, coronary artery disease, stroke, pericardial disease, arrhythmias, and valvular and vascular dysfunction as a result of exposure to chemotherapy and/or radiation. Anthracyclines remain the most common cause of chemotherapy-induced cardiomyopathy (CCM) with varying clinical presentations including: acute, early onset, and late-onset. Many individuals develop cardiac dysfunction over the long-term, ranging from subclinical cardiac dysfunction to end-stage symptomatic heart failure. The focus of this review is on characterization of symptomatic heart failure in children with cancer therapy-related cardiac dysfunction (CTRCD) primarily due to CCM and utilization of advanced heart failure therapies, including ventricular assist device (VAD) support and heart transplantation, with consideration of unique patient-related factors.

Coronary endothelial dysfunction appears to be a manifestation of a systemic process: A report from the Women’s Ischemia Syndrome Evaluation – Coronary Vascular Dysfunction (WISE-CVD) study

BackgroundCoronary microvascular dysfunction (CMD) is prevalent in symptomatic women with ischemia but no obstructive coronary artery disease (INOCA). Urine albumin-creatinine ratio (UACR) is a measure of renal microvascular endothelial dysfunction. Both are predictors of adverse cardiovascular events. It is unknown if CMD could be a manifestation of a systemic process. We evaluated the relationship between renal microvascular dysfunction and CMD as measured by invasive coronary function testing (CFT).Methods and resultsWe measured urine albumin and creatinine to provide UACR in 152 women enrolled in the Women’s Ischemia Syndrome Evaluation–Coronary Vascular Dysfunction (WISE-CVD) study (2008–2015) with suspected INOCA who underwent CFT. Invasive CFT measures of endothelial and non-endothelial dependent coronary microvascular function were obtained. Subjects were divided into those with detectable (≥20 mg/g) and undetectable urine albumin (<20 mg/g). The group mean age was 54 ± 11 years, with a moderate cardiac risk factor burden including low diabetes prevalence, and a mean UACR of 12 ± 55 mg/g (range 9.5–322.7 mg/g). Overall, coronary endothelial-dependent variables (change in coronary blood flow and coronary diameter in response to cold pressor testing) had significant inverse correlations with log UACR (r = -0.17, p = 0.05; r = -0.18, p = 0.03, respectively).ConclusionsAmong women with INOCA and relatively low risk factor including diabetes burden, renal microvascular dysfunction, measured by UACR, is related to coronary endothelial-dependent CMD. These results suggest that coronary endothelial-dependent function may be a manifestation of a systemic process. Enhancing efferent arteriolar vasodilatation in both coronary endothelial-dependent function and renal microvascular dysfunction pose potential targets for investigation and treatment.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT00832702.

Exercise training mitigates ER stress and UCP2 deficiency-associated coronary vascular dysfunction in atherosclerosis

Endoplasmic reticulum (ER) stress and uncoupling protein-2 (UCP2) activation are opposing modulators of endothelial dysfunction in atherosclerosis. Exercise reduces atherosclerosis plaques and enhances endothelial function. Our aim was to understand how exercise affects ER stress and UCP2 activation, and how that relates to endothelial dysfunction in an atherosclerotic murine model. Wild type (C57BL/6, WT) and apolipoprotein-E-knockout (ApoEtm1Unc, ApoE KO) mice underwent treadmill exercise training (EX) or remained sedentary for 12 weeks. Acetylcholine (ACh)-induced endothelium-dependent vasodilation was determined in the presence of an eNOS inhibitor (L-NAME), UCP2 inhibitor (genipin), and ER stress inducer (tunicamycin). UCP2, ER stress markers and NLRP3 inflammasome signaling were quantified by western blotting. p67phox and superoxide were visualized using immunofluorescence and DHE staining. Nitric oxide (NO) was measured by nitrate/nitrite assay. ACh-induced vasodilation was attenuated in coronary arterioles of ApoE KO mice but improved in ApoE KO-EX mice. Treatment of coronary arterioles with L-NAME, tunicamycin, and genipin significantly attenuated ACh-induced vasodilation in all mice except for ApoE KO mice. Exercise reduced expression of ER stress proteins, TXNIP/NLRP3 inflammasome signaling cascades, and Bax expression in the heart of ApoE KO-EX mice. Further, exercise diminished superoxide production and NADPH oxidase p67phox expression in coronary arterioles while simultaneously increasing UCP2 expression and nitric oxide (NO) production in the heart of ApoE KO-EX mice. Routine exercise alleviates endothelial dysfunction in atherosclerotic coronary arterioles in an eNOS, UCP2, and ER stress signaling specific manner, and resulting in reduced TXNIP/NLRP3 inflammasome activity and oxidative stress.

Cutaneous Microvascular Impairment in 5‐Fluorouracil Treated Cancer Patients

INTRODUCTION Despite frequent use and high efficacy in treatment of several cancers, 5-Fluorouracil (5-FU) chemotherapy is associated with acute and late occurring cardiotoxicity, ranging from vasospastic angina to increased risk of overt cardiovascular disease mortality. To date, the mechanisms by which these toxicities occur are not well understood, with leading theories implicating coronary vascular dysfunction by way of endothelial-dependent vasodilator impairment. PURPOSE & HYPOTHESIS Therefore, the purpose of the present research was to evaluate multiple mechanisms of endothelial function within the cutaneous microcirculation of 5-FU treated cancer patients (5-FU) and matched controls (CON) using the noninvasive measure of laser Doppler flowmetry (LDF). We hypothesized that 5-FU would attenuate both acetylcholine (ACh)-induced and local heating-induced cutaneous vasodilation. METHODS 17 5-FU (13 M, 4 F; age = 63.5 ± 12 yr) and 16 CON (8 M, 8 F; age = 58.1 ± 16 yr) volunteered for this study. Red blood cell flux was acquired via LDF in the forearm at baseline and following 1) iontophoresis of 200 µL of 2% ACh and 2) ~ 35 min of localized heating at 42°C. CVC was calculated from red blood cell flux divided by mean arterial pressure and presented as the percent increase from baseline to peak (%CVC). RESULTS ACh resulted in a significantly increased CVC in both groups, with no differences in %CVC between groups (CON = 920 ± 107%, 5-FU = 842 ± 113%; p = .62). Local heating, however, elicited a significantly lower %CVC in 5-FU treated patients (CON = 567.5 ± 77.7%, 5-FU = 256.7 ± 71.8%; p = .012). CONCLUSION Given the primary role of endothelial nitric oxide in local heating-induced cutaneous vasodilation, but not during ACh, our findings suggest that 5-FU chemotherapy treatment may result in endothelial dysfunction through nitric oxide mediated mechanisms. Experiments to corroborate these findings through iontophoresis of N-ω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) and in human coronary endothelial cell culture are ongoing by our group and will provide additional mechanistic insight into 5-FU induced cardiotoxicity.