Whole blood viscosity in microvascular angina and coronary artery disease: Significance and utility.

INTRODUCTION AND OBJECTIVES: Whole blood viscosity (WBV) is the intrinsic resistance of blood flow in vessels, and when elevated induces endothelial shear stress and endothelial inflammation and can accelerate the atherosclerotic process. This study aims to compare WBV levels in patients with microvascular angina (MVA), patients with coronary artery disease (CAD), and normal controls, and to identify the relationship between WBV and high-sensitivity C-reactive protein as a marker of inflammation in MVA and CAD. METHODS: A total of 573 patients were studied. The MVA group consisted of 189 subjects, the CAD group consisted of 203 subjects, and the control group consisted of 181 age- and gender-matched individuals. WBV was calculated from hematocrit and plasma protein concentration at a low shear rate (0.5 s-1) and high shear rate (208 s-1) by a validated equation. RESULTS: Patients with CAD and MVA had significantly higher WBV at both low and high shear rates compared to the control group. Correlation analysis revealed a significant relationship between high-sensitivity C-reactive protein and WBV at low (r=0.556; p<0.001) and high shear rates (r=0.562) in the CAD group and at low (r=0.475) and high shear rates (r=0.493) in the MVA group. CONCLUSIONS: Overall, this study demonstrated a significant and independent association between blood viscosity and the existence of endothelial inflammation and the atherosclerotic process.

Microvascular Angina　- Long-Term Exercise Stress Test Follow-up.

BACKGROUND: A sizeable proportion of patients with primary stable microvascular angina (MVA; exercise-induced angina, positive exercise stress test [EST], normal coronary arteries) have recurrent symptoms during follow-up. There have been no previous studies, however, on the long-term results of EST and their correlation with symptom outcome.Methods and Results:Follow-up EST was performed in 71 MVA patients at an average of 16.2 years (range, 5-25 years) from the first EST. Angina status was assessed on weekly frequency of angina episodes and nitroglycerin consumption and by whether symptoms had worsened, improved, or remained unchanged over time. At follow-up EST, 41 patients (group 1) had exercise-induced ischemia, whereas 30 patients (group 2) had negative EST. Compared to group 2, group 1 patients more frequently had exercise-induced dyspnea, and had a greater maximum ST-segment depression and a lower coronary blood flow response to adenosine and cold pressor test, but group 2 patients had a more frequent history of rest angina. No differences between the 2 groups were found at follow-up in angina status or change in symptom status during follow-up. CONCLUSIONS: Electrocardiogram results improve significantly in a sizeable proportion of patients with MVA. Changes in EST results, however, were not associated with clinical outcome.

Coronary lumen volume to myocardial mass ratio in primary microvascular angina.

BACKGROUND: Microvascular angina (MVA) is an incompletely understood clinical entity. Computational analysis of coronary Computed Tomography Angiography (CTA) has shown an association between low coronary lumen volume to myocardial mass (V/M) ratio and lower Fractional Flow Reserve values, independent of plaque measures. We hypothesized that low V/M ratio may be present in patients with MVA. METHODS: A retrospective case-control analysis was performed using patients fulfilling guideline criteria for MVA with controls matched for age, gender, coronary risk factors and atherosclerotic plaque burden. V/M was extracted off site (Heartflow Inc; Redwood City, CA) employing allometric scaling laws that allow the definition of the coronary circulation beyond the epicardium. FFRCT values were calculated in the major epicardial coronary arteries for each group. RESULTS: A total of 30 patients with MVA and 32 matched controls were included in the study. Mean total coronary lumen volume (2302 mm3 ± 109 vs 2978 mm3 ± 134, p < 0.001) and mean myocardial mass (90.4 g ± 13.7 vs 100.4 g ± 20.1, p = 0.029) were lower in MVA patients compared to controls. Mean V/M ratio was significantly lower in MVA compared to controls (25.6 mm3/g ± 5.9 vs 30.0 mm3/g ± 6.5, p = 0.007; c-statistic 0.69). V/M ratio did not differ significantly between subclasses of angina severity (p = 0.747). No difference in mean nadir FFRCT values was found between MVA and control groups in the LAD (0.86 ± 0.07 vs 0.83 ± 0.07, p = 0.154), LCX (0.90 ± 0.05 vs 0.90 ± 0.06, p = 0.240) and RCA (0.90 ± 0.04 vs 0.90 ± 0.03, p = 0.773) vessels. CONCLUSION: Patients with microvascular angina demonstrate a significantly lower coronary CTA-derived coronary volume/myocardial mass ratio than asymptomatic controls.

Left atrial volume and function in patients with cardiac syndrome X assessed by real time three-dimensional echocardiography.

OBJECTIVE: The aim of this study was to evaluate left atrial (LA) volume and function using real time three-dimensional echocardiography (RT3DE) in patients with cardiac syndrome X (CSX). METHODS: Fifty patients with CSX (28 females; mean age 50.9±10.9 years) and 50 age- and gender-matched healthy controls (30 females; mean age 52.3±9.8 years) who had negative treadmill exercise test and normal coronary arteries on invasive coronary angiography were included in the study. Comprehensive two-dimensional (2D), pulsed and tissue Doppler, speckle tracking echocardiography, and RT3DE for the assessment of LA dynamics were performed in all study participants. RESULTS: Cardiac syndrome X and control groups have similar clinical characteristics regarding age, sex, body mass index, hypertension, diabetes, and smoking habit. 2D echocardiographic parameters were also similar between groups. Pulsed- and tissue Doppler parameters, IVRT, A, and Am values, were higher in CSX group, while Em , E/A, and Em /Am ratios were higher in the control group reflecting mild diastolic dysfunction. Regarding RT3DE parameters, LA maximum volume, minimum volume, volume before atrial contraction, LA maximum volume index, total and active stroke volumes were found to be increased in CSX patients. However, LA total stroke fraction, passive stroke volume, passive stroke fraction, peak systolic, and diastolic longitudinal strains were found to be lower in CSX patients. CONCLUSION: The main finding of this study was that CSX patients had altered LA booster pump, reservoir, and conduit functions. This finding may have clinical implications for early detection of abnormal LA dynamics in CSX patients.

Cryopreservation of Human Pluripotent Stem Cell-Derived Cardiomyocytes: Strategies, Challenges, and Future Directions.

In recent years, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have emerged as a vital cell source for in vitro modeling of genetic cardiovascular disorders, drug screening, and in vivo cardiac regeneration research. Looking forward, the ability to efficiently cryopreserve hPSC-CMs without compromising their normal biochemical and physiologic functions will dramatically facilitate their various biomedical applications. Although working protocols for freezing, storing, and thawing hPSC-CMs have been established, the question remains as to whether they are optimal. In this chapter, we discuss our current understanding of cryopreservation appertaining to hPSC-CMs, and proffer key questions regarding the mechanical, contractile, and regenerative properties of cryopreserved hPSC-CMs.

Association of Low Ficolin-Lectin Pathway Parameters with Cardiac Syndrome X.

In patients with typical angina pectoris, inducible myocardial ischaemia and macroscopically normal coronaries (cardiac syndrome X (CSX)), a significantly elevated plasma level of terminal complement complex (TCC), the common end product of complement activation, has been observed without accompanying activation of the classical or the alternative pathways. Therefore, our aim was to clarify the role of the ficolin-lectin pathway in CSX. Eighteen patients with CSX, 37 stable angina patients with significant coronary stenosis (CHD) and 54 healthy volunteers (HC) were enrolled. Serum levels of ficolin-2 and ficolin-3, ficolin-3/MASP-2 complex and ficolin-3-mediated TCC deposition (FCN3-TCC) were determined. Plasma level of TCC was significantly higher in the CSX than in the HC or CHD group (5.45 versus 1.30 versus 2.04 AU/ml, P < 0.001). Serum levels of ficolin-2 and ficolin-3 were significantly lower in the CSX compared to the HC or CHD group (3.60 versus 5.80 or 5.20 µg/ml, P < 0.05; 17.80 versus 24.10 or 26.80 µg/ml, P < 0.05). The ficolin-3/MASP-2 complex was significantly lower in the CSX group compared to the HC group (92.90 versus 144.90 AU/ml, P = 0.006). FCN3-TCC deposition was significantly lower in the CSX group compared to the HC and CHD groups (67.8% versus 143.3% or 159.7%, P < 0.05). In the CSX group, a significant correlation was found between TCC and FCN3-TCC level (r = 0.507, P = 0.032) and between ficolin-3/MASP-2 complex level and FCN3-TCC deposition (r = 0.651, P = 0.003). In conclusion, in patients with typical angina and myocardial ischaemia despite macroscopically normal coronary arteries, low levels of several lectin pathway parameters were observed, indicating complement activation and consumption. Complement activation through the ficolin-lectin pathway might play a role in the complex pathomechanism of CSX.

Impact of Early ST-Segment Changes on Cardiac Magnetic Resonance-Verified Intramyocardial Haemorrhage and Microvascular Obstruction in ST-Elevation Myocardial Infarction Patients.

The aim of this study was to explore the significance of different ST-segment changes before and after percutaneous coronary intervention (PCI), in relation to cardiac magnetic resonance (CMR)-verified microvascular obstruction (MVO) along with intramyocardial hemorrhage (IMH) in ST-elevation myocardial infarction (STEMI) patients.This study enrolled 108 STEMI patients who received primary PCI and had no contraindication of CMR investigation. Sum ST-segment elevation (STE), maximal STE on admission and sum ST-segment resolution (STR), and single-lead STR and residual STE at 60 minutes after primary PCI were assessed. MVO and IMH were determined by contrast-enhanced CMR.Patients were classified into 3 groups: 30 patients with MVO(-)/IMH(-), 25 with MVO(+)/IMH(-), and 53 with MVO(+)/IMH(+). Sum STE (P = 0.001), maximal STE (P < 0.001), and residual STE (P = 0.025) were highest and single-lead STR was lowest (P = 0.044) in the MVO(+)/IMH(+) group. Receiver operator characteristics curve analysis revealed that maximal STE was the most powerful factor for distinguishing between MVO(+) and MVO(-) patients (optimal threshold = 0.5 mV, area under the curve, AUC = 0.718, P < 0.001), or IMH(+) and IMH(-) patients (optimal threshold = 0.5 mV, AUC = 0.697, P < 0.001). In multivariate analysis, maximal STE was identified as the most powerful independent predictor of MVO (odds ratio [OR] = 4.30, P < 0.001) and IMH (OR = 2.44, P = 0.001), whereas sum STE was the strongest correlate of both the number of MVO segments (r = 0.42, P < 0.001) and IMH segments (r = 0.43, P < 0.001).The presence of MVO and IMH in infarcted tissue was relevant to ST-segment changes in STEMI patients. Maximal STE was a powerful independent predictor of the presence of MVO and IMH, whereas sum STE was a strong correlate of the number of MVO and IMH segments.

Nitric oxide synthetic pathway in patients with microvascular angina and its relations with oxidative stress.

A decreased nitric oxide (NO) bioavailability and an increased oxidative stress play a pivotal role in different cardiovascular pathologies. As red blood cells (RBCs) participate in NO formation in the bloodstream, the aim of this study was to outline the metabolic profile of L-arginine (Arg)/NO pathway and of oxidative stress status in RBCs and in plasma of patients with microvascular angina (MVA), investigating similarities and differences with respect to coronary artery disease (CAD) patients or healthy controls (Ctrl). Analytes involved in Arg/NO pathway and the ratio of oxidized and reduced forms of glutathione were measured by LC-MS/MS. The arginase and the NO synthase (NOS) expression were evaluated by immunofluorescence staining. RBCs from MVA patients show increased levels of NO synthesis inhibitors, parallel to that found in plasma, and a reduction of NO synthase expression. When summary scores were computed, both patient groups were associated with a positive oxidative score and a negative NO score, with the CAD group located in a more extreme position with respect to Ctrl. This finding points out to an impairment of the capacity of RBCs to produce NO in a pathological condition characterized mostly by alterations at the microvascular bed with no significant coronary stenosis.

Effect of exercise on circulating endothelial progenitor cells in microvascular angina.

BACKGROUND: Circulating endothelial progenitor cells (EPCs) might limit endothelial dysfunction in patients with microvascular angina (MVA). Endothelial colony-forming cells (ECFCs; displaying the CD34+/KDR+/CD45- phenotype) are currently regarded as true EPCs. The aim of this study was to evaluate exercise-induced ECFC mobilization and platelet reactivity in patients with MVA or with obstructive coronary artery disease (CAD). METHODS AND RESULTS: Exercise stress test (EST) was performed in 20 MVA patients, 20 CAD patients and 20 controls. Platelet reactivity was assessed before and after EST as formation of monocyte-platelet aggregates (MPAs) and CD41 platelet expression, without and with adenosine diphosphate (ADP) stimulation. ECFC number was measured before and 24h after EST. At rest, MPAs and CD41 platelet expression increased more with ADP in MVA patients (+71±11.0% and +37±7.5%, respectively), than in CAD patients (+37±8.6% and +19±4.5%, respectively) and controls (+29±3.5% and +21±3.1%, respectively; P<0.001 for both). At rest, ECFCs tended to be lower in CAD patients, compared to MVA patients and controls (4.1±5.0%, 7.2±6.0% and 7.3±7.0% cells/10(5), respectively; P=0.056). After EST, ECFCs increased less in MVA patients (+2.8±11) compared to CAD patients (+3.3±15; P<0.05) and controls (+7.4±24; P<0.01). CONCLUSIONS: In MVA patients, EST is able to blunt the peculiar increase of platelet reactivity to ADP present at rest; in contrast, no potential protective response of ECFCs to exercise was seen in these patients.

ß-actin-positive mononuclear cells participate in coronary microvascular medial hyperplasia by migrating through adventitia into media, with special reference to microvessel angina.

Coronary microvascular hyperplasia is a cause of microvessel angina, although the underlying cellular mechanisms remain unclear. We examined how mononuclear cells expressing ß-actin (ß-MNCs), which were identified in coronary vessels, induce coronary microvascular hyperplasia.The presence of ß-MNCs in coronary hyperplastic arterial (HAM) and venous microvessels (HVM) was examined by endomyocardial biopsy in 25 patients with suspected microvessel angina. ß-MNCs were identified in 14 HAMs obtained from 11 patients. Basic fibroblast growth factor and heparin sulfate were injected into the infarcted myocardium to induce HAM and HVM in 28 beagles, and then we examined the role of ß-MNCs in the onset of HAM and HVM. The following changes were observed after infarction induction in beagles: (a) migration of ß-MNCs from the existing microvessels into the interstitial space at 1-2 weeks; (b) those traversing the adventitia into the media, but not intima, of microvessels; (c) their transformation to smooth muscle cells (SMCs) and/or connective tissues (collagen and elastin fibers); (d) and medial hyperplasia without intimal hyperplasia. Medial hyperplasia was classified into SMC-proliferative and both SMC- and connective tissue-proliferative types. ß-MNCs expressed CD(34) but did not express other major vessel-related cell markers.ß-MNCs are a vascular progenitor, and migrate out of the adventitia into media, and participate in the etiology of coronary microvascular medial hyperplasia.

Patients with syndrome X have normal transmural myocardial perfusion and oxygenation: a 3-T cardiovascular magnetic resonance imaging study.

BACKGROUND: The pathophysiology of chest pain in patients with cardiac syndrome X remains controversial. Advances in perfusion imaging with cardiovascular magnetic resonance (CMR) now enable absolute quantification of regional myocardial blood flow (MBF). Furthermore, blood oxygen level-dependent (BOLD) or oxygenation-sensitive CMR provides the unprecedented capability to assess regional myocardial oxygenation. We hypothesized that the combined assessment of regional perfusion and oxygenation with CMR could clarify whether patients with syndrome X show evidence of myocardial ischemia (reduced perfusion and oxygenation) during vasodilator stress compared with normal volunteers. METHODS AND RESULTS: Eighteen patients with syndrome X (chest pain, abnormal exercise treadmill test, normal coronary angiogram without other causes of microvascular dysfunction) and 14 controls underwent CMR scanning at 3 T. Myocardial function, scar, perfusion (2-3 short-axis slices), and oxygenation were assessed. Absolute MBF was measured during adenosine stress (140 µg/kg per minute) and at rest by model-independent deconvolution. For oxygenation, using a T2-prepared BOLD sequence, signal intensity was measured at adenosine stress and rest in the slice matched to the midventricular slice of the perfusion scan. There were no significant differences in MBF at stress (2.35 versus 2.37 mL/min per gram; P=0.91), BOLD signal change (17.3% versus 17.09%; P=0.91), and coronary flow reserve measurements (2.63 versus 2.53; P=0.60) in patients with syndrome X and controls, respectively. Oxygenation and perfusion measurements per coronary territory were also similar between the 2 groups. More patients with syndrome X (17/18 [94%]) developed chest pain during adenosine stress than controls (6/14 [43%]; P=0.004). CONCLUSIONS: Patients with syndrome X show greater sensitivity to chest pain compared with controls but no evidence of deoxygenation or hypoperfusion during vasodilatory stress.

Microvascular coronary dysfunction in women: pathophysiology, diagnosis, and management.

Women exhibit a greater symptom burden, more functional disability, and a higher prevalence of no obstructive coronary artery disease compared to men when evaluated for signs and symptoms of myocardial ischemia. Microvascular coronary dysfunction (MCD), defined as limited coronary flow reserve and/or coronary endothelial dysfunction, is the predominant etiologic mechanism of ischemia in women with the triad of persistent chest pain, no obstructive coronary artery disease, and ischemia evidenced by stress testing. Evidence shows that approximately 50% of these patients have physiological evidence of MCD. MCD is associated with a 2.5% annual major adverse event rate that includes death, nonfatal myocardial infarction, nonfatal stroke, and congestive heart failure. Although tests such as adenosine stress cardiac magnetic resonance imaging may be a useful noninvasive method to predict subendocardial ischemia, the gold standard test to diagnose MCD is an invasive coronary reactivity testing. Early identification of MCD by coronary reactivity testing may be beneficial in prognostication and stratifying these patients for optimal medical therapy. Currently, understanding of MCD pathophysiology can be used to guide diagnosis and therapy. Continued research in MCD is needed to further advance our understanding.

Microvascular angina: assessment of coronary blood flow, flow reserve, and metabolism.

Microvascular angina (MVA) is an often overlooked cause of significant chest pain. Decreased myocardial perfusion secondary to dysregulated blood flow in the microvasculature can occur in the presence or absence of obstructive epicardial coronary artery disease. The corresponding myocardial ischemia and angina is now a well-established diagnosis, made by detection of decreased coronary flow reserve (CFR). Although low CFR and MVA are associated with poor prognosis, there is initial evidence for reversibility of this abnormal vascular regulation with aggressive medical therapy and control of associated risk factors. Current assessment of MVA is carried out predominantly during cardiac catheterization; however, noninvasive techniques to assess CFR are being developed, including PET, MRI, and CT modalities. Quantitative tracer techniques or imaging of metabolic disturbances reflecting ischemia will likely enhance diagnostic approaches for such patients as well as allow more frequent monitoring of response to therapy.

Comparison of angiographic with myocardial perfusion scintigraphy findings in cardiac syndrome X (CSX).

OBJECTIVE: Cardiac syndrome X (CSX) is defined by an angina-like chest pain, a positive response to stress testing and normal or near normal coronary angiogram. We evaluated the angiographic findings in patients with cardiac syndrome X and compared it with myocardial perfusion scintigraphy findings. PATIENTS AND METHODS: The study included 39 females aged 40-58 years (mean, 49.79 +/- 4.69 [SD] and 13 males ranging from 40 to 54 years (mean, 47.54 +/- 3.76 [SD] with CSX. By reviewing the angiographic film, some variables including stenosis (less than 30% of vessel diameter), delay run off, delay wash out, calcification and tortuosity were evaluated. Thirty-two had been undergone on myocardial perfusion imaging (MPI). RESULTS: The most frequent abnormal angiographic finding in three territories was stenosis item. Overall, 22 of 32 (68.75%) CSX patients had ischemia on MPI. The result of the myocardial perfusion imaging was not concordant with five angiographic findings. CONCLUSION: We suggest that the presence of angiographic coronary findings such as stenosis, delay run off, delay wash out, calcification and tortuosity are not invariably associated with atherosclerosis, and also seen in CSX patients.

Effect of spinal cord stimulation on cardiac adrenergic nerve function in patients with cardiac syndrome X.

BACKGROUND: In patients with cardiac syndrome X (CSX) who present with refractory angina episodes, spinal cord stimulation (SCS) has beneficial effects. The mechanisms of SCS, however, remain speculative. We assessed the effects of SCS on cardiac sympathetic function in these patients. METHODS AND RESULTS: We studied 11 CSX patients treated by SCS for refractory angina (mean age, 60 +/- 9 years; 5 men and 6 women), both during SCS therapy (SCS-ON) and after withdrawal of SCS therapy (SCS-OFF), using a randomized crossover design. Planar and single photon emission computed tomography iodine 123 metaiodobenzylguanidine (MIBG) myocardial scintigraphy and technetium 99m sestamibi (MIBI) bicycle exercise stress testing were performed at the end of each period. Compared with 10 healthy control subjects, CSX patients showed a lower heart-mediastinum ratio for MIBG uptake (2.19 +/- 0.3 vs 1.69 +/- 0.3, P = .001) and a higher cardiac MIBG uptake score (4.0 +/- 2.5 vs 19.7 +/- 27, P = .08). There were no differences in CSX patients during the SCS-ON and SCS-OFF phases of the study in heart-mediastinum ratio (1.74 +/- 0.3 vs 1.69 +/- 0.3, P = .13), cardiac washout rate of MIBG (42.9% +/- 14% vs 43.3% +/- 14%, P = .08), or MIBG defect score (18.7 +/- 25 vs 19.7 +/- 27, P = .22). Reversible perfusion defects during the SCS-OFF phase were detected in 8 patients; an improvement in perfusion defects was observed in 2 patients (25%) during the SCS-ON phase. CONCLUSIONS: Our data confirm the presence of abnormal cardiac adrenergic nerve function in CSX patients. SCS was unable to result in significant improvement of cardiac MIBG uptake abnormalities, suggesting that its therapeutic effects are unlikely to be mediated by modulation of cardiac adrenergic nerve activity.

Coronary artery calcium score assessed by a 64 multislice computed tomography and early indexes of functional and structural vascular remodeling in cardiac syndrome X patients.

BACKGROUND: Regardless of normal coronary angiograms, coronary artery calcium (CAC) can be found in cardiac syndrome X (CSX) patients. According to some data, a relationship between the CAC score and markers of early atherosclerosis in CSX has been observed. Our aim was to assess whether the extent of the CAC score assessed by multislice computed tomography (MSCT) with a 64-slice system in CSX patients is related to brachial artery reactivity, intima-media thickness (IMT), and arterial compliance indexes. METHODS AND RESULTS: High-resolution ultrasound was used to measure flow-mediated dilatation (FMD) and nitroglycerin-mediated vasodilatation, as well as the following parameters of arterial structural changes: IMT, pulse wave velocity, total arterial compliance, and stiffness index. MSCT was used to assess the presence and the quantity of CAC. The study group consisted of 46 CSX patients (mean age, 56.3 +/- 9 years), whereas the control group comprised 21 healthy subjects (mean age, 54.9 +/- 7 years). The assessment of the vascular parameters showed significantly decreased FMD and increased IMT in the CSX subjects (9.06% +/- 3.2% and 0.67 +/- 0.1 mm, respectively) in comparison to the control subjects (17.42% +/- 8.4% [P = .008] and 0.57 +/- 0.2 mm [P = .021], respectively). CAC was detectable in 19 CSX patients (41%) (CAC range according to Agatston score, 2-500; mean, 101.6; median, 26.5) and in 1 control subject (4.8%) (CAC value, 13). CSX patients with detectable CAC were characterized by a significantly higher age (P = .001), lower body mass index (P = .017), and increased stiffness index (P = .020); there were no differences in FMD and IMT values. In a multivariate logistic and linear regression analysis, age was the only risk factor independently associated with the presence of CAC (P = .001) and the log(CAC + 1) value (P = .01). In the subgroup of women, log(CAC + 1) significantly correlated with age (r = 0.587, P = .002) and stiffness index (r = 0.427, P = .024), and in a borderline significant manner, it correlated with weight (r = -0.329, P = .07) and waist-hip ratio (r = 0.315, P = .07). There were no significant correlations in the male subgroup. CONCLUSIONS: Low ranges of CAC are frequently detectable in CSX patients, and the results are age-related and independent of impaired early indexes of functional and structural vascular remodeling.