Effects of dietary oxysterols on coronary arteries in hyperlipidaemic hamsters

The aim of this study was to evaluate the effect of dietary oxysterols on coronary atherosclerosis and vasospasm. Golden Syrian hamsters were fed three diets with different lipid contents for 3 months: (1) a normolipidaemic diet containing 25 g corn oil–fish oil (4:1, w/w)/kg (group Low L); (2) a hyperlipidaemic diet composed of the normolipidaemic diet supplemented with 150 g lard+30 g cholesterol/kg (group High L); (3) a third diet, similar to the hyperlipidaemic diet, in which 4 g cholesterol/kg was replaced by a mixture of oxysterols (group High L+OS). The oxysterol mixture contained (g/kg): 5,6α-epoxycholesterol 211, 5,6β-epoxycholesterol 179, 7α-hydroxycholesterol 67, 7β-hydroxycholesterol (7βOH) 185, 7-ketocholesterol (7 K) 235; and trace amounts of 7-hydroperoxycholesterols (approximately 30 g/kg). Atherosclerosis was evaluated by measuring myocardial Ca, oxysterols and acyl-CoA cholesterol acyl transferase (ACAT) activity; furthermore, coronary reactivity to sodium nitroprusside (5×10-6 m) was measured and the morphology of coronary arteries was visualized by transmission electron microscopy. Coronary spasm was determined by evaluating reactivity to serotonin (5×10-6 m). Feeding the high-lipid diet (group High L) increased the plasma level of 7βOH, 7 K and cholestanetriol. The presence of oxysterols in the diet (group High L+OS) further increased the concentrations of 7βOH and 7 K in the plasma. However, as evidenced by myocardial Ca, ACAT activity and coronary reactivity to sodium nitroprusside, severe atherosclerosis did not develop during the 3-month diet. 7 K was increased in myocardial lipids of groups High L and High L+OS. Electron microscopy did not show the development of atherosclerosis in group High L, whereas vascular wall thickening, endothelial damage and smooth muscle cell proliferation and migration occurred when oxysterols were present in the food. Serotonin (5×10-6 m) induced exacerbated coronary vasoconstriction in group High L that was completely reversed by dietary oxysterols. In conclusion, dietary oxysterols exhibit anti-spasmodic properties, but they cannot be used as agents against excess dietary lipid-induced coronary spasm because of their atherogenic properties.

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Mechanisms of angina in patients with biopsy-proven viral myocarditis: insights from intracoronary acetylcholine testing

European Heart Journal ◽

10.1093/ehjci/ehaa946.2063 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

A Seitz ◽

V Martinez Pereyra ◽

A Hubert ◽

K Klingel ◽

R Bekeredjian ◽

...

Keyword(s):

Coronary Arteries ◽

Coronary Spasm ◽

Viral Myocarditis ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Funding Source ◽

Pathophysiological Mechanism ◽

Ecg Changes ◽

Ventricular Ejection Fraction ◽

Microvascular Spasm

Abstract Background Patients with myocarditis often present with angina pectoris despite unobstructed coronary arteries. The underlying pathophysiological mechanism of angina in these patients remains to be elucidated. Coronary artery spasm is a well-known cause of angina in patients with unobstructed coronary arteries. In this study, we sought to assess the frequency of coronary vasomotor disorders in patients with biopsy-proven viral myocarditis. Methods In total, 700 consecutive patients who underwent endomyocardial biopsy for suspected myocarditis between 2008 and 2018 were retrospectively screened. Of these patients, viral myocarditis was confirmed in 303 patients defined as histological/immunohistological evidence of myocardial inflammation and presence of viral genome confirmed by PCR. Of these patients, 34 patients had angina despite unobstructed coronary arteries and underwent intracoronary acetylcholine (ACh) provocation testing in search of coronary spasm. Epicardial spasm was defined as acetylcholine-induced reproduction of the patient's symptoms associated with ischemic ECG changes and >90% epicardial vasoconstriction. Microvascular spasm was defined as symptom reproduction and ECG changes in the absence of significant epicardial vasoconstriction. Results Patients were 49±16 years old, 62% were male and left ventricular ejection fraction was 54±16%. Most frequent viruses were parvovirus B19 (PVB19, 59%) and human herpes virus 6 (HHV6, 26%), 2 patients had combined PVB19/HHV6 infection and 3 patients other herpesviruses (CMV, EBV, VZV). Epicardial spasm was observed in 10 patients (29%) during ACh testing and microvascular spasm was found in 11 patients (32%). The rate of coronary spasm (epicardial and microvascular) was higher in the PVB19 subgroup compared to HHV6 (80% vs. 33%, p=0.031). In particular, there was a higher prevalence of microvascular spasm in PVB19 compared to HHV6 (45% vs. 0%, p=0.018). Conclusion We observed a high prevalence of microvascular and epicardial spasm in patients with biopsy-proven viral myocarditis suggesting coronary spasm as a potential underlying mechanism for angina in these patients. Microvascular spasm was most often observed in patients with PVB19-associated myocarditis. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Robert-Bosch-Stiftung; Berthold-Leibinger-Stiftung

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The interplay between myocardial bridging and coronary spasm in patients with myocardial infarction and non-obstructive coronary arteries: pathogenic and prognostic implications

European Heart Journal Acute Cardiovascular Care ◽

10.1093/ehjacc/zuab020.139 ◽

2021 ◽

Vol 10 (Supplement_1) ◽

Author(s):

RA Montone ◽

F Gurgoglione ◽

MG Del Buono ◽

MC Meucci ◽

G Iannaccone ◽

...

Keyword(s):

Myocardial Infarction ◽

Unstable Angina ◽

Coronary Arteries ◽

Obstructive Coronary Artery Disease ◽

Coronary Spasm ◽

Interquartile Range ◽

Myocardial Bridging ◽

Adverse Cardiovascular Event ◽

Provocative Test

Abstract Funding Acknowledgements Type of funding sources: None. Background Myocardial bridging (MB) is associated with endothelial dysfunction and may represent a cause of angina in patients with non-obstructive coronary artery disease (NOCAD). Purpose Herein, we assessed the interplay between MB and coronary vasomotor disorders, evaluating also their prognostic relevance in patients with myocardial infarction and non-obstructive coronary arteries (MINOCA) or stable NOCAD. Methods We prospectively enrolled consecutive NOCAD patients undergoing intracoronary acetylcholine provocative test to assess the presence of epicardial or microvascular spasm in patients with suspected angina or MINOCA. Myocardial bridging was diagnosed by coronary angiography. The incidence of major adverse cardiac events (MACE), defined as the composite of cardiac death, non-fatal MI and rehospitalisation for unstable angina, was assessed at follow-up. We also assessed angina status using Seattle Angina Questionnaires (SAQ). Results We enrolled 310 patients (mean age 60.6 ± 11.9; 136 [43.9%] men; 169 [54.5%] stable NOCAD and 141 [45.5%] MINOCA). MB was found in 53 (17.1%) patients. MB was an independent predictor of spasm and MINOCA (p < 0.05). At follow-up (median 22 months, interquartile range [13-32]), patients with MB had a higher rate of MACE and a lower SAQ score (all p < 0.001) compared with patients without MB. The rate of MACE was considerably higher in patients with both spasm and MB than in the remaining patients (12/42 [28.6%] vs. 13/268 [4.8%], p < 0.001). Conclusion Among patients with NOCAD coronary spasm associated with MB predicts a worse clinical presentation with MINOCA and a worse clinical outcome at medium-long term follow-up, thus identifying a high-risk subset of patients with MB with relevant therapeutic implications. MB and clinical outcomesCharacteristicsOverall population(n= 310)Presence of Myocardial bridging(n= 53)Absence of Myocardial bridging(n = 257)p valueMACE [n, (%)]25 (8.1)12 (22.6)13 (5.1)<0.001CV Death [n, (%)]1 (0.3)0 (0.0)1 (0.4)0.649MI occurrence [n, (%)]6 (1.9)2 (3.8)4 (1.6)0.286Hospitalization for unstable angina [n, (%)]18 (5.8)10 (18.9)8 (3.1)< 0.001Recurrent angina [n, (%)]70 (22.6)20 (37.7)50 (19.4)0.004SAQ [median (IQR)]82 [78; 88]78 [68; 84]84 [78; 88]< 0.001Follow-up time [months, median (IQR)]22 [15;32]20 [15; 28]23 [15; 34]0.10CV Cardiovascular; MI: Myocardial Infarction; IQR: InterQuartile Range; MACE: Major Adverse Cardiovascular Event; SAQ: Seattle Angina Questionnaire.Abstract Figure Outcomes

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Functional medial thickening and folding of the internal elastic lamina in coronary spasm

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00959.2010 ◽

2011 ◽

Vol 300 (2) ◽

pp. H423-H430 ◽

Cited By ~ 10

Author(s):

Yasumi Uchida ◽

Yasuto Uchida ◽

Akimasa Matsuyama ◽

Atsushi Koga ◽

Yuko Maezawa ◽

...

Keyword(s):

Electron Microscopy ◽

Structural Changes ◽

Light And Electron Microscopy ◽

Coronary Spasm ◽

Cellular Level ◽

Internal Elastic Lamina ◽

Circular Smooth Muscle ◽

The Media ◽

Medial Thickening ◽

Elastic Lamina

Although there are a number of studies on vasospastic angina, the structural changes at the cellular level that occur in the coronary arterial wall during spasm are not well known. Coronary spasm was induced by brushing the coronary adventitia in nine anesthetized beagles, and structural changes in the spastic coronary segments were examined by light and electron microscopy, making comparisons with the adjacent nonspastic segments. The % diameter stenosis of the spastic segments as measured angiographically was 79.4 ± 12% (mean ± SD). Light microscopic changes in the spastic and nonspastic segments were as follows: medial thickness 1,512 vs. 392 μm ( P < 0.0001) and % diameter and % area stenoses of spastic segment 81.0% and 96.5%, respectively, indicating that spasm was induced by medial thickening. Circular smooth muscle cells (SMCs) in the media were arranged in parallel with the internal (IEL) and external (EEL) elastic lamina in nonspastic segments but radially rearranged in spastic segments. SMCs were classified by their patterns of connection to IEL into six types by electron microscopy. Of these, three contracted and pulled the IEL toward the EEL, causing folding of the IEL and waving of EEL resulting in thickening of the media and narrowing of the lumen. We conclude that coronary spasm was elicited by radial rearrangement of the medial SMCs due to their own contraction and resultant medial thickening and folding of IEL, creating a piston effect to narrow the lumen, i.e., spasm.

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Smooth muscles from spastic coronary artery segments show hypercontractility to histamine

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1990.259.1.h9 ◽

1990 ◽

Vol 259 (1) ◽

pp. H9-H13 ◽

Cited By ~ 2

Author(s):

S. Satoh ◽

H. Tomoike ◽

W. Mitsuoka ◽

S. Egashira ◽

H. Tagawa ◽

...

Keyword(s):

Smooth Muscle ◽

Coronary Artery ◽

Coronary Arteries ◽

Muscle Fibers ◽

Coronary Spasm ◽

Smooth Muscles ◽

Bolus Administration ◽

Luminal Diameter ◽

Endothelial Denudation ◽

Significant Difference

An animal model of coronary spasm was produced in Gottingen miniature pigs by a selective endothelial denudation of the coronary artery. Five months after the denudation, intracoronary bolus administration of 10 micrograms/kg histamine reduced the luminal diameter angiographically by 57 +/- 16 and 17 +/- 10% (P less than 0.01) in the previously denuded and contralateral control coronary arteries. Muscle fibers of 0.08–0.1 mm wide were prepared from circumferential bundles of the medial smooth muscle in the spastic and nonspastic coronary arteries. Upward shifts of either dose-tonic contraction relationships in Ca2(+)-containing solution or dose-monophasic contraction relationships in Ca2(+)-free solution were noted in muscle fibers taken from the spastic site compared with those from the nonspastic site with no difference between the mean effective dose values. After skinning the muscle fibers with saponin, there was no significant difference in the Ca2+ concentration-tension relationships between the two fibers. These findings suggest that an increased number of histaminergic receptors and/or augmentation of signal transduction, but not Ca2+ sensitivity of the contractile proteins in the medial smooth muscle cells, cause histamine-induced coronary hypercontraction.

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Feeding induces lipid accumulation and increased Na+ transport in in vitro Necturus antrum

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1990.259.6.g998 ◽

1990 ◽

Vol 259 (6) ◽

pp. G998-G1009

Author(s):

M. J. Rutten ◽

C. D. Moore ◽

R. Delcore ◽

L. Y. Cheung

Keyword(s):

Electron Microscopy ◽

Lipid Accumulation ◽

Corn Oil ◽

Short Circuit ◽

Nile Red ◽

Transepithelial Transport ◽

Na Transport ◽

Ussing Chambers ◽

Lipid Granules

We investigated the effects of feeding on lipid accumulation and transepithelial transport using in vitro Necturus gastric antral mucosae. Antra from fed Necturi were examined for lipid accumulation using light, fluorescence, histochemical, and electron microscopy. Ussing chambers were used for measurement of potential difference (PD), transepithelial resistance (Rt), short-circuit current (Isc), and unidirectional fluxes of 22Na+ and [3H]mannitol. Light microscopy of antra from 2-day postfed animals showed many intracellular lipid granules in surface mucous epithelial cells. These granules could be distinguished from other intracellular organelles by their high affinity for osmium and the lipid fluorescent probe Nile red. Glycoprotein cytochemical staining showed these granules to be distinct from the epithelial cell mucous granules. Electron microscopy showed the lipid granules to be part of a membranous reticular network. Two-day postfed animals also had a approximately 3.5-fold increase in amiloride-sensitive Isc and PD, a decrease in Rt, and an increased luminal-to-serosal Na+ fluxes. Transepithelial [3H]mannitol fluxes were low and remained unchanged in both fasted and 2-day postfed animals. After 2 days of feeding, the PD and Isc began to decrease followed by a secondary increase in Rt. Feeding Necturi a corn oil diet did not induce the appearance of either cellular lipid or alterations in Isc but produced a transient increase in Rt. Our data show that feeding (goldfish) to Necturi causes an increase in both lipid accumulation and amiloride-sensitive Na+ transport in gastric antral cells.

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Contractile responsiveness of coronary arteries from exercise-trained rats

Journal of Applied Physiology ◽

10.1152/jappl.1997.83.2.434 ◽

1997 ◽

Vol 83 (2) ◽

pp. 434-443 ◽

Cited By ~ 27

Author(s):

Janet L. Parker ◽

Mildred L. Mattox ◽

M. Harold Laughlin

Keyword(s):

Nitric Oxide ◽

Coronary Artery ◽

Nitric Oxide Synthase ◽

Exercise Training ◽

Sodium Nitroprusside ◽

Coronary Arteries ◽

Internal Diameter ◽

Relaxation Responses ◽

Proximal Coronary Artery ◽

Oxide Synthase

Parker, Janet L., Mildred L. Mattox, and M. Harold Laughlin.Contractile responsiveness of coronary arteries from exercise trained rats. J. Appl. Physiol. 83(2): 434–443, 1997.—The purpose of this study was to determine whether exercise training alters vasomotor reactivity of rat coronary arteries. In vitro isometric microvessel techniques were used to evaluate vasomotor properties of proximal left anterior artery rings (1 ring per animal) from exercise-trained rats (ET; n = 10) subjected to a 12-wk treadmill training protocol (32 m/min, 15% incline, 1 h/day, 5 days/wk) and control rats (C; n = 6) restricted to cage activity. No differences in passive length-tension characteristics or internal diameter (158 ± 9 and 166 ± 9 μm) were observed between vessesls of C and ET rats. Concentration-response curves to K+ (5–100 mM), prostaglandin F2α(10−8–10−4M), and norepinephrine (10−8–10−4) were unaltered ( P > 0.05) in coronary rings from ET rats compared with C rats; however, lower values of the concentration producing 50% of the maximal contractile response in rings from ET rats ( P = 0.05) suggest that contractile sensitivity to norepinephrine was enhanced. Vasorelaxation responses to sodium nitroprusside (10−9-10−4M) and adenosine (10−9-10−4M) were not different ( P > 0.05) between vessels of C and ET rats. However, relaxation responses to the endothelium-dependent vasodilator acetylcholine (ACh; 10−10-10−4M) were significantly blunted ( P < 0.001) in coronary rings from ET animals; maximal ACh relaxation averaged 90 ± 5 and 46 ± 12%, respectively, in vessels of C and ET groups. In additional experiments, two coronary rings (proximal and distal) were isolated from each C ( n = 7) and ET ( n = 7) animal. Proximal coronary artery rings from ET animals demonstrated decreased relaxation responses to ACh; however, ACh-mediated relaxation of distal coronary rings was not different between C and ET groups. N G-monomethyl-l-arginine (inhibitor of nitric oxide synthase) blocked ACh relaxation of all rings. l-Arginine (substrate for nitric oxide synthase) did not improve the blunted ACh relaxation in proximal coronary artery rings from ET rats. These studies suggest that exercise-training selectively decreases endothelium-dependent (ACh) but not endothelium-independent (sodium nitroprusside) relaxation responses of rat proximal coronary arteries; endothelium-dependent relaxation of distal coronary arteries is unaltered by training.

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Endothelium-dependent vasodilation of canine coronary collateral vessels

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1991.261.6.h1797 ◽

1991 ◽

Vol 261 (6) ◽

pp. H1797-H1801 ◽

Cited By ~ 3

Author(s):

N. M. Flynn ◽

D. Kenny ◽

L. R. Pelc ◽

D. C. Warltier ◽

Z. J. Bosnjak ◽

...

Keyword(s):

Sodium Nitroprusside ◽

Coronary Arteries ◽

Maximal Response ◽

Small Arteries ◽

Relaxing Factor ◽

Coronary Collateral ◽

Prostaglandin F2 Alpha ◽

Collateral Vessels ◽

Endothelium Dependent Relaxation

The objective of this study was to determine whether endothelium-mediated relaxation occurs in canine coronary collateral vessels. Responses to endothelium-dependent vasodilators in coronary collateral vessels (250-350 microns) were compared with those obtained in normal native coronary arteries of similar size. Rings of small arteries and collateral vessels were suspended in baths, and tension was recorded. All rings were constricted with prostaglandin F2 alpha (3 microM) and subsequently exposed to cumulative concentrations of acetylcholine or bradykinin. In separate experiments, the procedure was repeated in the presence of 300 microM NG-monomethyl-L-arginine (L-NMMA) to inhibit endothelium-mediated vasodilation. Endothelium-dependent relaxation was further studied in the presence of indomethacin, and endothelium-independent relaxation was examined with sodium nitroprusside. Acetylcholine and bradykinin relaxed both normal native and collateral rings. In preconstricted small arteries and collateral vessels the concentration at 50% of maximal response of acetylcholine was 85.5 +/- 19.5 and 61.0 +/- 14.0 microns, and bradykinin was 11.9 +/- 7.4 and 10.7 +/- 2.1 microns, respectively. L-NMMA attenuated the response to acetylcholine and bradykinin in both groups. The results indicate that endothelium is present and functional in canine coronary collateral vessels. Both small coronary arteries and collateral vessels are equally responsive to endothelium-dependent vasodilators and inhibition of endothelium-dependent relaxing factor.

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P6004Safety assessment and results of coronary spasm provocation testing in patients with MINOCA compared to patients with stable angina and unobstructed coronary arteries

European Heart Journal ◽

10.1093/eurheartj/ehz746.0724 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Cited By ~ 1

Author(s):

S Probst ◽

A Seitz ◽

G Pirozzolo ◽

A Becker ◽

T Schaeufele ◽

...

Keyword(s):

Myocardial Infarction ◽

Risk Factor ◽

Coronary Arteries ◽

Stable Angina ◽

Troponin T ◽

Coronary Spasm ◽

St Segment Elevation ◽

Risk Factor Data ◽

Provocation Testing ◽

Factor Data

Abstract Background Approximately 10% of patients with acute myocardial infarction do not have a culprit lesion. Such patients have been labelled as MINOCA (myocardial infarction with non-obstructive coronary arteries) and several pathophysiological etiologies have been described as potential explanations. This includes spontaneous coronary dissection, tako-tsubo-syndrome and coronary spasm. The latter can be diagnosed during invasive provocative testing. The aim of this study was to assess the frequency of coronary spasm and the safety of intracoronary provocation testing using acetylcholine in MINOCA patients compared to patients with stable angina and unobstructed coronary arteries. Methods Between 2007 and 2018 180 consecutive patients with either MINOCA or stable angina and unobstructed coronary arteries were enrolled. MINOCA was defined as acute onset of chest pain with either ST-segment elevation on the ECG or significant high sensitive troponin T elevation but no relevant epicardial stenosis (<50%) according to the current ESC guidelines. All patients underwent intracoronary acetylcholine provocation testing (ACH-test) in search of coronary spasm according to a standardized protocol immediately after diagnostic coronary angiography. Apart from systematic assessment of clinical, demographic and risk factor data, data regarding complications during the ACH-test were meticulously recorded. Results Eighty patients with MINOCA and 100 consecutive patients with stable angina were recruited (52% women, mean age 62±13 years). Overall, 59% had hypertension and 20% had diabetes. Comparison of clinical, demographic and risk factor data did not reveal any statistically significant differences except for a female preponderance in the stable patients (61% vs. 40%, p=0.007). The ACH-test revealed a coronary vasomotor disorder in 68% of cases. In 32% of cases the ACH-test was either inconclusive or negative. Epicardial spasm was found in 31% of patients with a higher prevalence among the MINOCA patients compared to the stable angina patients (41% vs. 23%, p=0.002). Microvascular spasm was found in 37% with a higher prevalence among the stable angina patients compared to the MINOCA cohort (49% vs. 23%, p=0.002). Assessment of complications during the ACH-test revealed that 13 MINOCA patients and 15 stable angina patients had minor complications such as intermittent atrioventricular block, sinusbradycardia, paroxysmal atrial fibrillation, ventricular ectopic beats or transient hypotension. Comparison of minor complications between the two groups did not reveal statistically significant differences (16% vs. 15%, p=0.839). None of the patients experienced any irreversible complications. Conclusion Coronary spasm is a frequent cause for MINOCA. Intracoronary spasm provocation testing using acetylcholine is feasible in such patients. The complication rate during ACH-testing in MINOCA patients is low and comparable to patients with stable angina. Acknowledgement/Funding Berthold-Leibinger-Foundation, Ditzingen, Germany

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