Nitric oxide is released into circulation with whole-body, periodic acceleration

STUDY OBJECTIVE: To determine if comfortably applied, whole-body, periodic acceleration releases significant amounts of nitric oxide (NO) into the circulation of healthy subjects and patients with inflammatory diseases. MATERIALS: Fourteen healthy adults and 40 adult patients with inflammatory diseases underwent single 45-min trials of whole-body, periodic acceleration with a new "passive exercise" device, while an ECG and a digital pulse wave were obtained with a photoelectric-plethysmograph sensor. METHODS: The position of the dicrotic notch from the pulse waveform was computed from the amplitude of the pulse divided by the height of the dicrotic notch above the end-diastolic level (a/b ratio). Increase of the a/b ratio reflects the vasodilator action of NO that causes downward movement of the dicrotic notch in the diastolic limb of the digital pulse, thereby elevating the a/b ratio. RESULTS: Application of whole-body, periodic acceleration was well tolerated in all participants, and all completed the 45-min treatment. The peak value of the a/b ratio markedly rose during periodic acceleration and returned to baseline during a 5-min recovery period in all healthy subjects and patients with inflammatory diseases. CONCLUSIONS: Whole-body, periodic acceleration increased pulsatile shear stress to the endothelium leading to vasodilatation and a fall in the dicrotic notch, consistent with increased NO bioactivity in every healthy adult and adult patient with inflammatory disease so treated. Therefore, passive exercise using whole-body, periodic acceleration produces an important benefit that occurs with active exercise.     

Osteopontin is released from the heart into the coronary circulation in patients with a previous anterior wall myocardial infarction.

The present study was designed to clarify whether osteopontin, an extracellular matrix protein, is released from the heart into the coronary circulation in patients with a previous (>3 months) anterior wall myocardial infarction (MI). Using a commercially available enzyme immunoassay kit, plasma concentrations of osteopontin were measured in 30 patients (26 men, 4 women; mean age, 61+/-12 years). Blood samples were obtained from the aortic root and coronary sinus. The difference in the plasma concentrations of osteopontin in the aortic root and coronary sinus, which reflects the cardiac production of osteopontin released into the coronary circulation, was compared with the left ventricular ejection fraction (LVEF) and volumes obtained from contrast left ventriculography. Plasma osteopontin concentrations were significantly higher in the coronary sinus than in the aortic root (672+/-446 vs 610+/-398 ng/ml, p=0.02). The transcardiac gradient of plasma osteopontin concentration correlated negatively with LVEF (r=-0.55, p=0.0005) and positively with left ventricular (LV) end-diastolic (r=0.63, p=0.0001) and end-systolic volume indexes (r=0.79, p<0.0001). This is the first study to show that in patients with a previous anterior wall MI osteopontin is released from the heart into the coronary circulation in proportion to the LV systolic function and volumes, suggesting that this extramatrix protein is associated with post-MI LV remodeling.     

Transitory appearance of collateral circulation during coronary spasm

The authors report the case of a patient with coronary spasm characterised on exercise stress testing by an initial depression of the ST segment followed by ST elevation at the 3rd minute of recovery. Coronary angiography showed an important, transient collateral system arising from the left coronary artery, probably minimising the effects of complete occlusion of a dominant right coronary artery. The authors discuss effort-induced spasm and collateral circulation.     

C-reactive protein is released in the coronary circulation and causes endothelial dysfunction in patients with acute coronary syndromes

Background

C-reactive protein (CRP) plasma levels correlate with cardiovascular events. Although a direct role for CRP in atherothrombosis has been suggested, at the moment little is known about its involvement in the pathophysiology of acute coronary syndromes (ACS). Thus, the aim of this study was to determine whether CRP is produced in the culprit lesion and released within the coronary circulation of patients with ACS and whether it may affect coronary endothelial function.

Methods

Blood samples were simultaneously obtained from the aorta (Ao) and the coronary sinus (CS) of patients with normal coronary artery (n = 16), stable angina (n = 30), and ACS (n = 29) for later measurement of plasma CRP levels. Endothelium-dependent and -independent coronary vasodilation were evaluated by means of a Doppler Flow Wire in response to the increasing intracoronary doses of acetylcholine and adenosine, respectively.

Results

CRP plasma levels were significantly higher across the coronary circulation only in ACS patients with the culprit lesion located in the left coronary artery, while no differences between CS and Ao CRP plasma levels were observed in all other groups. Transcardiac CRP levels were correlated with impairment in coronary endothelium-dependent vasodilation. In six additional patients (SA = 3 and ACS = 3), subjected to coronary atherectomy, real-time quantitative PCR revealed presence of CRP mRNA only in unstable plaques.

Conclusions

Thus, CRP is produced and released within the coronary circulation of patients with ACS; this is associated with impairment of endothelial function, suggesting a new pathophysiological link between CRP and ACS.     

Acute coronary syndrome after diclofenac induced coronary spasm

Zusammenfassung Wir berichten über einen 67-jährigen Patienten, der mit dem Bild eines akuten Vorderwandmyokardinfarktes im Rahmen eines akuten Koronarsyndroms in die Klinik eingeliefert wurde. Die sofort durchgeführte Herzkatheteruntersuchung zeigte einen frischen Thrombus im proximalen Ramus interventrikularis anterior (RIVA) bei sonst unauffälligen Koronararterien. Nach PTCA mit Stent-Implantation in den proximalen RIVA war der Patient vollkommen beschwerdefrei. Die CK, CKMB sowie das Troponin T blieben im Normbereich. Im Verlauf entwickelte der Patient eine Podagra des rechten Großzehengrundgelenkes, welches mit Colchicin, Diclofenac und lokaler Kühlung behandelt wurde. Fünf Stunden nach Gabe von Colchicin sowie Diclofenac klagte der Patient über heftige Angina pectoris-Symptomatik mit elektrokardiographischen Zeichen eines akuten Hinterwand- und Vorderwandmyokardinfarktes. Eine erneute durchgeführte Herzkatheteruntersuchung zeigte ausgeprägte Vasospasmen der rechten Koronararterie. Nach intrakoronarer Verapamil- und Nitroglycerin-Gabe waren die Koronarspasmen deutlich rückläufig und der Patient war beschwerdefrei. Anamnestisch berichtete der Patient, dass er am Abend ca. 6 h vor dem akuten Koronarsyndrom ebenfalls Diclofenac eingenommen hätte. Bei zweimaliger in unmittelbarem Zusammenhang mit der Diclofenac-Einnahme stehenden akuten Koronarsymptomatik ist von einem Diclofenac induziertem Vasospasmus auszugehen.     

Fibrinopeptide A: a marker of acute coronary thrombosis

To determine whether coronary thrombosis in vivo is reflected by elevations in levels of fibrinopeptide A (FPA) in plasma, we sequentially characterized plasma FPA levels associated with evolving infarction in patients admitted to the cardiac care unit early after the onset of symptoms, in patients with transmural infarction admitted later, and in patients with nontransmural infarction. Studies were also performed in patients in whom the diagnosis of infarction was suspected but subsequently excluded. FPA values were significantly higher in patients with transmural infarction (42.3 +/- 11.2 ng/ml [mean +/- SEM], n = 53) compared with those in patients with nontransmural infarction (4.8 +/- 1.6 ng/ml, n = 17) or with those in patients in whom infarction was subsequently excluded as a diagnosis (3.5 +/- 0.6 ng/ml, n = 17, p less than .01 for both). Elevations in FPA level were greatest in patients with transmural infarction from whom samples were obtained soon after the onset of symptoms. Thus, in 39 patients from samples were obtained within 10 hr after the onset of symptoms, FPA levels were significantly higher than in 14 patients from whom samples were obtained initially more than 10 hr after the onset of symptoms (55.5 +/- 14.7 vs 4.9 +/- 1.4 ng/ml, p less than .01). In 30 of the 39 patients with evolving transmural infarction from whom samples were obtained within the first 10 hr after the onset of symptoms, the level of FPA was greater than 8 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adrenomedullin is increased in alveolar macrophages and released from the lungs into the circulation in severe heart failure

Adrenomedullin (AM) is a potent vasorelaxing peptide with natriuretic, diuretic, and growth inhibitory properties. Plasma concentrations and myocardial AM expression are increased in heart failure (HF). Since AM and AM binding sites are abundantly expressed in the lungs, we investigated to what extent pulmonary AM and AM receptor subtypes [CRLR/RAMP2 (AM₁) and CRLR/RAMP3 (AM₂)] are changed in HF and whether the lungs contribute to the increased plasma concentrations of AM reported in HF. Pulmonary AM mRNA and protein expression were increased by 2.8- and 2.6-fold, respectively, whereas mRNA expression of RAMP2 and CRLR was decreased in rats with HF 7 days after induction of MI compared to sham-operated rats (P < 0.05). Pulmonary AM receptor density was substantially decreased in HF rats compared to sham (3.7 ± 0.6 vs. 29.9 ± 1.1 fmol/mg membrane protein; P < 0.05). Immunoreactivities against AM and the AM receptor components CRLR, RAMP2, and RAMP3 in the pulmonary tissue were seen in vascular smooth muscle cells, vascular endothelial cells, and in alveolar macrophages. AM mRNA expression in alveolar macrophages obtained from HF rats by bronchoalveolar lavage was 2.9-fold higher than in sham-operated rats (P < 0.05). An even more substantial increase of AM mRNA expression was found in alveolar macrophages from patients with HF (10-fold, P < 0.05), and this increase displayed a negative correlation to left ventricular systolic function (P < 0.05). Furthermore, a net release of AM from the lungs into the circulation was only found in HF patients with the most severe left ventricular systolic dysfunction. Thus, our data demonstrate increased expression and decreased receptor binding of AM in the lungs in severe HF. Furthermore, our data indicate that alveolar macrophages are an important source of pulmonary AM in both experimental and clinical HF. Finally, a net release of AM from the lungs into the circulation was only found in patients with severe systolic dysfunction.     

Cholinergic constriction in the general circulation and its role in coronary artery spasm

The release of acetylcholine from autonomic nerves in those tissues that receive a cholinergic innervation is widely believed to dilate blood vessels. Exogenously administered acetylcholine in vivo does dilate vascular beds and produce hypotension; however, this latter effect is indirect and probably the result of liberation of endothelium-derived relaxing factor (EDRF) from endothelial cells. Some blood vessels contain a substantial population of medial constrictor receptors for acetylcholine, and the implications of this presence for vascular control systems has been largely ignored, although it needs to be considered. A survey of the evolution of vasomotor control systems indicates that acetylcholine serves principally as an excitatory transmitter to blood vessels. Neurally mediated cholinergic constriction and not dilation is found in fish, amphibians, reptiles, and birds, with responses initiated by medial muscarinic receptors. Acetylcholine constricts many vascular preparations from these lower animals, but some vessels relax, reflecting the emergence of an EDRF responsive to acetylcholine. An examination of cholinergic responses in mammalian vessels reveals that cholinergic (neurogenic) dilation is limited to a very few vascular beds and to only a few species. Both experimental evidence and evolutionary considerations support the likelihood that cholinergic (neural) constriction operates in some vascular regions in mammals and, in particular, in the coronary circulation of some species, including humans. In fact, constriction, and not dilation, may be the dominant vascular response to activation of the cholinergic axis in most mammals, including humans. The complications and contradictions introduced by the simultaneous presence of both EDRF and a cholinergic constrictor innervation involving medial muscarinic receptors are discussed. A variety of evidence is also presented that implicates cholinergic constriction in at least some instances of coronary artery spasm and sudden death.     

Increased endogenous endothelin-1 in coronary circulation is associated with restenosis after coronary angioplasty

BACKGROUND: The relationship between vasoactive substances, including endothelin-1, nitric oxide, serotonin, angiotensin II and noradrenaline, and coronary restenosis after percutaneous transluminal coronary angioplasty (PTCA) is not clear. OBJECTIVE: To determine whether any vasoactive substance may be a marker of coronary restenosis after PTCA. METHODS: Twenty-nine patients with angina pectoris underwent elective PTCA. Three months after PTCA, coronary angiography was performed again to study the patency of the lesions. Seven patients had coronary restenosis (greater than 50% stenosis) (restenosis group) and the rest of the patients were without restenosis (patency group). Their blood samples were obtained from the coronary sinus before, immediately after and three months after PTCA. RESULTS: Endothelin-1 levels obtained immediately after PTCA (3.44+/-0.26 pg/mL) and three months after PTCA (3.57+/-0.29 pg/mL) were significantly higher than those obtained before PTCA (3.00+/-0.26 pg/mL) in the restenosis group, but not in the patency group (3.34+/-0.15 pg/mL, 3.02+/-0.17 pg/mL and 3.14+/-0.18 pg/mL, respectively). A transient decrease in nitrite/nitrate levels was observed immediately after PTCA in both groups. The serotonin levels three months after PTCA were significantly decreased in the patency group, but not in the restenosis group, and the levels of angiotensin II and noradrenaline did not change in either group throughout the study. CONCLUSIONS: Among several vasoactive substances, endothelin-1 seems to be associated with the process of coronary restenosis after PTCA. Increased endothelin-1 levels in the coronary circulation after PTCA may indicate an increased risk of coronary restenosis.     

Prostanoids, coronary circulation and coronary artery spasm in open chest dogs and miniature pigs

Effects of prostanoids on coronary circulation were studied in anesthetized open chest dogs with intact coronary arteries or in closed chest G?ttingen miniature pigs with denuded vessels. In the latter model, coronary artery spasm was repeatedly provoked at the previously denuded area by histamine i.c. after pretreatment with cimetidine i.v., H2-blocker. In the canine model, prostacyclin (PGI2) dilated to a greater extent the diameter of the large epicardial coronary artery than did PGE2, and both equally reduced the total coronary resistance. Vasoconstrictive effects of carbocyclic thromboxane A2, a stable analogue of thromboxane A2 (TxA2) on the epicardial coronary artery was augmented from 1.1 +/- 0.3 to 6.5 +/- 1.3% (p less than 0.01) after pretreatment with cyclooxygenase inhibitors. In case of G?ttingen miniature pigs 3 months after endothelial denudation and cholesterol freeding, neither PGI2 nor indomethacin prevented histamine-induced coronary artery spasm. Thiothromboxane A2, a stable analogue of TxA2, did not provoke coronary artery spasm in the animals. Therefore, prostanoids may not be crucial to the provocation or prevention of coronary artery spasm from which myocardial ischemia ensues.     

Properties of the exchangeable splenic platelets released into the circulation during exercise-induced thrombocytosis

The human spleen normally retains about one-third of the body's platelets in an exchangeable pool which can be released into the circulation by alpha-adrenergic stimulation. Some previous investigators concluded that the splenic platelet population was enriched in a subpopulation of large, young, dense platelets (megathrombocytes) but more recent research suggests that platelet size, age, and density are largely independent variables. In this investigation the properties of the splenic platelets were studied after their release into the circulation by acute strenuous exercise in 11 normal subjects. The exercise caused a rise in mean platelet count from 245 +/- 49 to 328 +/- 71 x 10(9)/L--a net increase of 24 +/- 6% after correction for haemoconcentration. The mean platelet volume (MPV) of citrated platelets increased from 6.38 +/- 0.78 to 6.59 +/- 0.68 fL after exercise (P less than 0.01)--a rise of 3.7 +/- 4.1% suggesting that the MPV of the splenic platelet population was about 20% greater than that of the normal circulating population. The age distribution of the platelets was studied by measuring the platelet monoamine oxidase (MAO) activity several days after irreversible inhibition by tranylcypromine, when the young platelets had normal MAO activity but the older platelets had only 20% of normal activity. The mean platelet MAO activity did not change after exercise, indicating that the age distributions of the circulating and splenic populations were very similar. The platelet contents of several putative markers of platelet age (sialic acid, serotonin, beta-thromboglobulin, beta-N-acetylglucosaminidase) were also unchanged after exercise. Modal platelet density decreased slightly but not significantly after exercise. The splenic platelet population has a larger MPV but appears to have similar age and density distributions to the basal circulating population.     

Recurrence of coronary artery spasm after successful percutaneous transluminal coronary angioplasty

A 47-year-old man presented with angina, and coronary angiograms showed a significant organic stenosis with spasm in the left anterior descending coronary artery. Percutaneous transluminal coronary angioplasty was successfully performed for the organic lesion in the left anterior descending coronary artery. Symptom of angina due to coronary artery spasm recurred, even without restenosis at the site of successful angioplasty.     

Recent insights into coronary collateral circulation.

The functional significance of coronary collaterals in humans has been debated for many years. Correlations have now been made between the anatomic appearance of coronary collateral vessels visualized at the time of intracoronary thrombolytic therapy during the acute phase of myocardial infarction and the creatine kinase time--activity curve, infarct size, and aneurysm formation. These studies demonstrate a protective role of collaterals in hearts with coronary obstructive disease, showing smaller infarcts, less aneurysm formation, and improved ventricular function compared with patients in whom collaterals were not visualized. There is ample evidence that collaterals respond to myocardial ischemia by opening preexistent channels. When the cardiac myocyte is rendered ischemic, collaterals develop actively by growth with DNA replication and mitosis of endothelial and smooth muscle cells. Heparin-binding growth factors are present in the heart, but their biological activity is quiescent under normal physiological conditions. Once ischemia develops, these factors are activated and become available for receptor occupation, which may initiate angiogenesis after exposure to exogenous heparin. This characteristic of heparin to potentiate the mitogenic activity of acidic fibroblast growth factor has recently been used in the clinical setting as a possible therapeutic modality in patients with coronary artery disease. Patients performing 20 rounds of exercise serially after receiving intravenous injection of heparin showed significantly greater increases in exercise capacity and improvement of clinical symptoms compared with the control group who performed the same exercise without heparin. Further study of neovascularization may lead to a new therapeutic strategy for ischemic heart disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

Coronary artery spasm immediately after percutaneous transluminal coronary recanalization

A 55-year-old man developed acute inferior myocardial infarction. A coronary arteriogram performed within two hours later showed complete occlusion of the right coronary artery, which was not resolved by two doses of 300 micrograms of intracoronary nitroglycerin. It was recanalized with 50% luminal diameter narrowing after 600,000 units of urokinase. Immediately after this thrombolytic therapy, the patient experienced chest pain, and the coronary artery became completely obstructed again. The pain was promptly relieved by 300 micrograms of intracoronary nitroglycerin, with disappearance of the obstruction. The observations during the procedure indicate that coronary artery spasm can occur after successful thrombolytic therapy on an occluded artery, inducing postinfarction angina, and might culminate in a second complete occlusion after percutaneous transluminal coronary recanalization.     

Cardiogenic shock caused by severe coronary artery spasm immediately after coronary stenting

Coronary artery spasm is common during percutaneous coronary intervention and is easily relieved by intracoronary administration of vasodilators. We report the case of a patient who had severe, protracted, generalized spasm of the entire left coronary artery system during coronary artery stenting. The spasm, which was unresponsive to intracoronary vasodilators administered via guiding catheter, resulted in pulmonary edema and cardiogenic shock. Local injection of nitroglycerin via a transit catheter in the coronary artery eventually resolved the spasm and reversed the cardiogenic shock. To our knowledge, this is the 1st report of such a case in the English-language medical literature.     

Vasodilator resistant lethal spasm after uncomplicated off-pump coronary surgery

We report a case of lethal spasm of non-grafted coronary arteries after an uncomplicated off-pump coronary artery bypass grafting in a patient with no predisposing factors other than smoking. Transcatheter intraluminal injection of several vasodilators failed to relieve the spasm. The patient remained in profound cardiogenic shock due to broad acute myocardial infarction and died of multiple organ failure.