The relationship between coronary collateral circulation and neutrophil/lymphocyte ratio in patients with coronary chronic total occlusion.

OBJECTIVES: To investigate the relationship between neutrophil/lymphocyte ratio (NLR) and coronary collateral circulation (CCC) in patients with coronary chronic total occlusion. SUBJECTS AND METHODS: Our study population consisted of 275 consecutive patients with chronic total occlusion. One hundred and thirty-eight patients with chronic total occlusion were included in the study. They were classified into 2 groups as follows: impaired CCC (group 1: Rentrop grades 0-1) and good CCC (group 2: Rentrop grades 2-3). The NLR was calculated from the complete blood count. RESULTS: The NLR values of the patients with impaired CCC (4.5 ± 0.7) were significantly higher than of those with good CCC (2.7 ± 0.6, p < 0.001). In the multivariate logistic regression test, NLR (OR 33.36, 95% CI 8.189-135.7, p < 0.001), high-sensitivity C-reactive protein (hs-CRP; OR 2.152, 95% CI 1.226-3.777, p = 0.008), estimated glomerular filtration rate (OR 1.167, 95% CI 1.049-1.298, p = 0.004) and systolic blood pressure (OR 1.068, 95% CI 1.009-1.1310, p = 0.025) were independent predictors of impaired CCC. The NLR value >3.55 yielded an area under the curve value of 0.957 (95% CI 0.921-0.992, p < 0.001) and demonstrated a sensitivity of 95% and a specificity of 90% for the prediction of CCC. A moderate correlation between NLR and hs-CRP was observed (r = 0.443; p < 0.001). CONCLUSION: Our findings reveal that NLR correlates with the impaired development of coronary collaterals.

Obesity and coronary microvascular disease - implications for adipose tissue-mediated remote inflammatory response.

It is believed that obesity has detrimental effects on the coronary circulation. These include immediate changes in coronary arterial vasomotor responsiveness and the development of occlusive large coronary artery disease. Despite its critical role in regulating myocardial perfusion, the altered behavior of coronary resistance arteries, which gives rise to coronary microvascular disease (CMD) is poorly understood in obesity. A chronic, low-grade vascular inflammation has been long considered as one of the main underlying pathology behind CMD. The expanded adipose tissue and the infiltrating macrophages are the major sources of pro-inflammatory mediators that have been implicated in causing inadequate myocardial perfusion and, in a long term, development of heart failure in obese patients. Much less is known the mechanisms regulating the release of these cytokines into the circulation that enable them to exert their remote effects in the coronary microcirculation. This mini review aims to examine recent studies describing alterations in the vasomotor function of coronary resistance arteries and the role of adipose tissue-derived pro-inflammatory cytokines and adipokines in contributing to CMD in obesity. We provide examples of regulatory mechanisms by which adipokines are released from adipose tissue to exert their remote inflammatory effects on coronary microvessels. We identify some of the important challenges and opportunities going forward.

Association between neutrophil-lymphocyte ratio and impaired myocardial perfusion in patients with known or suspected coronary disease.

OBJECTIVE: To determine whether an elevated neutrophil-lymphocyte ratio (NLR) is associated with chronically impaired myocardial perfusion in patients with known or suspected coronary disease. BACKGROUND: Elevated NLRs are positively associated with cardiac events, anatomic coronary disease, and myocardial infarct size. However, no study has evaluated the association between NLR and chronically impaired myocardial perfusion. METHODS: This study included 683 patients undergoing cardiac positron emission tomography (PET) with a calculable NLR within 90 days of PET. The primary outcome was myocardial perfusion defect size measured in percent of left ventricular mass (%LV60). RESULTS: NLR was independently associated with %LV60 when analyzed as both a continuous and binary outcome (p < 0.001). Individuals with NLR above the 90th percentile had a 5-fold increased likelihood of significant perfusion defects compared to individuals with NLR between the 10th and 25th percentiles (Odds ratio = 4.7, p < 0.001). CONCLUSION: An elevated NLR demonstrated strong associations with myocardial perfusion.

Regulation of coronary venular barrier function by blood borne inflammatory mediators and pharmacological tools: insights from novel microvascular wall models.

We hypothesized that postcapillary venules play a central role in the control of the tightness of the coronary system as a whole, particularly under inflammatory conditions. Sandwich cultures of endothelial cells and pericytes of precapillary arteriolar or postcapillary venular origin from human myocardium as models of the respective vascular walls (sandwich cultures of precapillary arteriolar or postcapillary venular origin) were exposed to thrombin and components of the acutely activatable inflammatory system, and their hydraulic conductivity (L(P)) was registered. L(P) of SC-PAO remained low under all conditions (3.24 ± 0.52·10(-8)cm·s(-1)·cmH(2)O(-1)). In contrast, in the venular wall model, PGE(2), platelet-activating factor (PAF), leukotriene B(4) (LTB(4)), IL-6, and IL-8 induced a prompt, concentration-dependent, up to 10-fold increase in L(P) with synergistic support when combined. PAF and LTB(4) released by metabolically cooperating platelets, and polymorphonuclear leucocytes (PMNs) caused selectively venular endothelial cells to contract and to open their clefts widely. This breakdown of the barrier function was preventable and even reversible within 6-8 h by the presence of 50 µM quercetin glucuronide (QG). LTB(4) synthesis was facilitated by biochemical involvement of erythrocytes. Platelets segregated in the arterioles and PMNs in the venules of blood-perfused human myocardium (histological studies on donor hearts refused for heart transplantation). Extrapolating these findings to the coronary microcirculation in vivo would imply that the latter's complex functionality after accumulation of blood borne inflammatory mediators can change rapidly due to selective breakdown of the postcapillary venular barrier. The resulting inflammatory edema and venulo-thrombosis will severely impair myocardial performance. The protection afforded by QG could be of particular relevance in the context of cardiosurgical intervention.

The indirect alloimmune response causes microvascular endothelial dysfunction-a possible role for alloantibody.

BACKGROUND: The causes of endothelial dysfunction after cardiac transplantation are unknown. Here, we have investigated whether the indirect alloimmune response mediates endothelial dysfunction in a major histocompatibility complex class I mismatch model. METHODS: PVG.RT1 rat hearts were transplanted into thymectomized CD8 T-cell-depleted allogeneic (PVG.R8) or syngeneic (PVG.RT1) recipients. Alloantibody was assessed at 2, 4, and 8 weeks. Cardiac allograft vasculopathy, the nature of the inflammatory infiltrate, and origin of endothelial cells were examined at 1, 2, 4, and 8 weeks. Endothelial function was assessed by Langendorff preparations at 1, 2, and 4 weeks. RESULTS: Recipients produced alloantibody and showed luminal occlusion at 1 (17.7%±8.0%), 2 (23.2%±4.9%), 4 (34.3%±5.0%), and 8 weeks (58.1%±1.8%) posttransplantation. The major inflammatory features of the allografts consisted of CD11b monocytes, CD4 T cells, and C4d deposition. At 1 week, the basal coronary flow and the vasodilator response to 5-hydroxytrytamine of syngeneic and allografted hearts were inhibited compared with normal hearts. At 4 weeks, the basal coronary flow of allografts was 54% lower than syngrafts (P<0.01), and 5- hydroxytrytamine and sodium nitroprusside did not evoke an increase in coronary flow in the allograft heart compared with syngeneic controls (P<0.01). Culture of aortic rings with antibody to major histocompatibility complex class I inhibited endothelium-dependent vasodilation to acetylcholine. CONCLUSION: Transient microvascular endothelial dysfunction occurred in syngeneic and allogeneic cardiac grafts after transplantation. Syngeneic but not allogeneic grafts recovered, suggesting the indirect immune response, consisting of CD4 T cells, monocytes, and antibody, mediates endothelial dysfunction. A possible role for alloantibody in endothelial dysfunction is discussed.

[Dendritic cells and coronary collateral circulation in coronary heart disease].

OBJECTIVE: To determine the relationship between the number,phenotype and functional status of dendritic cells (DCs) and coronary collateral circulation (CCC) in coronary heart disease (CHD). METHODS: Forty patients with severe coronary stenosis were recruited and divided into a CCC formation group (Group A, n=22) and a non-CCC formation group (Group B, n=18). Density gradient centrifugation was applied to separate the mononuclear cells (MNCs) from coronary artery blood samples, and MNCs were cultured and proliferated in vitro. The morphology of DCs was observed under converted microscope. The number of harvested cells and DCs was counted by hematocytometer. Flow cytometry was applied to investigate the phenotype and the mean fluorescence intensity (MFI). Mixed lymphocyte reaction was used to test the function of DCs to stimulate the proliferation of T lymphocytes. Stimulation index (SI) was calculated and compared. RESULTS: (1) After in vitro proliferation, DCs were cultured successfully from the mononuclear cells from coronary artery blood samples and the morphology of DCs was not different in the 2 groups. (2) The number of mononuclear cells (MNC no) was (3.95+/-1.41)*10(6), in the CCC group and (2.76+/-0.92)*10(6) in the non-CCC group. The MNC number was significantly increased in the CCC group (P=0.003). (3) The number of DCs was (1.54+/-0.96)*10(6) in the CCC group, and (0.99+/-0.46)*10(6) in the non-CCC group (P=0.033). (4)There was no statistical significance in the percent of CD1a+, CD1a+CD80+, CD1a+CD83+, CD1a+CD86+ cells, and MFI in the 2 groups (P>0.05). (5) SI was 4.96+/-2.30 in the CCC group, whereas 2.66+/-1.04 in the non-CCC group. The SI in the CCC group increased significantly(P=0.0003). CONCLUSION: In CHD patients with severe coronary stenosis, patients with CCC formation have higher number of DCs and stronger potential of T lymphocyte stimulation.

The heart in rheumatoid arthritis.

Morbidity and mortality rates are higher in rheumatoid arthritis (RA) patients than in the general population. Many studies have shown that coronary artery disease is one of the most common causes of death in RA and seems to occur at a younger age than in the general population. RA per se is as much a cardiovascular (CV) risk factor as diabetes, arterial hypertension and dyslipidemia etc., and so it is necessary to plan a follow-up using the same diagnostic and therapeutic approaches as those commonly used for primary and secondary prevention in non-RA patients at high CV risk. All of the cardiac structures can be affected during the course of RA (valves, the conduction system, the myocardium, endocardium and pericardium, and the coronary arteries), and cardiac complications include a variety of clinical manifestations. As these are all associated with an unfavourable prognosis, it is essential to detect subclinical cardiac involvement in still asymptomatic RA patients in order to assure adequate long-term treatment.

Effects of antibodies obtained from patients with dilated cardiomyopathy on the function of isolated rat hearts.

BACKGROUND: Cardiac autoantibodies may play a pathophysiological role in cardiac dysfunction of patients suffering from dilated cardiomyopathy (DCM). Immunoadsorption (IA), which removes antibodies from patients' plasma, may consequently improve cardiac function in DCM. The functional effects of DCM antibodies are only partly understood. MATERIALS AND METHODS: DCM patients (n = 10) were treated with IA by application of antibody columns directed against human immunoglobulin (Ig). IA was also performed with plasma taken from 10 healthy donors (controls). The antibodies eliminated and purified by IA were collected and dialysed. Rat hearts were isolated and perfused retrogradely via the aorta in Langendorff mode. During constant-pressure and constant-volume perfusion of the hearts, the influence of diluted antibodies on contractility, relaxation, and on coronary perfusion was analysed. RESULTS: Antibodies obtained from controls had no effect on contractility and relaxation of isolated perfused hearts during constant-pressure and constant-volume perfusion. In contrast, during constant-pressure perfusion, collected DCM antibodies caused immediate and dose-related reduction of contractility (dLVP/dtmax: dilution -1:32 = -7.1 +/- 1.1%; dilution -1:2 = -20.1 +/- 2.1%; P < 0.001) and diastolic relaxation (dLVP/dtmin: dilution -1:32 = -11.1 +/- 1.5%; dilution -1:2 = -23.9 +/- 2.2%; P < 0.001). The heart rate did not change significantly in either group. The effects of DCM antibodies on contractility and relaxation remained detectable during constant-volume perfusion. The observed reduction of contractility and diastolic relaxation was accompanied by impairment of coronary perfusion. CONCLUSION: In the rat heart, antibodies obtained from DCM patients may impair contractility and relaxation, and thereby probably also coronary perfusion.

Lymph node occupancy is required for the peripheral development of alloantigen-specific Foxp3+ regulatory T cells.

We previously demonstrated that L-selectin (CD62L)-dependent T cell homing to lymph nodes (LN) is required for tolerance induction to alloantigen. To explore the mechanisms of this observation, we analyzed the development and distribution of regulatory T cells (Treg), which play an important protective role against allograft rejection in transplantation tolerance. Alloantigen-specific tolerance was induced using either anti-CD2 plus anti-CD3 mAbs, or anti-CD40L mAbs plus donor-specific transfusion, in fully mismatched (BALB/c donor, C57BL/6 recipient) vascularized cardiac allografts. An expansion of CD4(+)CD25(+)CD62L(high) T cells was observed specifically within the LN of tolerant animals, but not in other anatomic sites or under nontolerizing conditions. These cells exhibited a substantial up-regulation of Foxp3 expression as measured by real-time PCR and by fluorescent immunohistochemistry, and possessed alloantigen-specific suppressor activity. Neither LN nor other lymphoid cells expressed the regulatory phenotype if recipients were treated with anti-CD62L mAbs, which both prevented LN homing and caused early allograft rejection. However, administration of FTY720, a sphingosine 1-phosphate receptor modulator that induces CD62L-independent T cell accumulation in the LNs, restored CD4(+)CD25(+) Treg in the LNs along with graft survival. These data suggest that alloantigen-specific Foxp3(+)CD4(+)CD25(+) Treg develop and are required within the LNs during tolerization, and provide compelling evidence that distinct lymphoid compartments play critical roles in transplantation tolerance.

Further evidence that NK cells may contribute to the development of cardiac allograft vasculopathy.

In prior experiments, we found that recipients, even though specifically tolerant of donor antigens, will develop striking cardiac allograft vasculopathy (CAV) in allogeneic mouse heart transplants. This suggested that innate immune responses, in addition to conventional adaptive immunity, may be involved in the development of CAV. We accordingly performed transplants in the parental-to-F1 combination seeking supportive evidence of NK cell activity directed against the vessels of parental donor transplants as a manifestation of "hybrid resistance." When such lesions were indeed found, we investigated their pathogenesis employing immunopathological analysis, in vitro measurements of NK cytotoxicity, and donor-specific T-cell activity in F1 recipients of parental donor hearts. We present evidence that NK cells can promote cardiac allograft vasculopathy. Since NK cell activity is not well targeted by current immunosuppressive therapy, its control may offer a valuable new possibility for improving the long-term outcome of transplanted organs.

Effects of interleukin-6 produced in coronary circulation on production of C-reactive protein and coronary microvascular resistance.

We measured plasma levels of interleukin-6 and C-reactive protein at the orifice of the left coronary artery and at the great cardiac vein in patients who had coronary artery disease and those who had angiographically normal coronary arteries (controls). We also measured coronary microvascular resistance in the control group. We found increased levels of interleukin-6 in the coronary circulation of patients who had coronary artery disease compared with controls. This increase correlated with C-reactive protein production in the coronary circulation and coronary microvascular resistance. These findings suggest that a localized cytokine/inflammatory pathway functions in the coronary circulation and that interleukin-6 is involved in modulating coronary vascular tone.

[Coronary microembolization: perfusion-contraction mismatch secondary to myocardial inflammation]. / Koronare Mikroembolisation: Perfusions-Kontraktions-Mismatch durch inflammatorische Reaktion des Myokards.

Atherosclerotic plaque rupture is a key event in the pathogenesis of acute coronary syndromes and during coronary interventions. Atherosclerotic plaque rupture does not necessarily lead to thrombotic occlusion of a coronary artery and subsequent myocardial infarction. Milder forms may result in the embolization of atherosclerotic and/or thrombotic debris into the coronary microcirculation. The characteristic consequences of coronary microembolization are arrhythmias, microinfarcts, and a reduced coronary reserve. Experimental studies revealed that an inflammatory reaction is causally involved in the progressive contractile dysfunction following coronary microembolization. Thus, anti-inflammatory treatment appears as a promising strategy to protect patients from the consequences of coronary microembolization.

[Cellular and humoral immunity in patients with acute disorder of coronary circulation]. / Sostoianie kletochnogo i gumoral'nogo immuniteta u bol'nykh s ostrym rasstroistvom koronarnogo krovoobrashcheniia.

The condition was studied of cell-bound and humoral immunity in patients with ischemic heart disease. The data secured permit reaching the conclusion that the unstable clinical course of angina pectoris is accompanied by unspecific alterations in the cellular link of immunity such as increase in the absolute number of T-lymphocytes and T-suppressors. In patients with myocardial infarction, in the acute period of the illness there develop inflammatory reactions involving participation of cell-bound (neutrophilic leucocytosis, a drop in the absolute number of acidophilic granulocytes, absolute number of lymphocytes, T-lymphocytes, T-suppressors, increase in T-helpers--T-suppressors ratio; decline in T-lymphocytes activity) and humoral (a drop in the level of Ig A, increase in blood serum concentration of circulating immune complexes) links of immunity.

Widespread coronary inflammation in unstable angina.

BACKGROUND: Inflammation within vulnerable coronary plaques may cause unstable angina by promoting rupture and erosion. In unstable angina, activated leukocytes may be found in peripheral and coronary-sinus blood, but it is unclear whether they are selectively activated in the vascular bed of the culprit stenosis. METHODS: We measured the content neutrophil myeloperoxidase content in the cardiac and femoral circulations in five groups of patients: two groups with unstable angina and stenosis in either the left anterior descending coronary artery (24 patients) or the right coronary artery (9 patients); 13 with chronic stable angina; 13 with variant angina and recurrent ischemia; and 6 controls. Blood samples were taken from the aorta, the femoral vein, and the great cardiac vein, which selectively drains blood from the left but not the right coronary artery. RESULTS: The neutrophil myeloperoxidase content of aortic blood was similar in both groups of patients with unstable angina (-3.9 and -5.5, with negative values representing depletion of the enzyme due to neutrophil activation) and significantly lower than in the other three groups (P<0.05). Independently of the site of the stenosis, the neutrophil myeloperoxidase content in blood from the great cardiac vein was significantly decreased in both groups of patients with unstable angina (-6.4 in those with a left coronary lesion and -6.6 in those with a right coronary lesion), but not in patients with stable angina and multiple stenoses, patients with variant angina and recurrent ischemia, or controls. There was also a significant transcoronary reduction in myeloperoxidase content in both groups with unstable angina. CONCLUSIONS: The widespread activation of neutrophils across the coronary vascular bed in patients with unstable angina, regardless of the location of the culprit stenosis, challenges the concept of a single vulnerable plaque in unstable coronary syndromes.

Increased autoantibodies against oxidized low-density lipoprotein in coronary circulation in patients with coronary spastic angina.

Oxidized low-density lipoproteins are important in the progression of atherosclerosis. Autoantibodies against malondialdehyde-modified low-density lipoproteins have been reported to be predictive of the progression of atherosclerosis. This study sought to examine whether plasma levels of autoantibodies against oxidized low-density lipoprotein increase in the coronary circulation in patients with coronary spastic angina. The authors examined plasma antioxidized low-density lipoprotein antibody levels (activity unit values (AcU)/mL) simultaneously in the coronary sinus and the aortic root in 20 patients with coronary spastic angina, 23 patients with stable exertional angina, and 15 control subjects by measuring plasma levels of immunoglobulin G (IgG) autoantibodies against malondialdehyde-modified low-density lipoproteins by enzyme-linked immunosorbent assay. The plasma antioxidized low-density lipoprotein antibody levels (AcU/mL) in the coronary sinus increased in coronary spastic angina (38 +/- 16) compared with stable exertional angina (23 +/- 7) and control subjects (20 +/- 6) (p < or = 0.0001). The levels (AcU/mL) in the aortic root also increased in coronary spastic angina (33 +/- 12) compared with stable exertional angina (23 +/- 7) and control subjects (20 +/- 6) (p < 0.005). Furthermore, the coronary sinus-arterial differences of the levels (AcU/mL) were also higher in coronary spastic angina (5 +/- 9) than in stable exertional angina (0 +/- 6) and healthy subjects (-1 +/- 5) (p < 0.05). The generation of malondialdehyde-modified low-density lipoproteins is reported to be associated with atherothrombosis. These findings suggest that elevated levels of autoantibodies against malondialdehyde-modified oxidized low-density lipoproteins in coronary circulation are associated with the development of atherothrombosis from the progression of atherosclerosis rather than with the extent of coronary atherosclerosis in patients with coronary spastic angina.

Perfusion-contraction mismatch with coronary microvascular obstruction: role of inflammation.

A close relationship exists between regional myocardial blood flow (RMBF) and function during acute coronary inflow restriction (perfusion-contraction matching). However, the relationship of flow and function during coronary microvascular obstruction is unknown. In 12 anesthetized dogs, the left circumflex coronary artery was perfused from an extracorporeal circuit. After control measurements, 3,000 microspheres (42 micrometer diameter) per milliliter per minute inflow were injected to cause a microembolism (ME, n = 6). With unchanged systemic hemodynamics and RMBF, posterior systolic wall thickening (PWT) decreased from 19.8 +/- 1.9% SD at control to 13.3 +/- 4.0, 10.3 +/- 3.8, and 6.9 +/- 4.7% (P < 0.05 vs. control) at 1, 4, and 8 h, respectively. For comparison, inflow was progressively reduced to match PWT to that of the ME group at 1, 4, and 8 h (stenosis, STE, n = 6). RMBF in the STE group was reduced in proportion to PWT. Infarct size was not different among groups (6.5 +/- 4.5 vs. 3.4 +/- 3.2%). However, the number of leukocytes infiltrating the area at risk was significantly greater in the ME group than in the STE group. Coronary microembolization results in perfusion-contraction mismatch and is associated with an inflammatory response.