The human coronary collateral circulation: development and clinical importance

Coronary collaterals are an alternative source of blood supply to myocardium jeopardized by ischaemia. In comparison with other species, the human coronary collateral circulation is very well developed. Among individuals without coronary artery disease (CAD), there are preformed collateral arteries preventing myocardial ischaemia during a brief vascular occlusion in 20-25%. Determinants of such anastomoses are low heart rate and the absence of systemic arterial hypertension. In patients with CAD, collateral arteries preventing myocardial ischaemia during a brief occlusion are present in every third individual. Collateral flow sufficient to prevent myocardial ischaemia during coronary occlusion amounts to one-fifth to one-fourth the normal flow through the open vessel. Myocardial infarct size, the most important prognostic determinant after such an event, is the product of coronary artery occlusion time, area at risk for infarction, and the inverse of collateral supply. Well-developed coronary collateral arteries in patients with CAD mitigate myocardial infarcts and improve survival. Approximately one-fifth of patients with CAD cannot be revascularized by percutaneous coronary intervention or coronary artery bypass grafting. Therapeutic promotion of collateral growth is a valuable treatment strategy in those patients. It should aim at growth of large conductive collateral arteries (arteriogenesis). Potential arteriogenic approaches include the treatment with granulocyte colony-stimulating factor, physical exercise training, and external counterpulsatio

Associations of short-term particle and noise exposures with markers of cardiovascular and respiratory health among highway maintenance workers

BACKGROUND: Highway maintenance workers are constantly and simultaneously exposed to traffic-related particle and noise emissions, and both have been linked to increased cardiovascular morbidity and mortality in population-based epidemiology studies. OBJECTIVES: We aimed to investigate short-term health effects related to particle and noise exposure. METHODS: We monitored 18 maintenance workers, during as many as five 24-hour periods from a total of 50 observation days. We measured their exposure to fine particulate matter (PM2.5), ultrafine particles, noise, and the cardiopulmonary health endpoints: blood pressure, pro-inflammatory and pro-thrombotic markers in the blood, lung function and fractional exhaled nitric oxide (FeNO) measured approximately 15 hours post-work. Heart rate variability was assessed during a sleep period approximately 10 hours post-work. RESULTS: PM2.5 exposure was significantly associated with C-reactive protein and serum amyloid A, and negatively associated with tumor necrosis factor α. None of the particle metrics were significantly associated with von Willebrand factor or tissue factor expression. PM2.5 and work noise were associated with markers of increased heart rate variability, and with increased HF and LF power. Systolic and diastolic blood pressure on the following morning were significantly associated with noise exposure after work, and non-significantly associated with PM2.5. We observed no significant associations between any of the exposures and lung function or FeNO. CONCLUSIONS: Our findings suggest that exposure to particles and noise during highway maintenance work might pose a cardiovascular health risk. Actions to reduce these exposures could lead to better health for this population of workers

Addition of dextran sulfate to blood cardioplegia attenuates reperfusion injury in a porcine model of cardiopulmonary bypass

Objective: Contact of blood with artificial surfaces and air as well as ischemia/reperfusion injury to the heart and lungs mediate systemic and local inflammation during cardiopulmonary bypass (CPB). Activation of complement and coagulation cascades leads to and accompanies endothelial cell damage. Therefore, endothelial-targeted cytoprotection with the complement inhibitor and endothelial protectant dextran sulfate (DXS, MW 5000) may attenuate CBP-associated myocardial and pulmonary injury. Methods: Eighteen pigs (DXS, n=10; phosphate buffered saline [PBS], n=8) underwent standard cardiopulmonary bypass. After aortic cross-clamping, cardiac arrest was initiated with modified Buckberg blood cardioplegia (BCP), repeated after 30 and 60min with BCP containing either DXS (300mg/10ml, equivalent to 5mg/kg) or 10ml of PBS. Following 30min reperfusion, pigs were weaned from CPB. During 2h of observation, cardiac function was monitored by echocardiography and invasive pressure measurements. Inflammatory and coagulation markers were assessed regularly. Animals were then sacrificed and heart and lungs analyzed. Results: DXS significantly reduced CK-MB levels (43.4±14.8ng/ml PBS, 35.9±11.1ng/ml DXS, p=0.042) and significantly diminished cytokine release: TNFalpha (1507.6±269.2pg/ml PBS, 222.1±125.6pg/ml DXS, p=0.0071), IL1beta (1081.8±203.0pg/ml PBS, 110.7±79.4pg/ml DXS, p=0.0071), IL-6 (173.0±91.5pg/ml PBS, 40.8±19.4pg/ml DXS, p=0.002) and IL-8 (304.6±81.3pg/ml PBS, 25.4±14.2pg/ml DXS, p=0.0071). Tissue endothelin-1 levels were significantly reduced (6.29±1.90pg/100mg PBS, 3.55±1.15pg/100mg DXS p=0.030) as well as thrombin-anti-thrombin formation (20.7±1.0μg/ml PBS, 12.8±4.1μg/ml DXS, p=0.043). Also DXS reduced cardiac and pulmonary complement deposition, neutrophil infiltration, hemorrhage and pulmonary edema (measured as lung water content, 81±3% vs 78±3%, p=0.047), indicative of attenuated myocardial and pulmonary CPB-injury. Diastolic left ventricular function (measured as dp/dtmin), pulmonary artery pressure (21±3mmHg PBS, 19±3mmHg DXS, p=0.002) and right ventricular pressure (21±1mmHg PBS, 19±3mmHg DXS p=0.021) were significantly improved with the use of DXS. Conclusions: Addition of DXS to the BCP solution ameliorates post-CPB injury and to a certain extent improves cardiopulmonary function. Endothelial protection in addition to myocyte protection may improve post-CPB outcome and recover

A serine/arginine-rich nuclear matrix cyclophilin interacts with the C-terminal domain of RNA polymerase II

The largest subunit of RNA polymerase II shows a striking difference in the degree of phosphorylation, depending on its functional state: initiating and elongating polymerases are unphosphorylated and highly phosphorylated respectively. Phosphorylation mostly occurs at the C-terminal domain (CTD), which consists of a repetitive heptapeptide structure. Using the yeast two-hybrid system, we have selected for mammalian proteins that interact with the phosphorylated CTD of mammalian RNA polymerase II. A prominent isolate, designated SRcyp/CASP10, specifically interacts with the CTD not only in vivo but also in vitro. It contains a serine/arginine-rich (SR) domain, similar to that found in the SR protein family of pre-mRNA splicing factors, which is required for interaction with the CTD. Most remarkably, the N-terminal region of SRcyp includes a peptidyl-prolyl cis-trans isomerase domain characteristic of immunophilins/cyclophilins (Cyp), a protein family implicated in protein folding, assembly and transport. SRcyp is a nuclear protein with a characteristic distribution in large irregularly shaped nuclear speckles and co-localizes perfectly with the SR domaincontaining splicing factor SC35. Recent independent investigations have provided complementary data, such as an association of the phosphorylated form of RNA polymerase II with the nuclear speckles, impaired splicing in a CTD deletion background and inhibition of in vitro splicing by CTD peptides. Taken together, these data indicate that factors directly or indirectly involved in splicing are associated with the elongating RNA polymerases, from where they might translocate to the nascent transcripts to ensure efficient splicing, concomitant with transcriptio

Impact of clopidogrel in coronary artery bypass grafting

Objective: Clopidogrel has become the standard of care to prevent thrombotic complications following cardiological interventions, in particular intracoronary stenting. In addition, patients with aspirin intolerance and those with carotid and peripheral vascular disease are also increasingly treated with clopidogrel. Platelet inhibition may become a concern for hemostasis in patients treated with clopidogrel who need emergency and undelayed surgery. Methods: We prospectively analyzed the intra- and postoperative outcome of 505 consecutive patients who underwent isolated CABG and compared two groups: those with clopidogrel exposure until 72 h prior to surgery (n=136) with those without exposition to clopidogrel (n=369). Patients undergoing emergency surgery because of failed PTCA and cardiogenic shock, associated valvular surgery, redo-CABG, and those with additional platelet IIb/IIIa receptor inhibitor exposure were excluded. Patients who received aspirin and/or heparin treatment prior to surgery were not excluded. Results: Patients who received clopidogrel had a higher prevalence of angina class III or IV (67 vs 39%, P<0.01), received more often revascularization within 48 h (41 vs 14%, P=0.02), and had received more frequently stenting (57 vs 13%). Chest tube drainage was significantly increased during the first 24 h following CABG in the group of patients who had clopidogrel treatment (1485 vs 780 ml, P=0.003) These patients also required more transfusion of platelets and fresh frozen plasma. Overall re-exploration rate because of bleeding was significantly higher in the clopidogrel group (5.9 vs 1.2%, P<0.01). Platelets transfused before chest closure had a beneficial effect on preservation of the hemostasis. Conclusions: Clopidogrel exposure 3 days or less prior to CABG surgery significantly increases the risk of postoperative bleeding, the need for perioperative transfusion and the incidence of re-exploration. Surgery should be performed using standard heparinization and anti-fibrinolytic strategies but aggressive correction of platelets dysfunction is required before chest closur

An indicator of sudden cardiac death during brief coronary occlusion: electrocardiogram QT time and the role of collaterals

Aims The coronary collateral circulation has a beneficial role regarding all-cause and cardiac mortality. Hitherto, the underlying mechanism has not been clarified. The aim of this prospective study was to assess the effect of the coronary collateral circulation on electrocardiogram (ECG) QTc time change during short-term myocardial ischaemia. Methods and results A total of 150 patients (mean age 63 ± 11 years, 38 women) were prospectively included in this study. An ECG was recorded at baseline and during a standardized 1 min coronary balloon occlusion. QT interval was measured before, during, and after balloon occlusion and was corrected for heart rate (QTc). Simultaneously obtained collateral flow index (CFI), expressing collateral flow relative to normal anterograde flow, was determined based on intracoronary pressure measurements. During occlusion of the left anterior descending coronary artery mean QTc interval increased from 422 ± 33 to 439 ± 36 ms (P < 0.001), left circumflex occlusion led to an increase from 414 ± 32 to 427 ± 27 ms (P < 0.001). QTc was not influenced by occlusion of the right coronary artery (RCA) (417 ± 35 and 415 ± 34 ms, respectively; P = 0.863). QTc change during occlusion of the left coronary artery was inversely correlated with CFI (R2 = 0.122, P = 0.0002). Conclusion Myocardial ischaemia leads to QT prolongation during a controlled 1 min occlusion of the left, but not the RCA. QT prolongation is inversely related to collateral function indicating a protective mechanism of human coronary collaterals against cardiac deat

Early intensification and autologous stem cell transplantation in patients with systemic AL amyloidosis: a single-centre experience

Primary systemic amyloidosis (AL amyloidosis) continues to have a very poor prognosis. Most therapeutic strategies remain unsatisfactory. Conventional chemotherapy is known to offer at best only moderate efficacy. Several studies have yielded higher complete response rates after high-dose chemotherapy and autologous stem cell transplantation (ASCT) in addition to improving outcomes in a subgroup of patients. However, the superiority of an intensive approach in AL amyloidosis has not been confirmed in a randomised trial. The precise role of ASCT remains unclear. We report our experience in 16 patients diagnosed with AL amyloidosis and treated in a multidisciplinary approach with high-dose melphalan and ASCT. Median age was 59 (39-71)years. The kidneys were predominantly affected in 75% of cases; two or more organs were affected in 38%. Median time from diagnosis to transplantation was 2 (1-4)months. Three patients (19%) developed acute renal failure and required transient dialysis. Transplant-related mortality was 6% after 100days. Haematological complete response (CR) was obtained in nine (56%) and organ response in six (38%) patients. Nine out of 12 patients (75%) with kidney involvement exhibited a sustained clinical benefit at 12months. Half of all the patients (n = 8) were alive after a median follow-up of 33months, including two in continuous CR. This suggests that high-dose chemotherapy and ASCT are still valid treatment options in AL amyloidosis and that a significant number of patients with renal involvement might benefit from this approac