Divergent effects of serotonin on coronary-artery dimensions and blood flow in patients with coronary atherosclerosis and control patients

BACKGROUND. Studies in animals have shown that serotonin constricts coronary arteries if the endothelium is damaged, but in vitro studies have revealed a vasodilating effect on isolated coronary segments with an intact endothelium. To investigate the effect of serotonin in humans, we studied coronary-artery cross-sectional area and blood flow before and after the infusion of serotonin in seven patients with angiographically normal coronary arteries and in seven with coronary artery disease. METHODS. We measured the cross-sectional area of the coronary artery by quantitative angiography and coronary blood flow with an intracoronary Doppler catheter. Measurements were obtained at base line and during intracoronary infusions of serotonin (0.1, 1, and 10 micrograms per kilogram of body weight per minute, for two minutes). We repeated the measurements after an infusion of ketanserin, an antagonist of serotonin receptors that is thought to block the effect of serotonin on receptors in the arterial wall but not in the endothelium. RESULTS. In patients with normal coronary arteries, the highest dose of serotonin increased cross-sectional area by 52 percent (P less than 0.001) and blood flow by 58 percent (P less than 0.01). The effect was significantly potentiated by administration of ketanserin. In patients with coronary-artery atherosclerosis, serotonin reduced cross-sectional area by 64 percent (P less than 0.001) and blood flow by 59 percent (P less than 0.001). Ketanserin prevented this effect. CONCLUSIONS. Serotonin has a vasodilating effect on normal human coronary arteries; when the endothelium is damaged, as in coronary artery disease, serotonin has a direct, unopposed vasoconstricting effect. When considered with other evidence, these data suggest that platelet-derived factors such as serotonin may have a role in certain acute coronary ischemic syndromes.     

Role of alpha 2-adrenoceptors in normal and atherosclerotic human coronary circulation.

BACKGROUND. Experimental studies on the effects of alpha 2-adrenoceptors on regional coronary blood flow in normal and ischemic myocardium are highly controversial. A beneficial effect on regional ischemic myocardium has been demonstrated in different animal preparations with either alpha 2-adrenoceptor blockade or stimulation. Animal studies also demonstrated that postsynaptic alpha 2-adrenoceptors mediate vasoconstriction in coronary and femoral vascular beds. The aims of the study were 1) to investigate the effects of regional alpha 2-adrenoceptor stimulation on regional coronary blood flow in subjects with angiographically normal coronary arteries, 2) to assess the effect of alpha 2-adrenoceptor blockade on coronary circulation in control subjects, and 3) to examine the influence of atherosclerosis on coronary blood flow response to alpha 2-adrenoceptor blockade. METHODS AND RESULTS. The effect of regional administration of BHT 933 (a selective alpha 2-adrenoceptor agonist) was studied in eight subjects with angiographically normal coronary arteries. The coronary blood flow velocity was measured using a subselective intracoronary 3F Doppler catheter and coronary diameter by quantitative coronary angiography. BHT 933 induced a reduction in coronary artery diameter from 2.5 +/- 0.6 mm to 1.8 +/- 0.4 mm (p less than 0.05) as well as in coronary blood flow velocity (from 6.4 +/- 0.9 cm/sec to 4.6 +/- 1.9 cm/sec, p less than 0.01). In some subjects, ST segment abnormalities occurred. In patients with angiographically normal coronary arteries (n = 6), the regional infusion of a selective alpha 2-adrenoceptor blocking agent after beta-blockade did not change coronary diameter or coronary blood flow velocity. In contrast, in patients with significant coronary stenoses (n = 6), regional infusion of an alpha 2-adrenoceptor blocking agent reduced regional coronary artery diameter (from 2.3 +/- 0.5 mm to 2.1 +/- 0.6 mm, p less than 0.01) as well as coronary blood flow velocity (from 5.8 +/- 0.8 cm/sec to 3.7 +/- 0.6 cm/sec, p less than 0.05); in addition, alpha 2-adrenoceptor blockade significantly increased coronary sinus plasma norepinephrine levels (from 300 +/- 144 pg/ml to 429 +/- 207 pg/ml, p less than 0.01). CONCLUSIONS. The selective in vivo stimulation of alpha 2-adrenoceptors produces a reduction in coronary blood flow and diameter in humans with angiographically normal coronary arteries. alpha 2-Adrenergic blockade does not change coronary blood flow in subjects with angiographically normal coronary arteries (suggesting no resting alpha 2-adrenergic vasoconstrictor tone), whereas in patients with coronary artery stenosis, regional coronary blood flow decreases after alpha 2-receptor blockade. Finally, our data also suggest that alpha 2-adrenoceptors participate in the modulation of sympathetic neuronal norepinephrine release in the human heart.     

Colorectal Cancer with Synchronous Resectable Liver Metastases: Monocentric Management in a Hepatobiliary Referral Center Improves Survival Outcomes

Background

Management of patients with synchronous colorectal liver metastases (SCRLM) should be individually tailored. This study compares patients managed by hepatobiliary centers from diagnosis with those referred for liver resection (LR).

Methods

Between 1998 and 2010, a total of 284 patients with SCRLM underwent resection; 106 resectable patients (1–3 unilobar metastases, diameter <100 mm, liver-only disease) were divided into two groups: 66 managed from diagnosis (group A) and 40 referred for LR (group B).

Results

Group A contained a greater proportion of multiple metastases (55.0 vs. 34.8 %, P = 0.042). Group B always received colorectal surgery as up-front treatment (vs. 18.2 %, P < 0.0001). In group B, chemotherapy before LR was more common (72.5 vs. 33.3 %, P = 0.0001) and lasted longer (P = 0.010). More patients in group B exhibited disease progression before LR (17.5 vs. 3.0 %, P = 0.025). Group A underwent fewer surgical procedures (80.3 % simultaneous resection vs. 0 %, P < 0.00001), with similar short-term outcomes. After a median follow-up of 42.0 months, group A exhibited higher 5 year disease-free survival (DFS, 64.8 vs. 30.8 %, P = 0.005) and fewer extrahepatic recurrences (21.5 vs. 47.5 %, P = 0.005). The late-referral group (>6 months, n = 24) had shorter median overall survival (OS) and DFS than group A (49.1 and 25.3 months vs. not achieved and not achieved, P < 0.05). The early-referral group exhibited OS and DFS similar to group A. Multivariate analysis confirmed late referral as a negative predictive factor of OS and DFS.

Conclusions

Monocentric management of SCRLM in hepatobiliary centers is associated with shorter preoperative chemotherapy, better disease control, fewer surgical procedures (simultaneous resection), and, compared with late-referred patients, better survival.     

Laparoscopic incisional and umbilical hernia repair in cirrhotic patients

BACKGROUND: Traditional approach to incisional hernias (IHs) in cirrhotic patients is plagued by a significant recurrence rate and frequent wound infections. The laparoscopic repair of IHs was designed to offer a minimally invasive and tension-free technique that yields less morbidity and fewer recurrences than the standard open repair. In cirrhotic patients there are additional reasons for the benefits of laparoscopy. First, preservation of the abdominal wall avoids interruption of large collateral veins. Second, nonexposure of viscera restricts electrolytic and protein losses, and improves absorption of ascites. Finally, the laparoscopic approach is associated with a lower perioperative blood loss (smaller abdominal incision). METHODS: A retrospective review was performed for 14 consecutive patients with ventral hernias and affected by chronic hepatitis or cirrhosis related to hepatitis C-B virus, who underwent laparoscopic repair at our institution between September 2002 and October 2004. All patients were in class A of Child-Pugh classification. RESULTS: There was no conversion to open operation. The mean size of the defects was 87 cm (range 1 to 480); incarceration was present in 2 patients and multiple (Swiss-cheese) defects in 1. In all cases, the mesh (average, 287 cm) was secured with transabdominal sutures and metal tacks or staples leaving the sac in situ. Operative time and estimated blood loss averaged 88 min (range 18 to 270) and 30 mL (range 10 to 150). Length of hospital stay averaged 2.6 days (range 1 to 6). There were 11 minor complications: seroma lasting >4 weeks (5), postoperative ileus (2), suture site pain >2 weeks (2), urinary retention (1), and skin breakdown (1). We experienced no recurrences with an average follow-up of 8 months (range 3 to 24). CONCLUSIONS: Laparoscopic IH repair is technically feasible and safe even in cirrhotic patients with fascial defects. This operation decreases postoperative pain, shortens the recovery period, and seems to reduce postoperative morbidity and recurrence. To the best of our knowledge, this is the first report in which a series of cirrhotic patients affected by incisional and umbilical hernias is treated with a laparoscopic approach.     

Filling the gap between science & clinical practice: prevention of stroke recurrence

Because of its high recurrence rate, active secondary prevention is mandatory once an episode of stroke has occurred. In non-cardioembolic stroke, in addition to lifestyle changes and to targeted treatments, current guidelines recommend Aspirin, Clopidogrel or Aspirin+extended-release dipyridamole. In cardioembolic stroke (due to atrial fibrillation or flutter [AF]), Vitamin K antagonists (VKAs) are recommended in most of patients. A favorable risk/benefit ratio of these treatments has been demonstrated also in elderly patients. However, registry data emphasize that such interventions are often under-used, especially in AF patients. A poor knowledge of current guidelines may play a role in hampering their application in clinical practice. The risk of major bleeding associated with antithrombotic drugs, their inherent limitations, such as socio-demographic (age > 80 years, living alone) and clinical (previous or recent bleeding, trauma, cancer, dementia) features, may account for the gap between current guidelines for stroke/TIA prevention and clinical practice.The objective of the present report is to evaluate the gap between current recommendations/guidelines for stroke/TIA prevention and clinical practice (registry findings). In our opinion new antithrombotic drugs and detailed educational programs (especially devoted to general practitioners and to some medical specialists), concerning efficacy, safety and limitations of these strategies, are needed to better manage stroke epidemics in the third millennium.     

Aspirin resistance, platelet turnover, and diabetic angiopathy: a 2011 update

In 2004 an editorial article on the so-called “aspirin resistance” and diabetic angiopathy as related to platelet turnover was published by one of us. An update of this issue is now presented.The evidence of an incomplete inhibition of platelet function by aspirin, despite doses of the drug proved to be clinically effective are employed, was first reported in the ‘80s, in studies devoted to platelet turnover. Based on this concept, the possibility of monitoring the entry of newly formed platelets into the circulation after aspirin ingestion was documented by measuring the return of thromboxane biosynthesis by platelets challenged in vitro by pairs of aggregating agents. The data obtained showed that platelets with intact cyclooxygenase activity could be detected into the circulation of control individuals as early as 4-6 hrs after aspirin ingestion, but at shorter time intervals in diabetic angiopathy. In the latter setting, it was concluded that “schedules of aspirin which may suffice in normals are not effective in patients with diabetic angiopathy, presumably because these patients have a high rate of entry of new platelets into the circulation”.As many as 25 years after its original publication, the clinical relevance of an accelerated platelet turnover as to “aspirin resistance” has been confirmed and extended to other clinical settings at high risk of ischemic events. Newer aspirin dosing and scheduling, tailored at reducing the individual patient risk related to an incomplete inhibition of platelet function by a standard aspirin dose should now be defined.