We investigated the effect of the nitric oxide (NO) synthase inhibitor N G ‐nitro‐ l ‐arginine methyl ester ( l ‐NAME) and the peptidase α‐chymotrypsin on non‐adrenergic, non‐cholinergic (NANC neural) bronchoconstriction induced by electrical stimulation of the vagus nerves and by capsaicin in anaesthetized guinea‐pigs in vivo using pulmonary insufflation pressure (PIP) as an index of bronchial tone. We also investigated the contribution of soluble guanylyl cyclase (SGC) to NANC neural relaxant mechanisms. In the presence of atropine and propranolol, electrical stimulation of the vagus nerves induced a frequency‐dependent increase in PIP above baseline of 67% at 2.5 Hz, of 128% at 5 Hz and of 230% at 10 Hz. l ‐NAME (1–50 mg kg −1 , i.v.), at doses inducing increases in systemic blood pressure, dose‐relatedly potentiated NANC bronchoconstriction. At 10 mg kg −1 i.v., l ‐NAME significantly ( P < 0.05) potentiated NANC bronchoconstriction by a further 106% at 2.5 Hz and a further 147% at 5 Hz but did not potentiate the increase in PIP at 10 Hz. l ‐NAME did not induce bronchocontriction in sham‐stimulated control animals. d ‐NAME did not potentiate NANC bronchoconstriction. Raising systemic blood pressure with phenylephrine did not potentiate vagally‐induced bronchoconstriction (2.5 Hz). The NO precursor l ‐arginine, but not d ‐arginine, (100 mg kg −1 , i.v.) significantly reversed the potentiation by l ‐NAME of NANC bronchoconstriction. l ‐Arginine alone significantly inhibited neurogenic bronchoconstriction at 10 Hz (by 74%); the inhibition of 25% at 2.5 Hz was not significant. l ‐NAME did not significantly affect the increases in PIP induced by intravenous substance P, neurokinin A (NKA) or capsaicin. The inhibitor of SGC, methylene blue (10 mg kg −1 , i.v.) potentiated (by 110–140%) NANC neural bronchoconstriction induced by lower frequencies of nerve stimulation and reversed the reduction in PIP induced by the SGC activator, sodium nitroprusside (SNP, 1.05 mg kg −1 , i.v.). SNP significantly ( P < 0.05) reduced by 65% the bronchoconstriction induced by nerve stimulation at 10 Hz. Methylene blue did not effect baseline PIP in sham‐stimulated controls. The airway effects of methylene blue and SNP were not associated with their cardiovascular effects. α‐Chymotrypsin (2 units kg −1 , i.v.) significantly potentiated vagally‐induced bronchoconstriction by a further 63% at 2.5 Hz, by a further 95.6% at 5 Hz but did not potentiate the increase in PIP at 10 Hz. α‐Chymotrypsin also potentiated (by 116%) capsaicin‐induced bronchoconstriction. Vasoactive intestinal peptide (VIP, 10 μg kg −1 i.v. infused over 1 min) significantly reduced by 70% the increase in PIP induced by NKA (0.1 μmol kg −1 i.v., infused over 30 s). The combination of α‐chymotrypsin (2 units kg −1 , i.v.) and l ‐NAME (5 mg kg −1 , i.v.) significantly potentiated NANC bronchoconstriction by a further 304% at 2.5 Hz, an increase in PIP which was greater than that induced by either α‐chymotrypsin or l ‐NAME alone ( P < 0.05). We conclude that endogenous NO and a bronchodilator peptide, possibly VIP, released in association with nerve stimulation, as well as activation of soluble guanylyl cyclase, regulate the magnitude of NANC neurogenic bronchoconstriction in guinea‐pigs in vivo .
Key Points Several trials failed to demonstrate the efficacy of plaque modification device in patients with severely calcified coronary lesions. Safety and efficacy of the Diamondback 360® Coronary OAS have been demonstrated by the ORBIT II trial. The 2‐year follow‐up of the ORBIT II trial extends the favorable results previously shown at 30‐day and 1‐year follow‐up. The single arm, non‐randomized character of the trial with indirect historical comparison may restrict the results to hypothesis generating and entail further prospective randomized trials.
Over the last 4 decades, percutaneous coronary intervention has evolved dramatically and is now an acceptable treatment option for patients with advanced coronary artery disease. However, trialists have struggled to establish the respective roles for percutaneous coronary intervention and coronary artery bypass graft surgery, especially in patients with multivessel disease and unprotected left-main stem coronary artery disease. Several pivotal trials and meta-analyses comparing these 2 revascularization strategies have enabled the relative merits of each technique to be established with regard to the type of ischemic syndrome, the coronary anatomy, and the patient’s overall comorbidity. Precision medicine with individualized prognosis is emerging as an important method of selecting treatment. However, the never-ending advancement of technology, in conjunction with the emergence of novel pharmacological agents, will in the future continue to force us to reconsider the evolving question: “Which treatment strategy is better and for which patient?”
No currently available treatments reduce the progression or suppress the inflammation of chronic obstructive pulmonary disease (COPD). However, with a better understanding of the inflammatory and destructive process, several targets have been identified, and new treatments are now in clinical development. Several specific therapies are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD, including adhesion molecule and chemokine-directed therapy, as well as therapies to inhibit tumour necrosis factor-α. Broad spectrum anti-inflammatory drugs are also in development, and include inhibitors of phosphodiesterase-4, p38 mitogen-activated protein kinase, nuclear factor-κB and phosphoinositide-3 kinase-γ. More specific approaches include antioxidants, inhibitors of inducible nitric oxide synthase, and leukotriene B 4 receptor antagonists. Inhibitors of epidermal growth factor receptor kinase and calcium-activated chloride channel inhibitors have the potential to inhibit mucus hypersecretion. Other therapies are targeted at the structural changes of COPD. Therapy to inhibit fibrosis is being developed against transforming growth factor-β 1 and protease activated receptor-2. There is also a search for serine proteinase and matrix metalloproteinase inhibitors to prevent lung destruction and the development of emphysema, as well as drugs such as retinoids that may even reverse this process. There is the need for validated biomarkers and monitoring techniques in early clinical studies with new therapies for chronic obstructive pulmonary disease.
Objectives This study explored whether an individual or a cluster of risk factors affects the extent of necrotic core (NC) assessed by intravascular ultrasound (IVUS) radiofrequency data (RFD) analysis. Background Several systemic diseases contribute to the development of coronary artery disease. Methods The Global Intravascular Radiofrequency Data Analysis Registry was a prospective, multicenter, nonrandomized database that enrolled 990 patients with coronary artery disease in whom 1 major coronary artery was imaged by IVUS-RFD. For the multivariable analysis, the population was divided into 4 classes: young women, young men (both ≤62 years), old women, and old men (>62 years). Mean NC area was categorized as 1: top quartile (≥0.62 mm2) or as 0: lower 3 quartiles. Results Young patients had less NC compared with older patients (0.40 ± 0.36 mm2 of NC vs. 0.50 ± 0.46 mm2 in old patients, p = 0.0007). Nondiabetic patients had less NC than diabetic patients (0.43 ± 0.41 mm2 of NC vs. 0.51 ± 0.44 mm2 in diabetic patients, p = 0.02). The NC area was lower in normotensive patients (0.40 ± 0.36 mm2) than in hypertensive patients (0.48 ± 0.44 mm2) (p = 0.02). In the bivariate analysis, age, hypertension, diabetes, and prior coronary artery bypass graft were statistically significant, however in logistic regression analysis, only age (odds ratio [OR]: 1.023, 95% confidence interval [CI]: 1.009 to 1.037, p = 0.001) and diabetes (OR: 1.636, 95% CI: 1.174 to 2.279, p = 0.004) remained statistically significant. In a per-class logistic regression analyses including only diabetes as covariate, the OR in young women was 2.1 (95% CI: 0.77 to 6.0, p = 0.14), in young men the OR was 1.6 (95% CI: 0.90 to 2.7, p = 0.11), in old women the OR was 2.3 (95% CI: 1.09 to 4.9, p = 0.03), and in old men the OR was 1.6 (95% CI: 0.96 to 2.7, p = 0.07). Further, when only patients with diabetes and hypertension were included, young men (OR: 2.0, p = 0.041), old women (OR: 3.04, p = 0.046), and old men (OR: 2.2, p = 0.025) were significant. Conclusions Individually and collectively, age and diabetes mellitus are associated with an increase in NC by IVUS-RFD analysis.
Background: To evaluate the impact of the extent of coronary disease (single- or multivessel) and of fluvastatin treatment on the incidence of long-term cardiac atherosclerotic complications in the Lescol Intervention Prevention Study (LIPS). Methods: A total of 1063 patients with single-vessel disease and 614 patients with multivessel disease were randomized to receive fluvastatin (40 mg bid) or placebo for at least 3 years following a first successful percutaneous coronary intervention. The incidence of cardiac atherosclerotic events (cardiac death, non-fatal myocardial infarction, and coronary re-interventions not related to restenosis) was evaluated. Results: Patients with multivessel disease tended to be older and presented a higher prevalence of associated risk factors and cardiovascular antecedents. The presence of multivessel disease markedly increased the risk of cardiac atherosclerotic events compared with single-vessel disease among patients allocated to placebo (RR 1.67 [95% CI: 1.24–2.25]; p<0.001). In patients treated with fluvastatin, however, no significant differences in long-term outcomes were observed between patients with multivessel disease and patients single-vessel disease (RR 1.28 [95% CI: 0.90–1.81]; p=0.2). Conclusions: Multivessel coronary disease impaired the 4-year outcomes after percutaneous intervention. However, the hazardous effect of multivessel disease was significantly reduced by long-term fluvastatin treatment.
The hemodynamic effects of nisoldipine and diltiazem were investigated in two groups of patients undergoing investigation for suspected coronary artery disease. Emphasis was placed on the coronary hemodynamic changes. Approximately equihypotensive doses of these two calcium channel blockers, nisoldipine (6 micrograms/kg) and diltiazem (500 micrograms/kg) were given intravenously. Although both drugs decreased peak systolic pressure by 28% and 24%, respectively, heart rate increased with nisoldipine (68 +/- 9 to 82 +/- 12 bpm) and remained unchanged with diltiazem (70 +/- 9 to 67 +/- 10 bpm). Nisoldipine increased mean coronary sinus blood flow from 146 +/- 40 to 176 +/- 35 ml/min and great cardiac vein flow from 87 +/- 20 to 109 +/- 24 ml/min, producing a significant reduction in the calculated global (from 0.79 +/- 0.2 to 0.43 +/- 0.12 mmHg min/ml) and regional (from 1.43 +/- 0.2 to 0.70 +/- 0.13 mmHg min/ml) coronary vascular resistances. There were no significant flow changes when corrected for heart rate. Global and regional myocardial oxygen consumptions were not significantly altered. Diltiazem had no significant effects on heart rate or global and regional blood flows, although the vascular resistances decreased by 32% and 35%, respectively. Diltiazem reduced global and regional arterio-coronary sinus oxygen differences, resulting in significant decreases in global (from 14.9 +/- 4.7 to 12.1 +/- 2.3 ml/min) and regional (from 5.6 +/- 0.9 to 5.2 +/- 1.2 ml/min) myocardial oxygen consumptions. The major difference between the drugs was in heart rate, despite the similar reductions in aortic pressure. The lack of a positive chronotropic response after diltiazem may explain the reduction in myocardial oxygen consumption.
