Naritsugu Sakaino

Hemodynamic, renal, and hormonal responses to brain natriuretic peptide infusion in patients with congestive heart failure.

BackgroundThis study was designed to examine the hemodynamic, renal, and hormonal effects of brain natriuretic peptide (BNP) infusion in patients with congestive heart failure (CHF) and in control subjects. Methods and ResultsWe infused synthetic human BNP at a rate of 0.1 ug/kg/min. BNP infusion decreased pulmonary capillary wedge pressure (control, from 5 ± 1 to 2 ± 1 mm Hg, p < 0.01; CHF, from 21 ± 3 to 14 ± 4 mm Hg, p < 0.05) and systemic vascular resistance (control, from 1,264 + 75 to 934 ± 52 dyne · sec · cm−5; CHF, from 2,485 ± 379 to 1,771 ± 195 dyne · sec · cm−5; p < 0.01, respectively) and increased stroke volume index (control, from 49.9 ± 2.7 to 51.5 ± 2.3 ml/m2, p = NS; CHF, from 25.6 ± 3.8 to 32.0 ± 3.9 ml/m2, p < 0.01). BNP infusion significantly increased urine volume (control, from 2.3 ± 0.7 to 7.5 ± 1.9 ml/min; CHF, from 0.8 ± 0.2 to 5.3 ± 1.0 ml/min; p < 0.01, respectively), excretion of sodium (control, from 79.2 + 21.6 to 332.8 ± 70.9 1LEq/min; CHF, from 77.4 ± 20.8 to 753.5 ± 108.0 μEq/min; p < 0.01, respectively), and excretion of chloride (control, from 72.5 ± 18.4 to 256.0 ± 43.3, Eq/min; CHF, from 74.0 + 19.6 to 708.8 ± 103.3 μEq/min; p < 0.01, respectively). Urinary excretion of sodium and of chloride in response to BNP infusion was higher in patients with CHF than in control subjects (p < 0.01, respectively). BNP infusion increased the levels of plasma atrial natriuretic peptide (control, from 65 ± 11 to 84 ± 14 pg/ml; CHF, from 262 ± 65 to 301 ± 62 pg/ml; p < 0.05, respectively) and decreased plasma aldosterone concentrations in both groups (control, from 43.3 ± 12.1 to 27.3 ± 7.1 pg/ml; CHF, from 91.1 ± 34.3 to 66.3 ± 27.2 pg/ml; p < 0.05, respectively). ConclusionsWe conclude that BNP infusion improves left ventricular function in patients with CHF by vasodilation and prominent natriuretic action.

Effect of acetylcholine on the highly stenotic coronary artery: Difference between the constrictor response of the infarct-related coronary artery and that of the noninfarct-related artery.

To examine the constrictor response of the infarct-related stenotic coronary artery in comparison with that of noninfarct-related stenotic arteries, acetylcholine in maximal doses of 100 micrograms for the left and 50 micrograms for the right coronary artery was injected into the 16 infarct-related coronary arteries of 16 patients with previous myocardial infarction (group 1) and into 19 stenotic coronary arteries of 16 patients with stable angina without myocardial infarction (group 2). Acetylcholines effects on lumen diameter and area were quantitatively analyzed at the stenotic segment and its proximal segment without significant stenosis. Acetylcholine decreased lumen diameter and area at the stenotic segments from 0.72 +/- 0.18 to 0.18 +/- 0.33 mm and from 0.45 +/- 0.22 to 0.10 +/- 0.22 mm2, respectively, in group 1 (both p less than 0.01) and from 0.75 +/- 0.22 to 0.49 +/- 0.30 mm and 0.48 +/- 0.29 to 0.26 +/- 0.23 mm2, respectively, in group 2 (both p less than 0.01). Acetylcholine decreased the diameter and area at the proximal segment from 2.71 +/- 0.75 to 2.38 +/- 0.6 mm and from 6.18 +/- 3.4 to 4.71 +/- 2.23 mm2, respectively, in group 1 (both p less than 0.01) and from 2.31 +/- 0.67 to 1.95 +/- 0.59 mm and from 4.5 +/- 2.97 to 3.22 +/- 1.96 mm2, respectively, in group 2 (both p less than 0.01). The changes in diameter and area at the stenotic segment in group 1 were significantly greater than those in group 2 (both p less than 0.01); there were no significant differences between groups in the changes at the proximal segment.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of magnesium on the tone of isolated human coronary arteries. Comparison with diltiazem and nitroglycerin.

To study the effects of magnesium (Mg2+) on human coronary arteries and to compare those effects with those of diltiazem and nitroglycerin, we measured the tension of ring segments from isolated human coronary arteries obtained at autopsy within 5 hours after death. Precontracted segments with 3 x 10(-6) M prostaglandin F2 alpha were studied after adding cumulative concentrations of these agents (1.0-8.0 mM, 10(-9)-10(-5) M, and 10(-10)-10(-6) M, respectively). Mg2+ significantly inhibited the tonic contraction compared with the time-matched controls at 1.0 and 2.0 mM (48.7 +/- 5.6% vs. 88.6 +/- 2.2%, p less than 0.01, 36.2 +/- 6.1% vs. 78.9 +/- 3.0%, p less than 0.01, respectively). 1.0 and 2.0 mM Mg2+ did not suppress, but actually increased, the amplitude of periodic contraction, but 8.0 mM Mg2+ reduced the amplitude compared with the controls (6.6 +/- 5.2% vs. 73.3 +/- 10.7%, p less than 0.01). Diltiazem at a concentration of 10(-5) M moderately inhibited the tonic contraction, and reduced the amplitude of periodic contraction almost completely. Nitroglycerin reduced the tonic contraction almost completely at a concentration of 10(-6) M but did not reduce the amplitude of periodic contraction at any concentration. We conclude that 1.0 and 2.0 mM Mg2+ inhibits the tonic contraction and that 8.0 mM Mg2+ inhibits the periodic as well as the tonic contraction of isolated human coronary arteries. Diltiazem inhibits the periodic contraction, whereas nitroglycerin suppresses tonic contraction without affecting the periodic contraction.

Increased constrictor response to acetylcholine of the isolated coronary arteries from patients with variant angina

The aim of this study was to determine whether isolated coronary arteries from patients with variant angina show hyperreactivity and/or supersensitivity to acetylcholine in vitro. Coronary arterial rings were obtained at autopsy within 3 h after death from six coronary arteries having spasm in four patients with variant angina and from 22 coronary arteries in 14 control patients with non-cardiac death. The coronary rings were suspended in the organ chamber filled with Krebs Henseleit solution bubbled with 95% O2 + 5% CO2, and their isometric tensions were monitored. Arterial rings isolated from both the patients with variant angina and the controls contracted dose-dependently in response to acetylcholine (10(-9)-10(-5) mol/l). EC50 of acetylcholine (i.e. concentration producing 50% of maximum contraction) was not significantly different between the coronary arteries from patients with variant angina and those from controls, but maximum contraction elicited by acetylcholine (expressed as a percentage of the contraction elicited by 60 mmol/l KCl) was significantly greater in the coronary arteries from patients with variant angina than those from controls. In conclusion, the isolated coronary arteries from patients with variant angina have hypercontractile reactivity to acetylcholine. This intrinsic alteration of the coronary reactivity to acetylcholine may play a role in the genesis of coronary spasm occurring in the situations of enhanced parasympathetic nervous discharge.

A study on coronary hemodynamics during acetylcholine-induced coronary spasm in patients with variant angina: Endothelium-dependent dilation in the resistance vessels.

The epicardial coronary artery of patients with variant angina is hyperreactive to the constrictive effect of acetylcholine, but it is not known whether the coronary microvasculature also constricts in response to acetylcholine. Incremental doses of acetylcholine were injected into the left coronary artery of 57 patients with variant angina and with spasm in this artery. By measuring coronary sinus blood flow, coronary hemodynamic status just before angiographic documentation of spasm was examined. Acetylcholine induced spasm in the left coronary artery in all patients. It also decreased the diameter of the nonspasm artery by 36 +/- 19% from baseline. For all patients, coronary sinus blood flow was 89 +/- 38 ml/min at baseline and increased to 104 +/- 61 ml/min during an acetylcholine-induced anginal attack (p less than 0.01). In 10 patients with spasm in both the left anterior descending and left circumflex arteries (that is, multivessel spasm), coronary sinus blood flow decreased from 84 +/- 21 to 52 +/- 26 ml/min (p less than 0.01). In the other 47 patients with spasm in only one of these two arteries (that is, single-vessel spasm), coronary sinus blood flow increased from 90 +/- 41 to 115 +/- 61 ml/min (p less than 0.01) without change in the rate-pressure product. It is concluded that in patients with variant angina, acetylcholine induces spasm and constriction in the epicardial coronary artery, whereas it dilates the resistance vessels presumably through the release of the endothelium-dependent relaxing factor.

Differential Effects of Strong and Regular Statins on the Clinical Outcome of Patients With Chronic Kidney Disease Following Coronary Stent Implantation – The Kumamoto Intervention Conference Study (KICS) Registry –

BACKGROUND The aim of this study was to examine the effects of different statins on the clinical outcomes of Japanese patients with coronary stent implants. METHODS AND RESULTS This study included 5,801 consecutive patients (males, 4,160; age, 69.7±11.1 years, mean±SD) who underwent stent implantation between April 2008 and March 2011. They were treated with a strong statin (n=3,042, 52%, atorvastatin, pitavastatin, or rosuvastatin), a regular statin (n=1,082, 19%, pravastatin, simvastatin, or fluvastatin) or no statin (n=1,677, 29%). The patients with chronic kidney disease (CKD) were divided into mild-to-moderate CKD (30≤eGFR<60, n=1,956) and severe CKD (eGFR <30, n=559). Primary endpoints included cardiovascular death and nonfatal myocardial infarction, including stent thrombosis and ischemic stroke. The clinical outcome for the primary endpoint in mild-to-moderate CKD patients treated with a strong statin (hazard ratio 0.50, 95% confidence interval 0.31-0.81; P=0.005) was significantly lower than in those on no statins, but that in the patients treated with a regular statin was not (P=0.160). The clinical outcome for the primary endpoint in severe CKD patients treated with a strong or regular statin was no different than not being on statin therapy (P=0.446, P=0.194, respectively). CONCLUSIONS In patients with mild-to-moderate CKD, only strong statins were associated with lower risk compared with no statin, but regular statins were not. It is possible that taking a strong statin from the early stage of CKD is useful for suppression of cardiovascular events.

Plaque REgression with Cholesterol absorption Inhibitor or Synthesis inhibitor Evaluated by IntraVascular UltraSound (PRECISE-IVUS Trial): Study protocol for a randomized controlled trial

BACKGROUND Although the positive association between achieved low-density lipoprotein cholesterol (LDL-C) level and the risk of coronary artery disease (CAD) has been confirmed by randomized studies with statins, many patients remain at high residual risk of events suggesting the necessity of novel pharmacologic strategies. The combination of ezetimibe/statin produces greater reductions in LDL-C compared to statin monotherapy. PURPOSE The Plaque REgression with Cholesterol absorption Inhibitor or Synthesis inhibitor Evaluated by IntraVascular UltraSound (PRECISE-IVUS) trial was aimed at evaluating the effects of ezetimibe addition to atorvastatin, compared with atorvastatin monotherapy, on coronary plaque regression and change in lipid profile in patients with CAD. METHODS The study is a prospective, randomized, controlled, multicenter study. The eligible patients undergoing IVUS-guided percutaneous coronary intervention will be randomly assigned to receive either atorvastatin alone or atorvastatin plus ezetimibe (10 mg) daily using a web-based randomization software. The dosage of atorvastatin will be increased by titration within the usual dose range with a treatment goal of lowering LDL-C below 70 mg/dL based on consecutive measures of LDL-C at follow-up visits. IVUS will be performed at baseline and 9-12 months follow-up time point at participating cardiovascular centers. The primary endpoint will be the nominal change in percent coronary atheroma volume measured by volumetric IVUS analysis. CONCLUSION PRECISE-IVUS will assess whether the efficacy of combination of ezetimibe/atorvastatin is noninferior to atorvastatin monotherapy for coronary plaque reduction, and will translate into increased clinical benefit of dual lipid-lowering strategy in a Japanese population.

Longitudinal propagation of contraction in the isolated conduit coronary arteries of humans and pigs.

We examined the longitudinal propagation of contraction in isolated human and pig coronary arteries. Epicardial coronary arteries of about 2 cm were cut open longitudinally, and the tension development of circular muscles was measured simultaneously at three sites (both cut ends and the midportion of the segment). Cyclic tension changes arising at one site of human coronary artery propagated smoothly to the other sites, and the whole length of segment worked as a single unit. Contraction induced by locally applied prostaglandin F2 alpha or histamine also propagated in four of seven preparations. The remaining three human and all seven pig coronary arteries showed propagation of such drug-induced contraction after treatment with 10 mM tetraethylammonium (TEA). In pig coronary arteries treated with TEA, electrical stimulation evoked a reproducible local contraction and its propagation. Propagation velocity was 9.0 +/- 0.7 at 0.8 mM calcium concentration and increased to 11.1 +/- 0.9 and 13.1 +/- 1.4 mm/sec as calcium concentration rose to 1.8 mM and 7.2 mM, respectively. Local contraction did not propagate at calcium concentrations of 0.2 mM or less. The calcium antagonist diltiazem decreased the propagation velocity dose dependently and blocked propagation of contraction at 0.3 microM without significant effects on the magnitude of local contraction. We conclude that smooth propagation of contraction develops in epicardial coronary arteries of humans and pigs and that the propagation may depend on calcium influx.

Effects of perivascular nerve stimulation on the flow rate in isolated epicardial coronary arteries of pigs

The effect of perivascular nerve stimulation on coronary contraction was examined by perfusing the isolated epicardial coronary artery of pigs. Coronary flow decreased in a frequency-dependent manner after electrical stimulation, with a maximum percent flow reduction of 23.8 +/- 1.1% (n = 10) at 20 Hz. The reduction in flow rate was not inhibited by phentolamine nor propranolol but was inhibited by atropine. Neostigmine enhanced the flow reduction induced by nerve stimulation. Acetylcholine reduced the flow rate dose dependently but norepinephrine showed no effect. We conclude that perivascular nerve stimulation of the epicardial coronary artery of pigs causes a modest flow reduction through activation of a cholinergic mechanism.

Synergistic effect of ezetimibe addition on coronary atheroma regression in patients with prior statin therapy: Subanalysis of PRECISE-IVUS trial.

Background The IMPROVE-IT trial showed that the clinical benefit of statin/ezetimibe combination appeared to be pronounced in patients with prior statin therapy. We hypothesized that the antiatherosclerotic effect of atorvastatin/ezetimibe combination was pronounced in patients with statin pretreatment. Methods In the prospective, randomized, controlled, multicenter PRECISE-IVUS trial, 246 patients undergoing intravascular ultrasound-guided percutaneous coronary intervention were randomized to atorvastatin/ezetimibe combination or atorvastatin alone. The dosage of atorvastatin was uptitrated with a treatment goal of lowering low-density lipoprotein cholesterol to below 70 mg/dl in both groups. Serial volumetric intravascular ultrasound was performed at baseline and 9–12 month follow-up to quantify the coronary plaque response in 202 patients. We compared the intravascular ultrasound endpoints in all subjects, stratified by the presence or absence of statin pretreatment. Results The baseline low-density lipoprotein cholesterol level (100.7 ± 23.1 mg/dl vs. 116.4 ± 25.9 mg/dl, p < 0.001) and lathosterol (55 (38 to 87)) µg/100 mg total cholesterol vs. 97 (57 to 149) µg/100 mg total cholesterol, p < 0.001) was significantly lower, and campesterol/lathosterol ratio (3.9 (2.4 to 7.4) vs. 2.6 (1.5 to 4.1), p < 0.001) was significantly increased in patients with statin pretreatment. Contrary to the patients without statin pretreatment (−1.3 (−3.1 to −0.1)% vs. −0.9 (−2.3 to 0.9)%, p = 0.12), the atorvastatin/ezetimibe combination showed a significantly stronger reduction in delta percent atheroma volume, compared with atorvastatin alone, in patients with statin pretreatment (−1.8 (−3.6 to −0.3)% vs. −0.1 (−1.6 to 0.8)%, p = 0.002). Conclusion Compensatory increase in cholesterol absorption observed in statin-treated patients might attenuate the inhibitory effects of statins on coronary plaque progression. A low-dose statin/ezetimibe combination might be a promising option in statin-hyporesponder.