Makoto Imai

Chronic Electrical Stimulation of the Carotid Sinus Baroreflex Improves Left Ventricular Function and Promotes Reversal of Ventricular Remodeling in Dogs With Advanced Heart Failure

Background—Autonomic abnormalities exist in heart failure and contribute to disease progression. Activation of the carotid sinus baroreflex (CSB) has been shown to reduce sympathetic outflow and augment parasympathetic vagal tone. This study tested the hypothesis that long-term electric activation of the CSB improves left ventricular (LV) function and attenuates progressive LV remodeling in dogs with advanced chronic heart failure. Methods and Results—Studies were performed in 14 dogs with coronary microembolization-induced heart failure (LV ejection fraction ≈25%). Eight dogs were chronically instrumented for bilateral CSB activation using the Rheos System (CVRx Inc, Minneapolis, Minn) and 6 were not and served as controls. All dogs were followed for 3 months, and none received other background therapy. During follow-up, treatment with CSB increased LV ejection fraction 4.0±2.4% compared with a reduction in control dogs of −2.8±1.0% (P<0.05). Similarly, treatment with CSB decreased LV end-systolic volume −2.5±2.7 mL compared with an increase in control dogs of 6.7±2.9 mL (P<0.05). Compared with control, CSB activation significantly decreased LV end-diastolic pressure and circulating plasma norepinephrine, normalized expression of cardiac &bgr;1-adrenergic receptors, &bgr;-adrenergic receptor kinase, and nitric oxide synthase and reduced interstitial fibrosis and cardiomyocyte hypertrophy. Conclusions—In dogs with advanced heart failure, CSB activation improves global LV function and partially reverses LV remodeling both globally and at cellular and molecular levels.

Exercise-induced post-ischemic left ventricular delayed relaxation or diastolic stunning: is it a reliable marker in detecting coronary artery disease?

OBJECTIVES The aim of this study was to determine whether post-ischemic left ventricular (LV) delayed relaxation could be detected by using strain imaging (SI) derived from 2-dimensional speckle-tracking echocardiography in patients with stable effort angina. BACKGROUND Regional LV delayed relaxation during early diastole is a sensitive sign of acute myocardial ischemia and may persist beyond recovery of exercise-induced ischemia. METHODS Regional LV transverse strain changes during the first one-third of diastole duration (strain imaging diastolic index [SI-DI]) were determined at baseline and 5 and 10 min after the exercise test in 162 patients with stable effort angina. The ratio of SI-DI before and after exercise (SI-DI ratio) was used to identify regional LV delayed relaxation. RESULTS A total of 117 patients had significant (> or =50% of luminal diameter) coronary stenoses. The mean SI-DI decreased from 78.0 +/- 9.7% to 27.6 +/- 16.0% (p < 0.0001) in 191 territories perfused by coronary arteries with significant stenoses 5 min after the treadmill exercise, whereas it remained unchanged in 280 territories perfused by arteries with nonsignificant stenoses. Ten minutes after exercise, regional delayed relaxation was still observed in 85% of territories perfused by stenotic coronary arteries. An SI-DI ratio with a cutoff value of 0.74 had a sensitivity of 97% and a specificity of 93% to detect significant coronary stenosis in the receiver-operator characteristic curve. CONCLUSIONS Detection of post-ischemic regional LV delayed relaxation or diastolic stunning after treadmill exercise using SI is a sensitive and reliable method for the detection of coronary artery disease.

Abnormal Regional Left Ventricular Systolic and Diastolic Function in Patients With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention: Clinical Significance of Post-Ischemic Diastolic Stunning

OBJECTIVES This study was designed to characterize both regional left ventricular (LV) systolic and diastolic function after percutaneous coronary intervention by using strain imaging (SI) derived from 2-dimensional speckle-tracking echocardiography. BACKGROUND Ischemic insult after coronary occlusion affects not only regional LV systolic but also diastolic function. METHODS Regional LV transverse peak strain and strain changes during the first one-third of diastole duration (strain imaging diastolic index [SI-DI]) were monitored in at-risk segments after percutaneous coronary intervention in 30 patients with coronary artery disease. The segments were divided into proximal and distal. Strain data in the at-risk segments were compared with values derived from remote nonischemic segments. RESULTS Coronary occlusion induced a marked reduction in the systolic strain in both proximal and distal at-risk segments (from 36.9 +/- 6.0% to 12.0 +/- 3.9% and from 31.9 +/- 5.6% to 6.2 +/- 3.3%, respectively, p < 0.0001). Concomitantly, SI-DI values decreased (from 76.6 +/- 5.3% to -21.2 +/- 9.1% and from 72.5 +/- 5.9% to -48.7 +/- 20.8%, respectively, p < 0.0001). Upon reperfusion, systolic deformation parameters returned to near-normal pre-occlusion values. However, SI-DI values in the both proximal and distal at-risk segments decreased (43.2 +/- 9.5%, p < 0.01, and -17.3 +/- 11.1%, p < 0.0001, respectively) 30 min after reperfusion and were still lower (51.5 +/- 9.9%, p < 0.01) in the distal at-risk segment 24 h after reperfusion. CONCLUSIONS SI analysis provides detailed mechanical characterization of regions with myocardial ischemic insult and can demonstrate post-ischemic diastolic stunning despite complete systolic functional recovery after reperfusion.

Detection of Postischemic Regional Left Ventricular Delayed Outward Wall Motion or Diastolic Stunning After Exercise-induced Ischemia in Patients with Stable Effort Angina by Using Color Kinesis

To determine whether postischemic diastolic stunning could be detected using color kinesis, we evaluated regional left ventricular (LV) diastolic wall motion in 36 patients with stable effort angina and a coronary stenosis (> or = 70% of luminal diameter), and in 30 control subjects. Regional LV filling fraction in the short-axis view during the first 30% of the LV filling time (color kinesis diastolic index) was determined before, 20 minutes, 1 hour, and 24 hours after the treadmill exercise test. In 33 of the 36 patients (92%), new regional LV delayed outward motion during early diastole (color kinesis diastolic index < or = 40%) was detected at 20 minutes after exercise. The regional LV delayed diastolic wall motion showed significant improvement but persisted 1 hour afterward in 20 of 36 patients (56%), and disappeared 24 hours after exercise. Detection of regional stunned myocardium with impaired diastolic function may be a useful tool for the diagnosis of coronary artery disease.

Darbepoetin-α prevents progressive left ventricular dysfunction and remodeling in nonanemic dogs with heart failure

In anemic patients with heart failure (HF), erythropoietin-type drugs can elicit clinical improvement. This study examined the effects of chronic monotherapy with darbepoetin-alpha (DARB) on left ventricular (LV) function and remodeling in nonanemic dogs with advanced HF. HF [LV ejection fraction (EF) approximately 25%] was produced in 14 dogs by intracoronary microembolizations. Dogs were randomized to once a week subcutaneous injection of DARB (1.0 microg/kg, n=7) or to no therapy (HF, n=7). All procedures were performed during cardiac catheterization under general anesthesia and under sterile conditions. LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF were measured before the initiation of therapy and at the end of 3 mo of therapy. mRNA and protein expression of caspase-3, hypoxia inducible factor-1alpha, and the bone marrow-derived stem cell marker c-Kit were determined in LV tissue. In HF dogs, EDV and ESV increased and EF decreased after 3 mo of followup. Treatment with DARB prevented the increase in EDV, decreased ESV, and increased EF. DARB therapy also normalized the expression of HIF-1alpha and active caspase-3 and enhanced the expression of c-Kit. We conclude that chronic monotherapy with DARB prevents progressive LV dysfunction and dilation in nonanemic dogs with advanced HF. These results suggest that DARB elicits beneficial effects in HF that are independent of the presence of anemia.