Dynamic changes in left ventricular regional wall thickness during premature ventricular contraction in conscious dogs

The contractile pattern of the regional left ventricular wall during premature ventricular contraction was analyzed in conscious dogs instrumented with an ultrasonic dimension gauge across the anterior and posterior left ventricular walls. Aortic flow was measured with an electromagnetic flow probe. A single premature ventricular contraction was induced by stimulating either the anterior or posterior wall with varied coupling intervals from 380 to 650 msec. Stroke volume of premature ventricular contraction was significantly smaller than that of premature atrial contraction with identical coupling intervals. In premature contractions, stroke volume was linearly related to coupling intervals. Though there was no isovolumic wall thickening in premature atrial contraction, the wall started to thicken during isovolumic ventricular systole in premature ventricular contraction. There was a clear inverse correlation between the ratio of the isovolumic wall thickening to the total wall thickening and coupling intervals.

In premature ventricular contractions with identical coupling intervals, the deformation of thickening characteristics was more pronounced in regions with closer proximity to the ectopic focus. Thus it is concluded that the pump function is depressed in premature ventricular contraction, in part due to the increased ratio of wall thickening during isovolumic systole before the opening of the aortic valve. Isovolumic wall thickening increases along with the shorter coupling intervals and closer proximity to the ectopic focus. These alterations in left ventricular mechanical function due to ectopic contraction might induce serious sequelae, depending upon the ectopic focus in the presence of already depressed regional function.     

Modification of pacing-induced alterations in diastolic properties of the regional myocardium by nifedipine in patients with coronary artery disease

Summary The effects of nifedipine on regional dysfunction during pacing-induced ischemia were studied in eight patients with coronary artery disease. Single-plane left ventriculograms were obtained using a high-fidelity micromanometer-tipped catheter in the control and post-pacing periods both before and after pretreatment with nifedipine. All patients developed typical anginal pain during pacing tachycardia before but not after pretreatment with nifedipine. After pacing, left ventricular end-diastolic pressure (EDP) increased from 10±5 (SD) mmHg to 23±9 mmHg (P<0.01) with enlargement of the end-diastolic volume (EDV). The ejection fraction (EF) was reduced from 66±10% to 54±13% (P<0.05). With nifedipine, a post-pacing increase in EDP was markedly attenuated together with a 17% reduction in left ventricular systolic pressure (P<0.05).The regional myocardial function was expressed by a radial coordinate system with its origin at the center of gravity of the end-diastolic contour. Two representative radial grids for normal and ischemic segments were selected. In the normal segment, the end-diastolic length (EDL) was augmented by 14% (from 26.1±5.2 mm to 29.7±6.1 mm,P<0.01) associated with a 23% increase in stroke excursion (P<0.05) with pacing stress. In the ischemic segments, EDL remained unchanged in the post-pacing beat but stroke excursion was significantly reduced (from 11.4±5.2 mm to 4.3±1.8 mm,P<0.01). After pretreatment with nifedipine, the responses of the regional myocardium to the same pacing stress were markedly reduced; the EDL of the control segment was 27.4±4.6 mm with equally augmented stroke excursion. EDL of the ischemic segment remained unchanged but post-pacing deterioration of segment shortening was remarkably improved (8.7±3.3 mm,P<0.05). With pacing stress before nifedipine, the control segment moved up to the higher portion of the single curve. In the ischemic segment, the diastolic pressure became higher at any given length and the pressure length curve clearly shifted upward, indicating regional alteration of the diastolic property. After nifedipine, this upward shift of the regional myocardial pressure-length relationship was markedly attenuated.Thus, we conclude that nifedipine favorably modifies the symptomatic and hemodynamic responses to transient ischemia due to pacing stress largely mediated by selective improvement of the ischemic segment.     

The evolutionarily conserved G protein-coupled receptor SREB2/GPR85 influences brain size, behavior, and vulnerability to schizophrenia

The G protein-coupled receptor (GPCR) family is highly diversified and involved in many forms of information processing. SREB2 (GPR85) is the most conserved GPCR throughout vertebrate evolution and is expressed abundantly in brain structures exhibiting high levels of plasticity, e.g., the hippocampal dentate gyrus. Here, we show that SREB2 is involved in determining brain size, modulating diverse behaviors, and potentially in vulnerability to schizophrenia. Mild overexpression of SREB2 caused significant brain weight reduction and ventricular enlargement in transgenic (Tg) mice as well as behavioral abnormalities mirroring psychiatric disorders, e.g., decreased social interaction, abnormal sensorimotor gating, and impaired memory. SREB2 KO mice showed a reciprocal phenotype, a significant increase in brain weight accompanying a trend toward enhanced memory without apparent other behavioral abnormalities. In both Tg and KO mice, no gross malformation of brain structures was observed. Because of phenotypic overlap between SREB2 Tg mice and schizophrenia, we sought a possible link between the two. Minor alleles of two SREB2 SNPs, located in intron 2 and in the 3' UTR, were overtransmitted to schizophrenia patients in a family-based sample and showed an allele load association with reduced hippocampal gray matter volume in patients. Our data implicate SREB2 as a potential risk factor for psychiatric disorders and its pathway as a target for psychiatric therapy.     

Stiffness of systemic arteries in patients with myocardial infarction. A noninvasive method to predict severity of coronary atherosclerosis

The static elastic properties of arterial tree (abdominal aorta and common carotid artery) were studied in 19 normal subjects and in 49 patients with myocardial infarction with an ultrasonic phase-locked echo-tracking system that allows continuous transcutaneous measurement of the arterial diameter. The stiffness index beta, which represented the mechanical properties in the arterial wall, was calculated from the relation between systemic blood pressure and the diameter of the artery. Patients with myocardial infarction underwent coronary angiography in their convalescent period to determine involved vessels. In 11 patients, coronary artery was patent; 15 patients had one-vessel disease, 12 had two-vessel disease, and the remaining 11 patients had three-vessel disease. In normal subjects, increasing age was associated with an increase in arterial stiffness. An average value of the stiffness index of the abdominal aorta was 8.58 +/- 3.02 (mean +/- SD) and that of common carotid artery was 9.17 +/- 2.22. In patients with three-vessel disease, these values were significantly higher (22.37 +/- 4.29 in abdominal aorta and 13.17 +/- 4.56 in common carotid artery) than those in normal subjects. Stiffness index of patients with two- or one-vessel disease was also increased but lower than those in patients with three-vessel disease (p less than 0.05). Forty-four of 49 patients with infarction had an arterial stiffness index of abdominal aorta higher than the 95% confidence limits of the normal data (p less than 0.05). Twenty-eight patients were outside the nomogram of common carotid artery (p less than 0.05). The mechanical properties of these elastic arteries provided sufficiently reliable information on changes caused by atherosclerosis.     

Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats

OBJECTIVES: We sought to elucidate how the local activation of matrix metalloproteinases (MMPs) is balanced by that of the endogenous tissue inhibitors of MMP (TIMPs) during left ventricular (LV) remodeling. BACKGROUND: Although it is known that the extracellular matrix (ECM) must be altered during LV remodeling, its local regulation has not been fully elucidated. METHODS: In Dahl salt-sensitive rats with hypertension, in which a stage of concentric, compensated left ventricular hypertrophy (LVH) at 11 weeks is followed by a distinct stage of congestive heart failure (CHF) with LV enlargement and dysfunction at 17 weeks, we determined protein and messenger ribonucleic acid (mRNA) levels of LV myocardial TIMP-2 and -4 and MMP-2, as well as their concomitant activities. RESULTS: No changes were found at the LVH stage. However, during the transition to CHF, TIMP-2 and -4 activities, protein and mRNA levels were all sharply increased. At the same time, the MMP-2 mRNA and protein levels and activities, as determined by gelatin zymography, as well as by an antibody capture assay, showed a substantial increase during the transition to CHF. The net MMP activities were closely related to increases in LV diameter (r = 0.763) and to systolic wall stress (r = 0.858) in vivo. CONCLUSIONS: Both TIMPs and MMP-2 remained inactive during hypertrophy, per se; they were activated during the transition to CHF. At this time, the activation of MMP-2 surpassed that of TIMPs, possibly resulting in ECM breakdown and progression of LV enlargement.     

Pericardial fluid as a new material for clinical heart research

This article will review the results of recent clinical studies relating to the pericardial fluid in patients with various heart diseases. In ischemic patients, several angiogenic growth factors are accumulated in a high concentration in pericardial fluid. These may contribute to the angiogenesis and arteriogenesis, which are self-protecting mechanisms of myocardial ischemia. In congestive heart failure, natriuretic peptides are released into the pericardial fluid in a higher concentration compared with plasma levels. This suggests that these peptides may act as autocrine and/or paracrine factors. Pericardial fluid from ischemic patients induces cell proliferation and apoptosis depending on the cell type. Intrapericardial drug administration may provide a reasonable therapeutic strategy for heart diseases. In conclusion, the analysis of pericardial fluid appears to be a logical approach for elucidation of the pathophysiology of the heart.     

Polysaccharide-coated liposomal amphotericin B for the treatment of murine pulmonary candidiasis.

Amylopectin-coated liposomal amphotericin B was investigated in a murine model of pulmonary candidiasis. The LD50 of amylopectin-coated liposomal amphotericin B in normal mice was more than 10.0 mg/kg, and that of conventional amphotericin B was 1.2 mg/kg. Amylopectin-coated liposomes showed twice the concentration in the lungs of conventional liposomes. Candida albicans was inoculated intratracheally into BALB/C mice. Twenty-four hours later, the number of Candida in the lungs of mice treated with amylopectin-coated liposomes was less than in those treated with conventional liposomes, and amylopectin-coated liposomes improved the survival rate of inoculated mice. Coating liposomes with amylopectin aids the targeting of amphotericin B to the lungs.     

Novel subgenotypes of hepatitis B virus genotypes C and D in Papua, Indonesia

Eight genotypes (A to H) and nine subtypes (adw2, adw4, ayw1, ayw2, ayw3, ayw4, adrq+, adrq-, and ayr) of hepatitis B virus (HBV) have been identified worldwide. They appear to be associated with geographical distribution, virological characteristics, and possibly clinical outcomes. We performed sequence analysis of part of the S gene and the entire precore/core gene of HBV isolates obtained from HBsAg-positive blood donors in Papua Province, Indonesia. Phylogenetic analysis of the S gene sequences revealed that 23 (85.2%) of the 27 HBV isolates tested belonged to genotype C (HBV/C) and 2 (7.4%) each to HBV/B and HBV/D. Interestingly, 19 (82.6%) of the 23 isolates of HBV/C clustered in a branch that was distinct from the previously reported subgenotypes C1 to C5 (HBV/C1 to HBV/C5). Similarly, two isolates of HBV/D clustered in a branch distinct from the reported subgenotypes HBV/D1 to HBV/D5. Phylogenetic analysis of the entire precore/core gene confirmed the consistent presence of the distinct branches in HBV/C and HBV/D. We therefore propose novel subgenotypes designated HBV/C6 and HBV/D6. The majority of HBV/C6 isolates in Papua had alanine at positions 159 and 177 (A159/A177) in the HBsAg. A159/A177 is different from the determinants for adrq+ (A159/V177), found throughout Asia, and adrq- (V159/A177), found in New Caledonia and Polynesia, possibly representing a unique antigenic group (provisionally referred to as adrq indeterminate). In conclusion, we have identified two novel HBV subgenotypes, HBV/C6 and HBV/D6, the first of which is the most prevalent subgenotype of HBV in Papua, Indonesia.