Systolic Posterior Wall Thickness Research Articles

Cornus officinalis Sieb. et Zucc. Alleviates Mitochondrial Abnormalities and Heart Failure through AMPK

Background: Traditional Chinese medicine (TCM) has clear advantages in stabilizing patients with heart failure (HF) and improving cardiac functions. Aims: This study aimed to investigate the role of Cornus officinalis Sieb. et Zucc. (Cor) in HF. Settings and Design: Rats with HF were treated with Cor or Cor with an adenosine monophosphate-activated protein kinase (AMPK) inhibitor, dorsomorphin dihydrochloride (Dor). Materials and Methods: The weight and echocardiography findings of the rats were examined. AMPK and p-AMPK expression levels were assessed using Western blots, mitochondrial changes were evaluated using transmission electron microscopy (TEM), and adenosine triphosphate (ATP) levels were detected in each group. Finally, the targets of Cor were analyzed using HERB ( http://herb.ac.cn ). Statistical Analysis Used: A Student’s t-test was used to compare two groups, and a one-way analysis of variance was performed for intergroup comparison. A p < 0.05 indicated that the difference was statistically significant. Results: Compared with that of the Sham group, the body weight of the Model group decreased; left ventricular end diastolic diameter (LVIDd) and left ventricular end systolic diameter (LVIDs) increased; and left ventricular end diastolic posterior wall thickness (LVPWd), left ventricular end systolic posterior wall thickness (LVPWs), left ventricular ejection fraction (EF), and stroke volume (SV) decreased. These effects were reversed by the Cor treatment. Western blot analysis indicated p-AMPK levels were higher in the Model group than those in the Sham group. After Cor treatment, p-AMPK levels increased but later decreased after treatment with Dor. In addition, myocardial mitochondrial abnormalities were reduced and ATP levels increased in the Cor group compared with the Model group, which were reversed by Dor. Lastly, Cor was found to target AMPK pathway-related genes. Conclusion: Cor exerts protective effects on HF by activating AMPK to improve mitochondrial function.

Contribution of Longitudinal and Circumferential Shortening to Stroke Volume and Ejection Fraction in Severe Aortic Stenosis

Background: Left ventricular (LV) stroke volume (SV) is ejected by a combination of longitudinal shortening (LS), circumferential shortening (CS) and ventricular twist. Longitudinal shortening is caused by the motion of the mitral annulus towards the apex, causing wall thickening (circumferential and radial shortening), and left ventricular cavity and SV reduction. The role of LS in aortic stenosis (AS) is not defined. Objective: The aim of this study was to analyze the LS and CS contribution to SV and left ventricular ejection fraction (LVEF) in severe AS. Methods: The study included 152 patients (70±12 years, 64 women) with severe AS (valve area <1 cm2 ) studied by cardiac Doppler echocardiography. The LS contribution to SV was evaluated by considering the base of the heart as a cylinder, with volume=base x height; the base was assumed as a circle with radius equal to (systolic septal thickness+systolic posterior wall thickness+end-systolic diameter)/2; and height, as an average of the mitral lateral, septal, anterior and inferior annulus systolic excursion. The CS contribution to SV was estimated as: SV - LS contribution to SV. Both contributions were expressed in absolute form and as SV percentages (% SV-LS and % SV-CS). Results: Longitudinal shortening contributed with approximately 2 thirds of SV (68±18 %) and CS with the rest. SV-LS correlated inversely with SV (r= - 0.45 p <0.001) and SV-CS had direct correlation (r=0.45 p <0.001). The % SV-LS contribution was greater in patients with LVEF < 50%. Percent SV-LS correlated inversely with relative wall thickness (RWT) (r=0.32, p < 0.01). Conclusion: The LS contribution to SV is greater than that of CS, and correlates inversely with SV. Percent SV-LS is higher in patients with LVEF <50%. The aforementioned findings could have implications when considering cut-off points for longitudinal function indices (strain) without considering LVEF and/or ventricular geometry

Effects of Carvedilol and Thyroid Hormones Co-administration on Apoptotic and Survival Proteins in the Heart After Acute Myocardial Infarction.

Cellular death and survival signaling plays a key role in the progress of adverse cardiac remodeling after acute myocardial infarction (AMI). Therapeutic strategies, such as co-treatment with beta-blocker carvedilol and thyroid hormones (THs), give rise to new approaches that can sustain the cellular homeostasis after AMI. Therefore, we sought to investigate the effects of carvedilol and TH co-administration on apoptosis and survival proteins and on cardiac remodeling after AMI. Male Wistar rats were distributed in 5 groups as follows: sham-operated group (SHAM), infarcted group (MI), infarcted plus carvedilol group (MI+C), infarcted plus TH group (MI+TH), and infarcted plus carvedilol and TH co-treatment group (MI+C+TH). Echocardiographic analysis was performed, and hearts were collected for western blot evaluation. The MI group presented systolic posterior wall thickness loss, an increase in the wall tension index, and an increase in atrial natriuretic peptide tissue levels than the SHAM group. However, in the MI+C+TH group, these parameters were equally to the SHAM group. Moreover, whereas the MI group showed Bax protein expression elevated in relation to the SHAM group, the MI+C+TH group presented Bax reduction and also Akt activation compared with the MI group. In addition, the MI+TH group revealed beta-1 adrenergic receptor (β1AR) upregulation compared with the MI and MI+C groups, whereas the MI+C+TH group presented lower levels of β1AR in relation to the SHAM and MI+TH groups. In conclusion, we suggest that carvedilol and TH co-administration may mediate its cardioprotective effects against adverse cardiac remodeling post-AMI through the Bax reduction, Akt activation, and β1AR decrease.

Effects of uncoupling protein 2 overexpression on myocardial mitochondrial dynamics in sepsis rats

To investigate the effects of uncoupling protein 2 (UCP2) overexpression on mitochondrial dynamics (mitochondrial division and fusion) of sepsis myocardial injury in rats. Forty male Sprague-Dawley (SD) rats were randomly divided into four groups (n = 10): sham operation group (Sham group) using normal saline instead of transfection and simulating cecal ligation and perforation (CLP); CLP group using normal saline instead of transfection, performing CLP to induce sepsis; adeno-associated virus (AAV) group using CLP after myocardial transfection with empty virus; UCP2 overexpression group (UCP2 group) CLP was performed 3 weeks after AAV-UCP2 (1×1015 vg/L, a total of 60 μL) myocardial transfection. The rats in each group were examined by echocardiography at 24 hours after the CLP, and then the rats were sacrificed immediately to harvest myocardial tissue. Myocardial ultrastructural changes were observed under the electron microscope, the expression of regulatory proteins related to myocardial mitochondrial dynamics [optic atrophy 1 (Opa1), dynamin-related protein 1 (Drp1) and fission 1 (Fis1)] were detected by Western Blot, and the level of mitochondrial adenosine triphosphate (ATP) production was detected by chemiluminescence. (1) The echocardiographic results showed that there was no significant difference in left ventricular mass (LVM) and stroke volume (SV). Compared with Sham group, left ventricular diastolic anterior wall thickness (LVAWd), left ventricular systolic anterior wall thickness (LVAWs), left ventricular diastolic posterior wall thickness (LVPWd), left ventricular systolic posterior wall thickness (LVPWs), left ventricular ejection fraction (LVEF) and left ventricular short axis shortening rate (LVFS) were significantly increased in CLP group and AAV group, while left ventricular systolic diameter (LVEDs), left ventricular diastolic diameter (LVEDd), left ventricular end-systolic volume (LVESV), and left ventricular end-diastolic volume (LVEDV) were significantly decreased. Compared with CLP group and AAV group, LVAWs, LVEF, LVFS were significantly decreased in UCP2 group, and LVEDs, LVEDV and LVESV were significantly increased [LVAWs (mm): 3.82±0.42 vs. 4.34±0.30, 4.44±0.12; LVEF: 0.921±0.038 vs. 0.979±0.019, 0.991±0.010; LVFS: (65.33±6.56)% vs. (80.11±8.23)%, (85.31±6.11)%; LVEDs (mm): 1.81±0.36 vs. 0.89±0.54, 0.60±0.17; LVEDV (μL): 137.09±50.05 vs. 89.72±53.04, 85.42±40.99; LVESV (μL): 10.48±4.59 vs. 2.48±3.52, 2.58±2.50, all P < 0.05]. (2) Electron microscope showed that the structure of myocardial fibers in the Sham group was clear and aligned with complete intervertebral disc and mitochondrial structure, no damage to mitochondrial membranes, and tight arrangement of cristae. In CLP group and AAV group, muscle fiber breakage, sarcoplasmic reticulum expansion, severe mitochondrial swelling and even cristage structure disorder were observed. In the UCP2 group, only myocardial fiber edema was observed, and the muscle fiber structure was more complete than that of Sham group and AAV group. The mitochondria were slightly swollen and the cristae were intact. (3) Western Blot showed that there was no significant difference in the expression of Opa1 and Fis1 in the four groups. The expression of Drp1 in CLP group and AAV group were significantly higher than that in Sham group. The expression of Drp1 in UCP2 group was significantly lower than that in CLP group and AAV group (Drp1/β-actin: 1.01±0.03 vs. 1.39±0.03, 1.49±0.03, both P < 0.05). (4) The results of immunofluorescence showed that the ATP content of CLP group and AAV group were significantly lower than that of Sham group; the ATP content of UCP2 group was significantly higher than that of CLP group and AAV group (μmol/L: 1.99±0.15 vs. 1.10±0.17, 1.13±0.19, both P < 0.05). UCP2 overexpression can significantly improve the systemic systolic function of myocardium in sepsis rats, protect myocardial mitochondrial ultrastructure, inhibit mitochondrial division, and improve mitochondrial ATP synthesis.

Carbonic anhydrase II/sodium-proton exchanger 1 metabolon complex in cardiomyopathy of ob−/− type 2 diabetic mice

Heart failure is the leading cause of death among diabetic people. Cellular and molecular entities leading to diabetic cardiomyopathy are, however, poorly understood. Coupling of cardiac carbonic anhydrase II (CAII) and Na+/H+ exchanger 1 (NHE1) to form a transport metabolon was analyzed in obese type 2 diabetic mice (ob−/−) and control heterozygous littermates (ob+/−). Echocardiography showed elevated systolic interventricular septum thickness and systolic posterior wall thickness in ob−/− mice at 9 and 16 weeks. ob−/− mice showed increased left ventricular (LV) weight/tibia length ratio and increased cardiomyocyte cross sectional area as compared to controls, indicating cardiac hypertrophy. Immunoblot analysis showed increased CAII expression in LV samples of ob−/−vs. ob+/− mice, and augmented Ser703 phosphorylation on NHE1 in ob−/− hearts. Reciprocal co-immunoprecipitation analysis showed strong association of CAII and NHE1 in LV samples of ob−/− mice. NHE1-dependent rate of intracellular pH (pHi) normalization after transient acid loading of isolated cardiomyocytes was higher in ob−/− mice vs. ob+/−. NHE transport activity was also augmented in cultured H9C2 rat cardiomyoblasts treated with high glucose/high palmitate, and it was normalized after CA inhibition. We conclude that the NHE1/CAII metabolon complex is exacerbated in diabetic cardiomyopathy of ob−/− mice, which may lead to perturbation of pHi and [Na+] and [Ca2+] handling in these diseased hearts.

Renal sympathetic denervation alleviates myocardial fibrosis following isoproterenol-induced heart failure.

The aim of the present study was to determine if renal sympathetic denervation (RSD) may alleviate isoproterenol-induced left ventricle remodeling, and to identify the underlying mechanism. A total of 70 rats were randomly divided into control (n=15), sham operation (n=15), heart failure (HF) with sham operation (HF + sham; n=20) and HF with treatment (HF + RSD; n=20) groups. The HF model was established by subcutaneous injection of isoproterenol; six weeks later, 1eft ventricular internal diameter at end-systole (LVIDs), left ventricular systolic posterior wall thickness (LVPWs), 1eft ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were measured. Plasma norepinephrine (NE), angiotensin II (Ang II) and aldosterone (ALD) levels were measured by ELISA. Myocardial collagen volume fraction (CVF) was determined by Masson's staining. Reverse transcription-quantitative polymerase chain reaction was used to determine the mRNA expression levels of ventricular transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF) and microRNAs (miRs), including miR-29b, miR-30c and miR-133a. The results demonstrated that LVIDs and LVPWs in the HF + RSD group were significantly decreased compared with the HF + sham group. By contrast, LVFS and LVEF in the HF + RSD group were significantly increased compared with the HF + sham group. RSD significantly reduced the levels of plasma NE, Ang II and ALD. CVF in the HF + RSD group was reduced by 38.1% compared with the HF + sham group. Expression levels of TGF-β and CTGF were decreased, whereas those of miR-29b, miR-30c and miR-133a were increased, in the HF + RSD group compared with the HF + sham group. These results indicated that RSD alleviates isoproterenol-induced left ventricle remodeling potentially via downregulation of TGF-β/CTGF and upregulation of miR-29b, miR-30c and miR-133a. RSD may therefore be an effective non-drug therapy for the treatment of heart failure.

Glucocorticoid treatment prevents progressive myocardial dysfunction resulting from experimental coronary microembolization.

The frequency and importance of microembolization in patients with acute coronary syndromes and during coronary interventions have recently been appreciated. Experimental microembolization induces immediate ischemic dysfunction, which recovers within minutes. Subsequently, progressive contractile dysfunction develops over several hours and is not associated with reduced regional myocardial blood flow (perfusion-contraction mismatch) but rather with a local inflammatory reaction. We have now studied the effect of antiinflammatory glucocorticoid treatment on this progressive contractile dysfunction. Microembolization was induced by injecting microspheres (42-microm diameter) into the left circumflex coronary artery. Anesthetized dogs were followed up for 8 hours and received placebo (n=7) or methylprednisolone 30 mg/kg IV either 30 minutes before (n=7) or 30 minutes after (n=5) microembolization. In addition, chronically instrumented dogs received either placebo (n=4) or methylprednisolone (n=4) 30 minutes after microembolization and were followed up for 1 week. In acute placebo dogs, posterior systolic wall thickening was decreased from 20.0+/-2.1% (mean+/-SEM) at baseline to 5.8+/-0.6% at 8 hours after microembolization. Methylprednisolone prevented the progressive myocardial dysfunction. Increased leukocyte infiltration in the embolized myocardium was prevented only when methylprednisolone was given before microembolization. In chronic placebo dogs, progressive dysfunction recovered from 5.0+/-0.7% at 4 to 6 hours after microembolization back to baseline (19.1+/-1.6%) within 5 days. Again, methylprednisolone prevented the progressive myocardial dysfunction. Methylprednisolone, even when given after microembolization, prevents progressive contractile dysfunction.

Myocardial dysfunction with coronary microembolization: signal transduction through a sequence of nitric oxide, tumor necrosis factor-alpha, and sphingosine.

Coronary microembolization results in progressive myocardial dysfunction, with causal involvement of tumor necrosis factor-alpha (TNF-alpha). TNF-alpha uses a signal transduction involving nitric oxide (NO) and/or sphingosine. Therefore, we induced coronary microembolization in anesthetized dogs and studied the role and sequence of NO, TNF-alpha, and sphingosine for the evolving contractile dysfunction. Four sham-operated dogs served as controls (group 1). Eleven dogs received placebo (group 2), 6 dogs received the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, group 3), and 6 dogs received the ceramidase inhibitor N-oleoylethanolamine (NOE, group 4) before microembolization was induced by infusion of 3000 microspheres (42-microm diameter) per milliliter inflow into the left circumflex coronary artery. Posterior systolic wall thickening (PWT) remained unchanged in group 1 but decreased progressively in group 2 from 20.6+/-4.9% (mean+/-SD) at baseline to 4.1+/-3.7% at 8 hours after microembolization. Leukocyte count, TNF-alpha, and sphingosine contents were increased in the microembolized posterior myocardium. In group 3, PWT remained unchanged (20.3+/-2.6% at baseline) with intracoronary administration of L-NAME (20.8+/-3.4%) and 17.7+/-2.3% at 8 hours after microembolization; TNF-alpha and sphingosine contents were not increased. In group 4, PWT also remained unchanged (20.7+/-4.6% at baseline) with intravenous administration of NOE (19.5+/-5.7%) and 16.4+/-6.3% at 8 hours after microembolization; TNF-alpha, but not sphingosine content, was increased. In all groups, systemic hemodynamics, anterior systolic wall thickening, and regional myocardial blood flow remained unchanged throughout the protocols. A signal transduction cascade of NO, TNF-alpha, and sphingosine is causally involved in the coronary microembolization-induced progressive contractile dysfunction.

Coronary Microembolization: the Role of TNF- α in Contractile Dysfunction

Coronary microembolization is a frequent complication of atherosclerotic plaque rupture in acute coronary syndromes and during coronary interventions. Experimental coronary microembolization results in progressive contractile dysfunction associated with a local inflammation. We studied the causal role of tumor necrosis factor-alpha (TNF- α) in the progressive contractile dysfunction resulting from coronary microembolization. Anesthetized dogs were subjected to either coronary microembolization with infusion of 3.000 microspheres (42 μ m diameter) per ml coronary inflow into the left circumflex coronary artery (n=9), or to intracoronary infusion of recombinant human TNF- α without microembolization (n=4), or to treatment with anti-murine TNF- α sheep antibodies prior to microembolization (n=4). Posterior systolic wall thickening (PWT; sonomicrometry) decreased from 21.1±5.3% (s.d.) at baseline to 5.5±2.2% (P<0.05) at 8 h after microembolization. Infarct size (1.8±1.9%; TTC and histology) and the amount of apoptosis (<0.1%; TUNEL and DNA-laddering) were small. TNF- α at the protein level (WEHI cytolytic assay) was increased and localized to leukocytes (immunostaining), which were increased in number (quantitative histology). In situ hybridization for TNF- α mRNA identified viable cardiomyocytes surrounding the microinfarcts as the major source of TNF- α. Supporting the role of TNF- α, infusion of TNF- α without microembolization decreased PWT from 27.3±6.9% at baseline to 10.1±4.9% after 8 h (P<0.05); in contrast, in the presence of TNF- α antibodies, microembolization no longer reduced PWT (19.3±7.0% at baseline v 16.9±5.0% at 8 h). In conclusion, TNF- α is the mediator responsible for the profound contractile dysfunction following coronary microembolization.

Perfusion-contraction mismatch with coronary microvascular obstruction: role of inflammation.

A close relationship exists between regional myocardial blood flow (RMBF) and function during acute coronary inflow restriction (perfusion-contraction matching). However, the relationship of flow and function during coronary microvascular obstruction is unknown. In 12 anesthetized dogs, the left circumflex coronary artery was perfused from an extracorporeal circuit. After control measurements, 3,000 microspheres (42 micrometer diameter) per milliliter per minute inflow were injected to cause a microembolism (ME, n = 6). With unchanged systemic hemodynamics and RMBF, posterior systolic wall thickening (PWT) decreased from 19.8 +/- 1.9% SD at control to 13.3 +/- 4.0, 10.3 +/- 3.8, and 6.9 +/- 4.7% (P < 0.05 vs. control) at 1, 4, and 8 h, respectively. For comparison, inflow was progressively reduced to match PWT to that of the ME group at 1, 4, and 8 h (stenosis, STE, n = 6). RMBF in the STE group was reduced in proportion to PWT. Infarct size was not different among groups (6.5 +/- 4.5 vs. 3.4 +/- 3.2%). However, the number of leukocytes infiltrating the area at risk was significantly greater in the ME group than in the STE group. Coronary microembolization results in perfusion-contraction mismatch and is associated with an inflammatory response.

Impact of a Low-Dose Reserpine/Thiazide Combination on Left Ventricular Hypertrophy Assessed with Magnetic Resonance Tomography and Echocardiography

This was the first study to investigate the capability of a low-dose combination of reserpine and the thiazide clopamide to induce regression of left ventricular hypertrophy (LVH). 20 Caucasian patients (12 men and 8 women, mean age 59 +-13 years) with arterial hypertension and LVH were treated in an open, intraindividual comparison with a fixed combination of reserpine O.1mg and clopamide 5mg once daily. At baseline, after 12 and 24 weeks of treatment, wall thickness of the patients’ left ventricles and left ventricular function were assessed by ECG-triggered magnetic resonance tomography (MRT) and by echocardiography. The medication was well tolerated. In all patients, diastolic blood pressure was normalised. During the course of therapy, mean systolic/diastolic blood pressure showed a marked decline by −21.7/−17.2mm Hg (2p < 0.0001). Heart rate was significantly lowered by 3.7 beats per minute. Mean end-diastolic interventricular septum thickness measured by MRT was reduced from 11.8mm by 15% (2p < 0.00001) after week 24, systolic posterior wall thickness by 10% (2p = 0.002) and diastolic posterior wall thickness by 20% (2p = 0.0001). Left ventricular end-diastolic and end-systolic inner ventricular diameters quantified by MRT showed no significant changes after 12 and 24 weeks of treatment. Ejection fraction increased from 64% by 8% after 24 weeks (2p < 0.0005). These findings were confirmed by echocardiography. However, there was no significant correlation between the parameters derived from the two methods.

Regional myocardial effects of intracoronary bradykinin in conscious dogs

This study examined in conscious dogs, the coronary and regional myocardial effects of bradykinin (BK) administered by intracoronary route and their modulation by an angiotensin-converting enzyme inhibitor. Eleven dogs were chronically instrumented with a left ventricular (LV) micromanometer, a circumflex coronary catheter, a flow probe, and ultrasonic crystals in the LV posterior wall. In the absence of systemic hemodynamic changes, BK (0.1-10 ng/kg i.c.) produced dose-dependent increases in coronary blood flow velocity (CBFV) and in LV posterior end-diastolic wall thickness (EDWT) but produced no change in LV regional myocardial function as assessed by LV posterior systolic wall thickening. The increases in LV EDWT and CBFV were linearly correlated. The BK B2 antagonist (HOE 140) abolished the effects of BK. Intracoronary enalaprilat (0.75 mg) extended the duration of the effect of BK on CBFV without modification of peak responses and induced a further increase in LV posterior EDWT but no change in LV regional myocardial function. Thus, in conscious dogs, the vasodilator effect of intracoronary BK alone or modulated by enalaprilat is not associated with changes in LV regional myocardial function.

1031-38 Beneficial Effects of Ramipril in a Model of Isoproterenol-induced Heart Failure in the Rat

To establish an experimental model of chronic heart failure, we assessed the morphologic, hemodynamic and neurohumoral effects of a single large dose for isoproterenol (ISO: 150 mg/kg BW s.c.). Two weeks after ISO-application 45 ISO- and 30 control-rats were examined. In addition, we investigated the effects of chronic treatment with ramipril (RAM: 10 mg/KG/d, n = 20). Echocardiography of ISO- and control-rats was performed in anesthetized rats to measure left ventricular (LV) mass and LV-enddiastolic dimension. An increase of LV-mass (LV diastolic posterior wall thickness: 2.8 ± 0.2 vs. 1.9 ± 0.3 mm, LV systolic posterior wall thickness: 4.3 ± 0.4 vs. 3.6 ± 0.3 mm; p &lt; 0.01) and LV enddiastolic dimension (6.9 ± 0.6 vs. 4.9 ± 0.3 mm p &lt; 0.01) was displayed. RAM-treated animals showed a highly significant decrease of LV mass and LV-enddiastolic dimension (p &lt; 0.001). Heart rate was increased in the ISO-group (p &lt; 0.005) compared to RAM- and control-rats (p &lt; 0.005). Central venous pressure was significantly increased in the ISO-group (5.8 ± 2.3; vs 2.3 ± 0.6 mmHG; p &lt; 0.01) and decreased to normal ranges in RAMrats. Mean arterial pressure was decreased in ISO- (121.3 ± 14.8 mmHg) and RAM-rats, (95 ± 3 mmHG) vs controls (132.4 ± 19.5 mmHG)(p &lt; 0.05). Mean renal blood flow between ISO-treated and control group was not significantly different, in contrast the mean blood flow in the abdominal aorta was decreased in the ISO-group (p &lt; 0.05). Cardiac ACE-activity (p &lt; 0.01), circulating atrial natriuretic peptide, renin- and aldosterone-levels were significantly higher in the ISO-treated group as compared tothe control group (p &lt; 0.05). ISO-treated hearts displayed morphological alterations such as myocyte necrosis, cellular reaction and fibrosis. RAM-treated hearts revealed the same infarct-like lesions but at a lower grade. In summary, a highly reproducible model of chronic heart failure was established. Hemodynamic measurements displayed a typical characteristic for advanced heart failure in the ISO-group. Blockade of the renin-angiotensinsystem (RAS) attenuated the observed changes indicating that the RAS may be involved in the development of catecholamine-induced congestive heart failure.

Changes in left ventricular size, wall thickness, and function in anemic patients treated with recombinant human erythropoietin

Left ventricular size and function were evaluated in 15 anemic chronic hemodialysis patients before and after the administration of recombinant human erythropoietin (rHuEPO). All patients were studied with two-dimensional and M-mode echocardiographic examinations before the initiation of rHuEPO (T1) and at 28 ± 7 weeks of rHuEPO therapy (T2). The two-dimensional targeted M-mode echocardiographic measurements obtained were: end-diastolic dimension (EDD); end-systolic dimension (ESD); stroke dimension (SD); dimensional shortening ( SD EDD ); systolic posterior wall thickness (PWs); diastolic posterior and interventricular septal thickness; end-systolic wall stress (ESWS); and left ventricular mass. Mean hematocrit in these patients increased almost 50%. The EDD decreased from a mean value (±SEM) of 6.41 ± 0.33 to 4.93 ± 0.21 cm ( p < 0.05). ESD decreased from a mean value of 4.16 ± 1.2 to 2.77 ± 0.06 cm ( p < 0.05). The calculated mean SD decreased slightly but not significantly from 2.21 ± 0.69 to 2.19 ± 0.60 cm. The calculated SD EDD increased from a mean 0.35 ± 0.09 to 0.44 ± 0.07 ( p < 0.05). ESWS fell from 59.2 ± 12.2 to 37.6 ± 9.3 gm/cm 2 ( p < 0.01), and left ventricular mass fell ( p < 0.05) from 347 ± 15.2 to 227 ± 59 gm. There was no significant difference in resting heart rate or systolic blood pressure between T1 and T2. The increase in dimension shortening reflects afterload reduction, as indicated by the fall in end-systolic wall stress. A primary improvement in myocardial contractile function as a consequence of an rHuEPO-mediated increase in red blood cell mass, may also play a role.

The Calcium Antagonist Nisoldipine Improves the Functional Recovery of Reperfused Myocardium Only When Given Before Ischemia

It is unclear whether the protective effects of calcium antagonists on reperfused myocardium are secondary to increased blood flow during ischemia (anti-ischemic action) or reperfusion (Gregg phenomenon), or are mediated through altered calcium kinetics in ischemic or reperfused myocardium. To study the effect of the calcium antagonist nisoldipine on the functional recovery of stunned myocardium, 32 enflurane-anesthetized dogs were subjected to 15 min of occlusion of the left circumflex coronary artery and subsequent 4 h of reperfusion. Eight dogs served as placebo controls (group I), and eight dogs received nisoldipine (5 micrograms/kg i.v.) before occlusion (group II), eight dogs at 10 min of occlusion (group III), and eight dogs at 4 min of reperfusion (group IV). The mean aortic pressure was kept constant with an intra-aortic balloon, and the heart rate did not change. In group I, posterior systolic wall thickening (WT, sonomicrometry) decreased from 18.3 +/- 2.4% (mean +/- SD) during control conditions to -3.0 +/- 2.0% at 13 min of occlusion. At 10 min of reperfusion, WT was 1.7 +/- 3.9% and did not recover further (-1.2 +/- 3.7% at 4 h of reperfusion). Posterior transmural blood flow (BF, colored microspheres) decreased from 1.42 +/- 0.43 ml/min/g during control conditions to 0.26 +/- 0.08 ml/min/g at 13 min of occlusion. BF was 2.07 +/- 0.93 ml/min/g at 10 min and 0.95 +/- 0.31 ml/min/g at 4 h of reperfusion. In groups III and IV, the WT and BF were not different from those in group I throughout the experimental protocol. In group II, however, the WT, although similar to the WT of group I before and during ischemia, recovered from 2.7 +/- 4.3% at 10 min to 11.8 +/- 6.0% at 4 h of reperfusion (p less than 0.05 vs. groups I, III, and IV). The BF in group II decreased from 2.52 +/- 0.66 ml/min/g after administration of nisoldipine to 0.22 +/- 0.14 ml/min g at 13 min of occlusion. The BF was 1.31 +/- 0.51 ml/min/g at 10 min and 1.33 +/- 0.43 ml/min/g at 4 h of reperfusion. Nisoldipine exerts no beneficial effect when given immediately before or after the onset of reperfusion. The improved functional recovery of reperfused myocardium in dogs pretreated with nisoldipine cannot be attributed to an increased regional myocardial blood flow during ischemia or reperfusion. The better myocardial recovery, therefore, appears to be related to an attenuated myocardial calcium overload during the first few minutes of ischemia.

Postextrasystolic potentiation does not distinguish ischaemic from stunned myocardium

Myocardial function is impaired by ischaemia, and it remains depressed during reperfusion following short periods of ischaemia (stunned myocardium). We tested whether ischaemic and reperfusion dysfunction, in particular the time course of its recovery, can be distinguished by postextrasystolic potentiation (PESP). In eight open-chest dogs, posterior systolic wall thickening (sonomicrometry) was reduced by graded occlusion of the left circumflex coronary artery (LCX) from 17.4 +/- 6.8% (SD) during control conditions to 10.7 +/- 1.3% (mild ischaemic dysfunction), 7.2 +/- 2.3% (moderate ischaemic dysfunction), 3.6 +/- 1.4% (severe ischaemic dysfunction), and -4.4 +/- 3.6% (complete coronary occlusion). Extrasystoles with constant prematurity and a fully compensated postextrasystolic interval were induced after at least 4 min steady-state ischaemia. After each ischaemic period full recovery of posterior systolic wall thickening was assured. During 8 h of reperfusion following a 15-min LCX occlusion, extrasystoles were induced when posterior systolic wall thickening was comparable to one degree of the preceding ischaemic dysfunction. The increases in posterior systolic wall thickening induced by PESP were 10.5 +/- 5.8% during control conditions, during ischaemia they were 11.5 +/- 3.5% (mild dysfunction), 12.3 +/- 4.6% (moderate dysfunction), 12.6 +/- 4.1% (severe dysfunction) and 10.4 +/- 4.4% (complete coronary occlusion), and during reperfusion they were 12.8 +/- 8.2% (severe dysfunction), 13.0 +/- 9.7% (moderate dysfunction) and 10.7 +/- 2.2% (mild dysfunction).(ABSTRACT TRUNCATED AT 250 WORDS)

BRL 34915 Ameliorates Oxygen Supply in Ischemic Myocardium by a Simultaneous Enhancement of Coronary Blood Flow and a Reduction of Myocardial function

In the presence of stenotic coronary arteries, oxygen supply in the poststenotic myocardium is reduced. A counterbalancing poststenotic metabolic vasodilatation is attenuated up to 30% by an alpha 2-adrenoceptor-mediated vasoconstrictor tone. In six open-chest dogs, we determined whether cumulative intracoronary doses (1, 4, and 14 micrograms) BRL 34915, a vasodilator with additional dose-dependent cardiodepressant properties, could enhance coronary blood flow and simultaneously reduce myocardial function in poststenotic myocardium, thereby increasing oxygen supply and decreasing oxygen demand. BRL 34915 increased mean left circumflex coronary blood flow [ml/(min.100 g)] dose-dependently from 59 +/- 12.4 (mean +/- SEM) (no BRL) to 227 +/- 43.9 (14 micrograms BRL) (p less than 0.05) in intact coronary arteries and from 36 +/- 7.2 (no BRL) to 74 +/- 13.2 (14 micrograms BRL) (p less than 0.05) distal to a severe stenosis, respectively. In contrast, posterior systolic wall thickening (%), was significantly decreased only by 14 micrograms BRL from 9.7 +/- 1.82 (no BRL) to 7.8 +/- 2.07 (14 micrograms BRL) (p less than 0.05) when coronary arteries were intact and from 8.7 +/- 2.02 (no BRL) to 4.1 +/- 1.39 (14 micrograms BRL) (p less than 0.05) in poststenotic myocardium. We conclude that BRL 34915 can both enhance coronary blood flow in the poststenotic myocardium and decrease myocardial function simultaneously, potentially narrowing the gap between oxygen supply and demand.

Felodipine prevents the poststenotic myocardial ischemia induced by alpha2-adrenergic coronary constriction

Alpha 2-adrenoceptor-mediated coronary constriction contributes to the precipitation of myocardial ischemia during sympathetic activation. Felodipine is a novel dihydropyridine calcium-channel antagonist with vascular selectivity. In this study, the effect of felodipine on alpha 2-adrenoceptor-mediated poststenotic coronary constriction was investigated. In ten open-chest dogs, the selective alpha 2-adrenoceptor agonist BHT 933 (200 micrograms IC) was infused before and after production of a severe stenosis on the left circumflex coronary artery. BHT 933 increased calculated resistance of the intact left circumflex coronary artery from 1.16 +/- 0.30 (SD) to 2.00 +/- 0.70 mmHg*min*100 g/ml (p less than 0.05) without changing posterior systolic wall thickening (sonomicrometry) (14.2 +/- 2.8% vs. 14.1 +/- 2.7%). In the presence of a severe stenosis, BHT 933 increased poststenotic coronary resistance from 1.59 +/- 0.54 to 2.88 +/- 1.16 mmHg*min*100 g/ml (p less than 0.05) and decreased posterior systolic wall thickening from 11.9 +/- 2.7% to 8.2 +/- 3.1% (p less than 0.05). In contrast, after intravenous pretreatment with felodipine (4 micrograms/kg), intracoronary infusion of BHT 933 did not change coronary resistance (1.69 +/- 0.61 vs. 1.61 +/- 0.64 mmHg*min*100 g/ml) and posterior systolic wall thickening (12.1 +/- 3.0% vs. 12.6 +/- 2.9%). In conclusion, felodipine prevents alpha 2-adrenoceptor-mediated coronary constriction and ischemic regional myocardial dysfunction distal to a severe coronary stenosis.