Adjustable Model of Chronic Left Ventricular Dysfunction

Background. As an adjunct to the development of skeletal muscle-powered left ventricular assist devices, an adjustable model of chronic left ventricular failure was developed.

Methods. Implantation of a left ventricular balloon to induce heart failure was accomplished via left thoracotomy. Upon recovery, left ventricular failure was simulated by manipulation of left ventricular balloon volume to chronically raise left atrial pressure.

Results. Left atrial pressure increased from a baseline of 9.3 ± 0.7 mm Hg to 18.5 ± 1.2 mm Hg, 20.2 ± 1.8 mm Hg, and 26.0 ± 1.2 mm Hg by the 2nd, 6th, and 10th postoperative week, respectively. Cardiac index declined from a baseline of 4.4 ± 0.3 L · min⁻¹ · m⁻², reaching stability by the 8th postoperative week at 3.0 ± 0.4 L · min⁻¹ · m⁻². Stroke volume index declined from 1.12 ± 0.1 mL · kg⁻¹ · beat⁻¹ to 0.60 ± 0.1 mL · kg⁻¹ · beat⁻¹ by the 10th postoperative week. Mean survival was 75 ± 7 days. Causes of death included left ventricular failure, thromboembolism, and euthanasia.

Conclusions. This method of simulating chronic left ventricular dysfunction proved to be stable and adjustable and has been useful in the development of ventricular assist systems.     

Effect of Low-Dose Positive Inotropic Drugs on Human Internal Mammary Artery Flow

Background. Dobutamine (a β-receptor agonist), enoximone (a type III selective phosphodiesterase inhibitor), and epinephrine (an - and β-mimetic) frequently are used in the perioperative management of patients undergoing coronary artery bypass grafting.

Methods. We performed a double-blind clinical study to compare the effects on internal mammary artery free flow of low doses of these three positive inotropic drugs. Thirty patients in whom the left internal mammary artery was used for coronary artery bypass grafting were randomized into three groups. Internal mammary artery free flow and hemodynamic measurements were evaluated before and 10 minutes after the intravenous infusion of dobutamine (3 μg · kg⁻¹ · min⁻¹), enoximone (200 μg/kg), or epinephrine (0.05 μg · kg⁻¹ · min⁻¹).

Results. A significant increase in free flow occurred only in the dobutamine group (33 ± 7.5 and 42.2 ± 7.9 mL/min before and after drug infusion, respectively; p = 0.013). Comparison of the increase in flow between the groups, however, showed no difference. These drugs, at doses designed to produce a positive inotropic effect, caused little increase in the free flow of the internal mammary artery.

Conclusions. The use of dobutamine, enoximone, and epinephrine as low-dose positive inotropic treatments in the perioperative and postoperative periods of coronary artery bypass grafting should depend on their positive inotropic effects rather than their vasodilative effects on the arterial grafts.     

Clinical evaluation of leukocyte-depleted blood cardioplegia for pediatric open heart operation

Background. Blood cardioplegia (BCP) is widely used for myocardial protection during open heart operation. However, BCP may have a chance to induce neutrophil-mediated myocardial injury during aortic cross-clamping. We clinically evaluated the myocardial protective effect of leukocyte-depleted blood cardioplegia (LDBCP) for initial and intermittent BCP administration in pediatric patients.

Methods. Fifty patients undergoing open heart operation for congenital heart disease between January 1997 and March 1999 were reviewed. Twenty-five were administered LDBCP for myocardial protection during ischemic periods (LDBCP group), and the remaining 25 were given BCP without leukocyte depletion (BCP group).

Results. The difference in plasma concentrations of malondialdehyde between coronary sinus effluent blood and arterial blood just after reperfusion in the LDBCP group (1.68 ± 0.56 μmol/L) was significantly lower than that in the BCP group (2.35 ± 0.62 μmol/L; p < 0.01). The LDBCP group showed significantly lower plasma concentrations of human heart fatty acid-binding protein at 50 minutes after reperfusion (LDBCP group, 103.5 ± 38.7 IU/L; BCP group, 144.8 ± 48.8 IU/L; p < 0.01) and the peak value of creatine kinase-MB during the first 24 postoperative hours (LDBCP group, 17.0 ± 8.5 IU/L; BCP group, 26.0 ± 11.6 IU/L; p < 0.01) than did the BCP group. The maximum dose of catecholamine was significantly smaller in the LDBCP group (LDBCP group, 3.20 ± 2.18 μg · kg⁻¹ · min⁻¹; BCP group, 5.60 ± 2.83 μg · kg⁻¹· min⁻¹; p < 0.01).

Conclusions. These results suggest the usefulness of LDBCP for protection from the myocardial injury that can be induced by BCP administration during aortic cross-clamping.     

Update 2001: Right latissimus dorsi cardiomyoplasty augments left ventricular systolic performance

As Originally Published in 1993: Right Latissimus Dorsi Cardiomyoplasty Augments Left Ventricular Systolic Performance by Stephen E. Park, MD, Brian L. Cmolik, MD, Robert R. Lazzara, MD, Dennis R. Trumble, MS, and James A. Magovern, MD. Department of Surgery, Allegheny General Hospital, Surgical Research, Allegheny-Singer Research Institute, and Allegheny Campus, The Medical College of Pennsylvania, Pittsburgh, Pennsylvania, USA

We hypothesized that the right latissimus dorsi cardiomyoplasty augments left ventricular performance. Five dogs underwent staged right latissimus dorsi cardiomyoplasty. Ventricular function was studied 1 to 3 weeks later. Left ventricular pressure was measured with a micromanometer and left ventricular dimensions with piezoelectric crystals. Inferior vena caval occlusion was used to vary preload. Pressure-volume data were collected with the muscle unstimulated and stimulated at 1:2 and 1:1 muscle/heart ratios. The end-systolic pressure-volume relation (mm Hg/mL), stroke work, preload recruitable stroke work, left ventricular end-diastolic volume, and the diastolic relaxation constant were calculated and expressed as mean ± standard deviation. Stimulated beats at a 1:2 ratio showed an increase in stroke work of 42.1% (978 ± 381 to 1,390 ± 449 g · cm; p < 0.01) and preload recruitable stroke work of 28.8% (59.4 ± 20.7 to 76.6 ± 11.0 g · cm/cm³; p = 0.05) compared with the unstimulated beats. With the stimulator on at 1:1, smaller changes occurred: stroke work increased 9% (1,167 ± 390 to 1,273 ± 363 g · cm; not significant) and preload recruitable stroke work increased 27% (63.9 ± 22.7 to 80.9 ± 23.1 g · cm/cm³; p = 0.05). There were no significant changes in the end-systolic pressure-volume relation. The diastolic relaxation constant did not change at 1:1 (36 ± 9.7 to 37 ± 6.4 ms; not significant) or 1:2 (36 ± 9.3 to 39 ± 8.2 ms; not significant). Left ventricular end-diastolic volume was unchanged at 1:1 (34 ± 10.7 to 32 ± 10.3 mL) and at 1:2 (31 ± 9.0 to 32 ± 8.7 mL). Right unconditioned latissimus dorsi cardiomyoplasty in anesthetized dogs with normal hearts resulted in enhanced systolic work and contractility with no change in diastolic relaxation at stimulation rates of 1:2 and 1:1.     

Prevention of Reperfusion Injury by Inhaled Nitric Oxide in Lungs Harvested From Non-Heart-Beating Donors

Background. In lung transplantation using non-heart-beating donors (NHBD), the postmortem period of warm ischemia exacerbates lung ischemia-reperfusion injury. We hypothesized that inhaled nitric oxide (NO) would reduce ischemia-reperfusion injury, and thus ameliorate the viability of the lung graft.

Methods. A blood-perfused, isolated rat lung model was used. Lungs were flushed and harvested from non-heart-beating donors after 30 minutes of in situ warm ischemia. The lung was then stored for 2 hours at 4°C. Inhaled NO at 30 ppm was given either during the period of warm ischemia, during reperfusion, or during both periods. Lung ischemia-reperfusion injury was assessed after 1 hour of reperfusion by measuring pulmonary vascular resistance, coefficient of filtration, wet-to-dry lung weight ratio, and myeloperoxidase activity.

Results. A severe IR injury occurred in lungs undergoing ischemia and reperfusion without NO as evidenced by high values of pulmonary vascular resistance (6.83 ± 0.36 mm Hg · mL⁻¹ · min⁻¹), coefficient of filtration (3.02 ± 0.35 mL · min⁻¹ · cm H₂O⁻¹ · 100 g⁻¹), and wet-to-dry lung weight ratio (8.07 ± 0.45). Lower values (respectively, 3.31 ± 0.44 mm Hg · mL⁻¹ · min⁻¹, 1.49 ± 0.34 mL · min⁻¹ · cm H₂O⁻¹ · 100 g⁻¹, and 7.44 ± 0.43) were observed when lungs were ventilated with NO during ischemia. Lung function was further improved when NO was given during reperfusion only. All measured variables, including myeloperoxidase activity were significantly improved when NO was given during both ischemia and reperfusion. Myeloperoxidase activity was significantly correlated with coefficient of filtration (r = 0.465; p < 0.05).

Conclusions. These data suggest that inhaled NO significantly reduces ischemia-reperfusion injury in lungs harvested from non-heart-beating donors. This effect might be mediated by inhibition of neutrophil sequestration in the reperfused lung.     

Preconditioning: myocardial function and energetics during coronary hypoperfusion and reperfusion

Background. Ischemic preconditioning (IP) is gaining more acceptance as a protective method in beating heart surgery. Yet it remains controversial whether preconditioning can attenuate myocardial dysfunction during reperfusion after severe coronary hypoperfusion. We examined this issue and also the issue of whether this protection is mediated by adenosine A₁ receptors.

Methods. In isolated, blood-perfused rabbit hearts, the effects of IP (3 minutes of no flow ischemia and 8 minutes of reperfusion) during 30 minutes of coronary hypoperfusion and 60 minutes of reperfusion were investigated. In two groups (n = 8 each) with and without (control group) preconditioning, ventricular function was assessed by load-insensitive measures: slope of the end-systolic pressure–volume relation (E_max), slope of the stroke work/end-diastolic volume relation (M_w), and end-diastolic pressure–volume relation. External efficiency was calculated, and contractile efficiency was assessed using the reciprocal of the myocardial oxygen consumption–pressure–volume area relationship. To investigate the possible role of adenosine, the adenosine A₁ receptor antagonist DPCPX (2.5 μmol/L) was administered before preconditioning in a third group (n = 7).

Results. The effects of hypoperfusion on systolic function, diastolic function (dP/dt_min, end-diastolic pressure–volume relation), external efficiency, and contractile efficiency were similar in both the IP and control groups. Lactate efflux was significantly reduced after preconditioning (p = 0.02). During reperfusion, recovery of systolic function and coronary flow were significantly improved in the IP group compared with controls: aortic flow, 85% versus 63% (p = 0.01); dP/dt_max, 91% versus 67% (p = 0.001); pressure–volume area, 97% versus 68% (p = 0.01); E_max, 74% versus 62% (p = 0.03); and M_w, 94% versus 84% (p = 0.04). Release of creatine kinase was reduced in the IP group, 9.6 ± 1.3 U · 5 min⁻¹ · 100 g⁻¹ wet weight, versus controls, 12.7 ± 2.7 U · 5 min⁻¹ · 100 g⁻¹ wet weight (p = 0.04). During reperfusion, contractile efficiency (p = 0.03) and external efficiency (p = 0.02) recovered better in preconditioned than in untreated hearts. Recovery was less pronounced in the DPCPX group compared with the IP group (p, not significant).

Conclusions. The results, derived from load-insensitive measures, confirm that IP provides protection after episodes of severe hypoperfusion by attenuating systolic dysfunction without improving diastolic dysfunction and reduces the severity of anaerobic metabolism as well as ischemic injury. Contractile efficiency and external efficiency both indicate improved energetics after IP (oxygen utilization by the contractile apparatus). The protective effect, at least in part, is mediated by adenosine A₁ receptors.     

Vascular delay and intermittent stimulation: keys to successful latissimus dorsi muscle stimulation

Background. The goal of this study was to obtain physiologically significant increases in peak left ventricular (LV) systolic pressure and stroke volume with latissimus dorsi muscle (LDM) stimulation in cardiomyoplasty (CMP). We hypothesized that preserving LDM integrity by vascular delay and intermittent stimulation would significantly increase LDM cardiac assistance.

Methods. In 4 control dogs and 12 dogs that had undergone a vascular delay (VD) procedure, LV dysfunction was induced by intracoronary microsphere injections. Cardiomyoplasty surgery was performed 14 days later, followed by progressive LDM conditioning. In the control dogs and in 6 of the VD dogs, the LDM was stimulated 24 hours per day (VD plus constant stimulation [CS]). In the other 6 VD dogs, LDMs were stimulated on a daily schedule of 10 hours on and 14 hours off (VD plus interrupted stimulation [IS]). Latissimus dorsi muscle stimulated beats were compared with nonstimulated beats 9 weeks later.

Results. In the control dogs, LDM stimulation had minimal effects. In VD + CS and VD + IS, LDM stimulation increased peak LV pressure, stroke volume, stroke work, and stroke power (p < 0.05). However, these changes were greater in the VD + IS group, in which LDM stimulation increased peak aortic pressure by 17.6 ± 1.7 mm Hg, peak LV pressure by 19.7 ± 1.1 mm Hg, peak positive LV dp/dt by 398 ± 144 mm Hg per second, stroke volume by 5.1 ± 0.7 mL, stroke work by 10.9 ± 0.9 gm · m, and stroke power by 122.7 ± 11.6 gm · m per second (p < 0.05 compared with VD + CS). Quantitative morphometric analysis showed minimal LDM degeneration in the VD + IS group (7.5% ± 1.1%), and VD + CS group (10.5% ± 4.5%) compared with the control group (29.5% ± 4.5%, p < 0.05).

Conclusions. VD and IS considerably increased the LV assistance with LDM stimulation. Further studies of this combined approach to CMP should be planned.     

Ventricular remodeling after cardiomyoplasty in heart failure sheep: passive and dynamic effects

Background. Recent reports claim that cardiomyoplasty (CMP) has a girdling effect on the left ventricle, to prevent dilatation and functional deterioration, but the mechanism of its long-term effects on the native heart is not known. We compared the relative role of CMP’s active squeezing and passive girdling in chronically failing hearts.

Methods. After induction of stable heart failure (left ventricular ejection FRACTION = 27% ± 7%) by staged coronary microembolization, CMP was performed in 11 of 18 sheep. After 8 weeks pacing training of the latissimus dorsi muscle (LDM), cardiac assist was begun with 1:2 synchronous bursts in 6 sheep (d-CMP, N = 6), and the LDM in the passive group (p-CMP, N = 5) remained unstimulated. Four (base line) and 30 weeks after induction of heart failure, the pressure-volume relationship was derived.

Results. After 30 weeks in d-CMP the slope (E_max) of the end-systolic pressure-volume relationship increased by 66% ± 55% (p < 0.05) and external work efficiency by 48% ± 41% (p < 0.01). In the passive CMP and control groups, slope and external work efficiency were unchanged. Conversely, left ventricular end-diastolic volume decreased (−14% ± 12%, p < 0.05) in the dynamic CMP group compared with a static course in the passive CMP group (3% ± 10%, p > 0.05) and an increase (18% ± 15%, p < 0.05) in controls.

Conclusions. Dynamic CMP improved native heart’s contractility and external work efficiency. In addition, whereas passive CMP has simply a girdling effect, dynamic CMP also induces reverse left ventricular chamber remodeling.     

Antiinflammatory effects of colforsin daropate hydrochloride, a novel water-soluble forskolin derivative

Background. To evaluate the effects of colforsin daropate hydrochloride (colforsin), a water-soluble forskolin derivative, on hemodynamics and systemic inflammatory response after cardiopulmonary bypass, we conducted a prospective randomized study.

Methods. Twenty-nine patients undergoing coronary artery bypass grafting were randomized to receive either colforsin treatment (colforsin; N = 14) or no colforsin treatment (control; N = 15). Administration of colforsin (0.5 μg · kg⁻¹ · min⁻¹) was started after induction of anesthesia and was continued for 6 hours. Perioperative cytokine and cyclic adenosine monophosphate levels, hemodynamics, and respiratory function were measured serially.

Results. Marked positive inotropic and vasodilatory effects were observed in patients receiving colforsin. Interleukin 1β, interleukin 6, and interleukin 8 levels after cardiopulmonary bypass were significantly (p < 0.05) lower in the colforsin group. Plasma levels of cyclic adenosine monophosphate increased significantly (p < 0.05) in the colforsin group, and the levels correlated inversely (r = −0.56, p = 0.002) with the respiratory index after cardiopulmonary bypass.

Conclusions. Intraoperative administration of colforsin daropate hydrochloride had potent inotropic and vasodilatory activity and attenuated cytokine production and respiratory dysfunction after cardiopulmonary bypass. The results indicate that the technique can be a novel therapeutic strategy for the systemic inflammatory response associated with cardiopulmonary bypass.     

Impact of Systemic Depulsation on Tissue Perfusion and Sympathetic Nerve Activity

Background. We postulated that pathophysiologic processes under nonpulsatile circulation are related to the behavior of the sympathetic nerve activity that regulates tissue perfusion.

Methods. Pulsatile and nonpulsatile pumps were installed in parallel in the left heart bypass circuit of anesthetized goats (n = 9) so that pulsatile circulation could be converted to nonpulsatile circulation instantly. At 5 minutes before and after systemic depulsation, we measured hemodynamic indices, renal nerve activity, and regional blood flow of the brain, heart, and renal cortex.

Results. Renal nerve activity was significantly elevated after systemic depulsation (15.6 ± 9.3 versus 19.4 ± 9.8 μV), when mean aortic pressure remained almost constant. The renal cortical flow was significantly reduced after depulsation (3.61 ± 1.23 versus 2.93 ± 1.19 mL · min⁻¹ · g⁻¹), whereas no significant difference was found in the regional blood flow of the brain or the heart.

Conclusions. The significant reduction of renal cortical blood flow after systemic depulsation is associated with a significant increase in renal nerve activity. Our results suggest that increased renal nerve activity plays an important role in the reduction of renal function after systemic depulsation.     

Retrograde perfusion with a sodium channel antagonist provides ischemic spinal cord protection

Background. Neuronal voltage-dependent sodium channel antagonists have been shown to provide neuroprotection in focal and global cerebral ischemic models. We hypothesized that retrograde spinal cord venous perfusion with phenytoin, a neuronal voltage-dependent sodium channel antagonist, would provide protection during prolonged spinal cord ischemia.

Methods. In a rabbit model, spinal cord ischemia was induced for 45 minutes. Six groups of animals were studied. Controls (group I, n = 8) received no intervention during aortic cross-clamping. Group II (n = 8) received systemic phenytoin (100 mg). Group III (n = 4) received systemic phenytoin (200 mg).Group IV (n = 8) received retrograde infusion of room temperature saline (22°C) only. Group V (n = 8) and group VI (n = 9) received retrograde infusion of 50 mg and 100 mg of phenytoin, respectively, (infusion rate: 0.8 mL · kg⁻¹ · min⁻¹ during the ischemic period). Mean arterial blood pressure was monitored continuously. Animals were allowed to recover for 24 hours before assessment of neurologic function using the Tarlov scale.

Results. Tarlov scores (0 = complete paraplegia, 1 = slight lower limb movement, 2 = sits with assistance, 3 = sits alone, 4 = weak hop, 5 = normal hop) were as follows (mean ± SEM): group I, 0.50 ± 0.50; group II, 0.25 ± 0.46; group IV, 1.63 ± 0.56; group V, 4.13 ± 0.23; and group VI, 4.22 ± 0.22 (p < 0.0001 V, VI versus I, II, IV by analysis of variance). No differences in mean arterial blood pressure were observed. All animals in group III became profoundly hypotensive and died before the conclusion of the 45-minute ischemic time.

Conclusions. Retrograde venous perfusion of the spinal cord with phenytoin, a voltage-sensitive sodium channel blocker, is safe and provides significant protection during prolonged spinal cord ischemia.     

Impaired distensibility of neoaorta after arterial switch procedure

Background. Although the arterial switch operation has become the standard surgical procedure for treatment of complete transposition, postoperative problems have not been fully appreciated. One such problem may be the postoperative function of great arteries that are manipulated radically.

Methods. The diameters at four levels of the aorta were measured in 36 patients who had undergone arterial switch operation and the distensibilities were calculated. The data were compared with that of age-matched controls.

Results. At the level of the Valsalva sinus, aortic diameters after one-staged and two-staged operations were 137.0% ± 21.3%N and 152.4% ± 17.7%N of the normal aorta, respectively. The distensibilities at the Valsalva sinus in patients after one-staged and two-staged operations were 1.2 ± 0.7 and 1.5 ± 0.8 cm² · dyn⁻¹ · 10⁻⁶, and at the supraaortic ridge were 2.5 ± 1.5 and 1.9 ± 1.5 cm² · dyn⁻¹ · 10⁻⁶, respectively.

Conclusions. In patients after arterial switch procedure, the distensibility of the base of aorta is decreased. Long-term follow-up is necessary to clarify the influence of the “stiffness” of the base of aorta.     

Epoxyeicosatrienoic acids (EET(11,12)) may partially restore endothelium-derived hyperpolarizing factor-mediated function in coronary microarteries.

Background. Endothelial cells derive nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). The cytochrome P-450–monooxygenase metabolites of arachidonic acid (epoxyeicosatrienoic acids [EETs]) have been suggested to be EDHF. This study was designed to examine the effect of EET_11,12 with regard to the possibility of restoring EDHF function when added into hyperkalemic cardioplegic solution.

Methods. Porcine coronary microartery rings were studied in a myograph. In groups 1 and 2, paired arteries were incubated in either hyperkalemic solution (K⁺ 20 mmol/L) or Krebs’ solution (control). In group 3, the paired arteries were incubated in hyperkalemia plus EET_11,12 (1 × 10^−6.5 mol/L) or hyperkalemia alone (control) at 37°C for 1 hour, followed by Krebs’ washout and then precontracted with 1 × 10^−8.5 mol/L U46619. The EDHF-mediated relaxation to EET_11,12 (group 1) or bradykinin (groups 2 and 3) was studied in the presence of N^G-nitro-l-arginine, indomethacin, and oxyhemoglobin.

Results. After exposure to hyperkalemia, the EDHF-mediated maximal relaxation by bradykinin (72.5% ± 7.8% versus 41.6% ± 10.6%; p < 0.05), but not by EET_11,12 (18.4% ± 3.3% versus 25.1% ± 4.9%; p > 0.05) was significantly reduced. Incubation with EET_11,12 partially restored EDHF function (33.3% ± 9.5% versus 62.0% ± 8.5%; p < 0.05).

Conclusions. In coronary microarteries, hyperkalemia impairs EDHF-mediated relaxation, and EET_11,12 may partially mimic the EDHF function. Addition of EET_11,12 into cardioplegic solution may partially restore EDHF-mediated function reduced by exposure to hyperkalemia.     

Sodium Nitroprusside Exacerbates Myocardial Ischemia–Reperfusion Injury

Background. The role of nitric oxide in myocardial ischemia–reperfusion is controversial. Although many studies claim that nitric oxide ameliorates reperfusion injury, others suggest that it exacerbates such injury, possibly through peroxynitrite production. These discordant results may be attributable to a dose-dependent phenomenon.

Methods. Isolated rabbit hearts sustained sequential periods of blood perfusion (20 minutes), warm ischemia (30 minutes), and reperfusion (20 minutes). During reperfusion, four groups underwent intracoronary infusion of saline solution (n = 6), or the nitric oxide donor sodium nitroprusside (100 nm/min [SNP100, n = 6], 1 nmol · L⁻¹/min⁻¹ [SNP1, n = 6], or 0.01 nmol · L⁻¹ · min⁻¹ [SNP0.01]). Left ventricular-developed pressure and oxygen consumption were measured after preischemic perfusion and reperfusion. Levels of myocardial nitrotyrosine, a marker for peroxynitrite, were measured after reperfusion with an immunoradiochemical assay.

Results. Postischemic-developed pressure and myocardial oxygen consumption were significantly higher in the saline group than all nitroprusside-reperfused groups (p < 0.01 for both parameters). However, there were no differences in either parameter between SNP100, SNP1, or SNP0.01. Nitrotyrosine levels were similar among the four groups (p = 0.43).

Conclusions. Nitroprusside exacerbates myocardial ischemia–reperfusion injury over a wide range of doses, although the mechanism does not appear to be mediated by peroxynitrite.     

Sex and age distribution of 1,25(OH)2D3 receptors in peripheral blood mononuclear cells from normal human subjects

Specific receptors for 1,25 Dihydroxyvitamin D₃ have been described in human peripheral blood mononuclear cells (PBMC). We have tried to find out whether these receptors could show any difference in sex or age distribution. Twenty two healthy men aged 21–66 yr (mean ± SD 41.0 ± 13.6) and nineteen healthy women aged 22–60 yr (38.9 ± 13.9) have been studied. The mean dissociation constant (Kd) was similar in both sexes (1.35 ± 0.70 × 10⁻¹⁰M in males, 1.13 ± 0.66 × 10⁻¹⁰M in females), but the concentration of binding sites (Nmax) was significantly lower in females (2.32 ± 0.92 fmol/10⁷ PBMC vs 4.43 ± 1.38 fmol/10⁷ PBMC in males; p = 0.0001). Neither Kd nor Nmax were significantly correlated with age. No difference was found between pre and postmenopausal women. Further studies are needed to elucidate if this sex difference in PBMC receptors for 1,25 Dihydroxy vitamin D₃ is of any pathophysiological relevance.     

Activity–rest stimulation of latissimus dorsi for cardiomyoplasty: 1-year results in sheep

Background. In dynamic cardiomyoplasty electrostimulation achieves full transformation of the latissimus dorsi (LD); therefore, its slowness limits the systolic support. Daily activity–rest could maintain partial transformation of the LD.

Methods. Sheep LD were burst-stimulated either 10 or 24 hours/day. Before and 2, 4, 6, and 12 months after stimulation, LD power output, fatigue resistance, and tetanic fusion frequency were assessed. Latissimus dorsi were biopsied at 6 months, and sheep sacrificed at 12 months.

Results. After 1 year of 10 hours/day stimulation LD was substantially conserved and contained large amounts of fast type myosin. From 2 months to 1 year of stimulation the power per muscle of the daily rested LD was greater than that of the left ventricle, being three to four times higher than in the 24-hour/day stimulation.

Conclusions. If extended to humans, these results could be the rationale for the need of a cardiomyostimulator, whose discontinuous activity could offer to patients the long-standing advantage of a faster and powerful muscle contraction.     

Bisphosphonate incadronate prevents total gastrectomy-induced osteopenia in rats

Purpose. Total gastrectomy (GX) leads to osteopenia. We examined the effects of bisphosphonate incadronate (INC), a potent inhibitor of bone resorption, on bone characteristics in rats that underwent total GX. Experimental design. Male Wistar rats were divided into four groups: (1) sham-operation (n = 10); (2) total GX control (n = 6); (3) total GX with 0.3 mg kg⁻¹ day⁻¹ oral administration of INC (n = 7); and (4) total GX with 3.0 mg kg⁻¹ day⁻¹ oral administration of INC (n = 7). Results. Total GX significantly impaired bone mineral density; these effects were prevented by treatment with INC. Similarly, in GX control rats, morphometrical changes of femoral metaphysis stained with Villanueva's and Villanueva-Goldner's: bone volume, tissue volume, mineral apposition rate, labeled/bone surface, bone formation rate, osteoid volume, mineralization lag time as well as serum osteocalcin, and urinary deoxypyridinoline demonstrated simultaneous existence of both osteomalacia and osteopenia; these impairments were also prevented by INC. However, GX-induced decrease in serum levels of calcium as well as 25-hydroxyvitamin D/24,25-dihydroxyvitamin D and the increase in 1,25-dihydroxyvitamin D were not prevented by administration of INC. Conclusions. These results enhance the understanding of the unique pathophysiology of both osteomalacia and osteoporosis induced by total GX and suggest the possibility of using INC as preventive therapy for osteopenia in GX-treated patients.     

Effects of cerivastatin on vascular function of human radial and left internal thoracic arteries

Background. Statins may enhance vascular function independently of effects on cholesterol. This study investigated the ability of statins to modulate the vascular recovery of arteries used as coronary bypass grafts.

Methods. Specimens of radial artery and left internal thoracic artery were obtained during coronary artery bypass grafting. The specimens were divided into vascular rings, which were incubated in the absence or presence of cerivastatin (10⁻⁶ mol/L) for either 2 or 24 hours. Using an organ bath technique, endothelial function was examined using acetylcholine (10⁻⁹ to 10⁻⁵ mol/L) after contraction by 3×10⁻⁸ mol/L of endothelin-1.

Results. Time-related endothelial dysfunction was shown in the control group of radial artery but not in the cerivastatin group: maximal endothelium-dependent vasodilation in the control and cerivastatin groups were 56.8% ± 10.2% and 65.9% ± 10.1% at 2 hours and 39.4% ± 4.7% and 68.4% ± 5.0% (p < 0.01, vs control) at 24 hours, respectively. On the other hand, in the left internal thoracic artery, those in the control and cerivastatin groups were 38.3% ± 8.2% and 45.0% ± 5.5% at 2 hours and 38.1% ± 8.2% and 56.5% ± 8.8% at 24 hours, respectively (NS).

Conclusions. In radial artery, cerivastatin significantly preserved endothelium-dependent vasodilation, which diminished with time in the control group. This could have very important implications in the clinical practice of coronary artery bypass grafting.     

Infra-stellate upper thoracic sympathectomy results in a relative bradycardia during exercise, irrespective of the operated side

Objective: Removal of accessory fibres coming from the sub-stellar thoracic chain to the heart during infra-stellate surgical upper thoracic sympathectomy (ISS) may be responsible for a decreased heart rate to workload relationship during exercise following surgery. We hypothesised that heart rate would decrease not only following right ISS. Methods: We performed repeated bicycle incremental exercise tests in 11 control subjects (26.9±9.5 years, 61.4±12.4 kg, 167±10 cm), and 11 patients (29.8±10 years, 59.3±12.0 kg, 168±7 cm) referred for bilateral ISS: results are mean±standard deviation. Surgery was performed at two distinct times allowing to study the consequences of unilateral and bilateral sympathectomy to confirm whether a significant relative bradycardia was constant and dependent on the operated side. Results: For control subjects, test durations were 13.55±3.29, 14.09±4.01 and 13.00±3.26 min and heart rates were 187±7, 187±8 and 186±7 beats min⁻¹ at the first, second and third test, respectively. Although time to exhaustion was comparable to controls and unchanged between tests: 12.32±2.87, 12.3±2.90, 12.33±3.76 min, heart rate at maximum exercise decreased significantly from 176±16 to 164±15, and 148±15 beats min⁻¹, before, following unilateral and bilateral ISS, respectively. The operated side did not allow for the prediction of the effect of unilateral sympathectomy. Conclusions: Patients should be informed of the exercise bradycardia resulting from ISS, although clinical tolerance seems excellent in endurance exercise. Contrary to previous reports at rest, during exercise no right-sided dominance was observed. These findings are consistent with reports of random distribution of sub-stellate cardiac fibres from anatomical studies.     

Effects of Wrapping Tightness on Acute Cardiac Function in Dynamic Cardiomyoplasty

Background. It has not been clarified how tightly the heart should be wrapped for maximal augmentation of cardiac function in cardiomyoplasty.

Methods. Hearts in acute failure induced by propranolol were wrapped with the left latissimus dorsi muscle, loosely (loose CMP), moderately (moderate CMP), and tightly (tight CMP) in each of 5 pigs. To measure the pressure between the latissimus dorsi muscle and the left ventricle (LV), a Millar pressure catheter with a latex balloon was placed on the anterior wall of the LV. Left ventricular wall tension was calculated according to Laplace's law, using the difference between the LV pressure and the balloon pressure.

Results. In the loose CMP, moderate CMP, and tight CMP groups, the mean balloon pressures during unassisted beats were 8.2, 10.4, and 13.2 mm Hg, respectively. During unassisted beats, the mean LV wall tension values were 38,683, 29,938 (p < 0.05 versus loose CMP), and 26,652 (p < 0.05 versus loose CMP) dynes/cm, respectively, the peak LV pressures were 76.8, 73.8, and 65 (p < 0.05 versus loose CMP) mm Hg, respectively, and the stroke volumes were 12.8, 9.2, and 8.5 (p < 0.05 versus loose CMP) mL, respectively. During assisted beats, the mean LV wall tension values were 20,059, 11,290, and 7,893 (p < 0.05 versus loose CMP) dynes/cm, respectively, the peak LV pressures were 94.1, 98.1, and 92.0 mm Hg, respectively, and the stroke volumes were 13.8, 11.6, and 9.4 (p < 0.05 versus loose CMP) mL, respectively.

Conclusions. During unassisted beats, tight CMP (13 mm Hg) had the advantage of diminishing LV wall tension, but the disadvantage of diminishing LV pressure and stroke volume, compared with loose CMP (8 mm Hg). Moderate CMP (10 mm Hg), however, had the advantage of diminishing LV wall tension without a decrease in LV pressure and stroke volume.