James Jenkins

A unified perspective on copper deficiency and cardiomyopathy.

Abstract Dietary copper restriction in rats results in cardiomyopathy. In rats fed copper-restricted diets from weaning for 5 to 8 weeks, a concentric hypertrophy is apparent, whereas postweaning copper restriction does produce cardiomyopathy without apparent hypertrophy. Both sets of circumstances appear to affect the integrity of the basal laminae of cardiac myocytes and capillaries. In rats fed copper-restricted diets from weaning, decreases in cytochrome c oxidase are related not only to coppers role as a coenzyme, but also to a marked decrease in the nuclear encoded subunits of the enzyme complex. Decreased levels of the δ-subunit of ATP synthase have been observed. However, such aberrations in mitochondrial enzymes, as well as morphologic alterations, apparently do not affect cardiac levels of ATP. This review suggests mechanisms of cardiac adaptation and initiation factors leading to cardiac hypertrophy. We present a hypothetical working model explaining the events leading to cardiac failure in the copper-deficient rat heart based on the present body of knowledge, and compare the pathology with other models of cardiomyopathies.

The effect of norepinephrine versus epinephrine on myocardial hemodynamics during CPR

Alpha-adrenergic agonists improve myocardial blood flow during CPR by increasing aortic diastolic pressure. Adrenergic agonists with beta-2 properties may enhance peripheral vasodilation and may prove less beneficial during CPR. The purpose of this study was to compare epinephrine (E), an alpha-1,2; beta-1,2 agonist, versus norepinephrine, an alpha-1,2; beta-1 agonist, on myocardial hemodynamics during CPR. Twenty swine were instrumented for pressure, arterial and coronary sinus oxygen content (CAO 2 and CCSO 2 , respectively), and myocardial blood flow measurements using tracer microspheres. CAO 2 , CCSO 2 , myocardial blood flow, myocardial oxygen delivery (MDO 2 ) and myocardial oxygen consumption (MVO 2 ), extraction ratio, and aortic diastolic pressure were determined during normal sinus rhythm and during CPR following a ten-minute arrest. After three minutes of CPR, the animals were allocated to receive either norepinephrine 0.08 mg/kg (n = 5), norepinephrine 0.12 mg/kg (n = 5), norepinephrine 0.16 mg/kg (n = 5), or epinephrine 0.20 mg/kg (n = 5). One minute after drug administration, all hemodynamic parameters were again determined. Three and one half minutes after drug administration defibrillation was attempted. A Newman-Keuls multiple comparison procedure was used to compare differences following drug administration. During CPR, aortic diastolic pressure averaged less than 13 mm Hg, and myocardial blood flow averaged less than 6 mL/min/100 g. All doses of norepinephrine and epinephrine improved all hemodynamic parameters over those seen during CPR. The two highest doses of norepinephrine significantly improved extraction ratio compared with norepinephrine 0.08 mg/kg ( P = .04). Epinephrine 0.20 mg/kg, norepinephrine 0.12 mg/kg, and 0.16 mg/kg significantly improved aortic diastolic pressure ( P = .007) and coronary perfusion pressure ( P = .012) compared with norepinephrine 0.08 mg/kg. With the two largest doses of norepinephrine, myocardial blood flow averaged 94 to 101 mL/min/100 g; average myocardial blood flow with epinephrine 0.20 mg/kg was 69 mL/min/100 g, and myocardial blood flow with norepinephrine 0.08 mg/kg was 35 mL/min/100 g. All the animals were defibrillated successfully with norepinephrine 0.12 and 0.16 mg/kg, 80% with epinephrine, and 40% with norepinephrine 0.08 mg/kg. Although equipressor doses of epinephrine 0.20 mg/kg and norepinephrine 0.16 mg/kg produced statistically similar hemodynamics, a trend toward improved myocardial blood flow and successful defibrillation rates was noted with norepinephrine 0.16 mg/kg. This trend also was noted with norepinephrine 0.12 mg/kg. Thus, alpha-adrenergic agonists such as norepinephrine, which lack beta-2 agonist properties, may be hemodynamically more beneficial during CPR than alpha-adrenergic agonists such as epinephrine with beta-2 activity.

The effect of norepinephrine versus epinephrine on regional cerebral blood flow during cardiopulmonary resuscitation

alpha-Adrenergic drugs improve cerebral blood flow (CBF) during cardiopulmonary resuscitation (CPR), in part, by reversing carotid artery collapse and by shunting blood from extracerebral to intracerebral vascular structures. Adrenergic drugs with beta 2-agonist properties may cause peripheral vasodilation, and thus may be less beneficial in this setting. The purpose of this study was to compare epinephrine (E), an alpha 1,2, beta 1,2-agonist, with norepinephrine (NE), an alpha 1,2, beta 1-agonist, on CBF during CPR. Twenty swine each weighing greater than 15 kg were instrumented for regional CBF measurements using tracer microspheres. Regional CBF was measured during normal sinus rhythm (NSR). Animals were then placed into ventricular fibrillation (VF). After ten minutes of VF, the animals received closed-chest CPR using a mechanical thumper. Regional CBF was measured during CPR. After three minutes of CPR, the animals were allocated to receive either E, 0.20 mg/kg (N = 5); NE, 0.08 mg/kg (N = 5); NE, 0.12 mg/kg (N = 5); or NE, 0.16 mg/kg (N = 5). Regional blood flows were again measured following drug administration. CBFs following drug administration were compared using an analysis of covariance adjusting for baseline differences during CPR. A Newman-Keuls multiple comparison was used to follow-up significant (P less than or equal to .05) differences. Statistical significance was considered at P less than or equal to .05. There was a clinically significant improvement in cerebral cortical flow with NE, 0.12 mg/kg, and NE, 0.16 mg/kg, compared with NE, 0.08 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative aspects of cardiac ultrastructure, morphometry, and electrocardiography of hearts from rats fed restricted dietary copper and selenium.

Comparative cardiac ultrastructure, morphometry, and electrocardiography after dietary copper and selenium restriction were examined. Male weanling Long-Evans rats were fed diets that were either adequate in both copper and selenium (Cu+/Se+) or restricted in either Cu (Cu−) or Se (Se−) for 8 wk. At wk 8, electrocardiograms (ECG) anddP/dts were obtained and heart tissue was utilized for electron microscopy. Upon examination, Cu− rats were anemic, exhibited a greater heart: body weight ratio, and developed concentric hypertrophy characterized by an enhanced thickening of the left and right ventricular free walls, and interventricular septum. ECG recordings from lead aVF in the Cu− group showed a greater R wave amplitude in comparison to the Cu+/Se+ group. Se− rats recorded a greater left ventricular +dP/dtmax than both the Cu+/Se+ and Cu− groups.Cardiac myofibril volume densities were decreased in both Cu− and Se− rats in comparison to the Cu+/Se+ rats. In addition Cu− rats showed a greater mitochondria: myofibril ratio. Sarcomere contractile protein disarray was present in both the Cu− and Se− groups. Se− myocytes also showed evidence of edema and mitochondrial fragmentation. The subcellular alterations suggest that similarities exist in the cardiac remodeling processes associated with copper and selenium restrictions.

Effect of direct mechanical ventricular assistance on myocardial hemodynamics during ventricular fibrillation

Direct mechanical ventricular assistance (DMVA) is a method of biventricular circulatory support that employs a pneumatic device to apply both systolic and diastolic forces directly to the ventricular myocardium. This study investigated the effects of DMVA on myocardial hemodynamics when applied after a prolonged cardiopulmonary arrest. Seven swine weighting 28.3 +/- 2.5 kg were instrumented for regional myocardial blood flow (MBF) measurements using tracer microspheres. Ventricular fibrillation was then induced. After 10 min of ventricular fibrillation, CPR was initiated for 3 min. DMVA was then applied through median sternotomy. Defibrillation was attempted after 3.5 min of DMVA. If unsuccessful, DMVA was instituted for another 17.5 min and a subsequent defibrillation attempt was made. Arterial oxygen content (CaO2), coronary sinus oxygen content (CcSO2), myocardial oxygen delivery/consumption (mDO2/mVO2), extraction ratio (ER), and endocardial/epicardial blood flow ratio (EN/EP) were determined during CPR, during the initial application of DMVA (DMVA1), and after the subsequent 17.5 min of DMVA in those animals not initially defibrillated (DMVA2). Three of the seven animals were successfully defibrillated during DMVA1. After the additional 17.5 min of DMVA, only one other animal was defibrillated. There was a significant improvement in CaO2, CcSO2, MBF, mDO2, mVO2, ER, and EN/EP after DMVA1 compared to CPR. Only mVO2 and ER improved significantly after DMVA2. These findings support the concept that physical diastolic augmentation may improve myocardial hemodynamics when DMVA is applied during cardiac arrest.

Submaximal, aerobic exercise training exacerbates the cardiomyopathy of postweanling Cu-depleted rats

To determine the dual effect of exercise training and copper depletion on myocardial function and ultrastructure, postweanling rats were either trained or sedentary while fed copper-adequate or copper-deficient diets for 8 wk. Rats developed characteristic myocardial subcellular degeneration and increased cardiac mitochondrial volume density when copper depleted, despite lack of overt cardiac hypertrophy, hypertension, or anemia. Training combined with copper depletion induced mild left ventricular hypertrophy. Basal laminae appeared fractionated in areas at capillary-myocyte interface, with focal pericapillary and interstitial collagen accumulation, where-as overt fibrosis was absent or minimal. Electrocardiograms revealed increased QRS wave and QT duration and notching of QRS complex with copper depletion, consistent with intraventricular conductance disturbances. The oxidative capacity of soleus muscle increased with training in copper-adequate rats, but was reduced with progressive copper depletion. These data suggest that copper depletion and training are synergistic in effecting focal accumulation of collagen, with deleterious effect on exercise capacity.

The effect of UK14,304-18 (an alpha-2 adrenergic agonist) on myocardial blood flow during cardiopulmonary resuscitation☆

Several recent studies have suggested that adrenergic drugs with peripheral postsynaptic alpha-2 agonist properties increase aortic diastolic pressure (ADP), and thus in the setting of CPR, may improve myocardial blood flow (MBF). This preliminary study investigated the effect of UK14,304-18, a postsynaptic alpha-2 adrenergic agonist on ADP, MBF, myocardial oxygen delivery/utilization (MDO2/MVO2), endocardial/epicardial blood flow ratio (EN/EP), coronary sinus oxygen content (CcsO2) and extraction ratio (ER) during CPR. Five swine were instrumented for MBF measurements using tracer microspheres. Catheters were also placed to measure arterial oxygen content (CaO2) and CcsO2. ADP, MBF, MDO2/MVO2, EN/EP, ER, CaO2 and CcsO2 were measured during normal sinus rhythm (NSR), and during CPR following a 10-min cardiorespiratory arrest. Following this, each animal received 2.0 mg/kg of UK14,304-18 through a right atrial line. ADP, MBF, MDO2/MVO2, EN/EP, ER, CaO2 and CcsO2 were again determined. Defibrillation was then attempted. To determine whether UK14,304-18 improved ADP, MBF and MDO2 over MVO2, compared to CPR alone, results were compared using a paired Student t-test. Statistical significance was considered at the P less than or equal to 0.05 level. No significant improvement in ADP, MBF, MDO2 or ER was noted following the administration of UK14,304-18. The lack of improvement in ADP and MBF may be secondary to a centrally acting postsynaptic alpha-2 agonist effect because of disruption of the blood brain barrier following a prolonged cardiac arrest or because of pharmacologically or structurally distinct populations of peripheral postsynaptic alpha-2 adrenoreceptors that develop in this setting.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiological responses to endotoxin in copper deficient rats

Abstract Copper deficient rats show high mortality after a normally sublethal dose of endotoxin. To begin examining the mechanisms, this study examined copper deficiency effects on certain responses to endotoxin. Weanling rats were fed 0.2 or 8 ppm copper for 5 weeks; endotoxin was given at 10 mg/kg, ip. Copper deficiency was confirmed by low activities of ceruloplasmin, and liver and serum superoxide dismutase. Compared to adequate rats, deficients showed the following responses to endotoxin: elevated serum transaminase activities (an indication of liver injury), prolonged hyperglycemia, slightly enhanced liver glycogen depletion, high resistance to hepatic lysosomel enzyme leakage, normal degree of rapid onset hypotension, no microvascular injury based on albumin clearance, slightly higher acute phase response based on serum zinc, and normal increase of tumor necrosis factor at typical time of peak accumulation. Thus, endotoxin-induced mortality in copper deficient rats may derive, at least in part, from a selective liver injury, but not from excessive serum glucose or liver glycogen depletion, impaired acute phase response, aggravated short term hypotension, exaggerated tumor necrosis factor release, fragile lysosomes or excessive microvascular injury.

The Effect of Norepinephrine Versus Epinephrine on Myocardial Hemodynamics During CPR

Alpha-adrenergic agonists improve myocardial blood flow during CPR by increasing aortic diastolic pressure. Adrenergic agonists with beta-2 properties may enhance peripheral vasodilation and may prove less beneficial during CPR. The purpose of this study was to compare epinephrine (E), an alpha-1,2; beta-1,2 agonist, versus norepinephrine, an alpha-1,2; beta-1 agonist, on myocardial hemodynamics during CPR. Twenty swine were instrumented for pressure, arterial and coronary sinus oxygen content (CAO2 and CCSO2, respectively), and myocardial blood flow measurements using tracer microspheres. CAO2, CCSO2, myocardial blood flow, myocardial oxygen delivery (MDO2) and myocardial oxygen consumption (MVO2), extraction ratio, and aortic diastolic pressure were determined during normal sinus rhythm and during CPR following a ten-minute arrest. After three minutes of CPR, the animals were allocated to receive either norepinephrine 0.08 mg/kg (n = 5), norepinephrine 0.12 mg/kg (n = 5), norepinephrine 0.16 mg/kg (n = 5), or epinephrine 0.20 mg/kg (n = 5). One minute after drug administration, all hemodynamic parameters were again determined. Three and one half minutes after drug administration defibrillation was attempted. A Newman-Keuls multiple comparison procedure was used to compare differences following drug administration. During CPR, aortic diastolic pressure averaged less than 13 mm Hg, and myocardial blood flow averaged less than 6 mL/min/100 g. All doses of norepinephrine and epinephrine improved all hemodynamic parameters over those seen during CPR. The two highest doses of norepinephrine significantly improved extraction ratio compared with norepinephrine 0.08 mg/kg (P = .04).(ABSTRACT TRUNCATED AT 250 WORDS)