Grant N. Pierce

The atherogenic effects of chlamydia are dependent on serum cholesterol and specific to Chlamydia pneumoniae

Epidemiological investigations have linked Chlamydia pneumoniae infection to atherosclerosis. It is not clear, however, whether C. pneumoniae infection plays a causal role in the development of atherosclerosis. Mice with low-density lipoprotein receptor deficiency were induced to develop atherosclerotic lesions in aorta with a cholesterol-enriched diet that increased serum cholesterol by two- to threefold. Using this mouse model, we found that the chlamydial infection alone with either the C. pneumoniae AR39 or the C. trachomatis MoPn strain failed to induce any significant atherosclerotic lesions in aorta over a period of nine months. However, in the presence of a high-cholesterol diet, infection with the C. pneumoniae AR39 strain significantly exacerbated the hypercholesterolemia-induced atherosclerosis, demonstrating that a hypercholesterolemic condition is required for the C. pneumoniae to aggravate the development of atherosclerosis. Although both AR39 and MoPn antigens were detected in aorta of mice infected with the corresponding strains, only mice infected with the C. pneumoniae strain AR39 displayed enhanced atherosclerotic lesions, suggesting that the C. pneumoniae species may possess a unique atherogenic property. This study may provide a model for further understanding the mechanisms of C. pneumoniae atherogenesis and evaluating chlamydial intervention strategies for preventing the advancement of atherosclerotic lesions enhanced by C. pneumoniae infection.

Calcium movements in relation to heart function

SummaryIt is widely recognized that calcium is of singular importance in the viability of the myocardial cell, nonetheless little is known concerning the precise nature of the action of calcium in myocardium as to how it maintains the life of the cell and how it may dictate the death of the cell. However, recent advances in research involved with the study of calcium movement in the heart have been highly valuable for the formulation of new concepts with respect to the physiological and pathological aspects of calcium metabolism in the myocardium. It is becoming clear that calcium movements are closely related to cardiac electrophysiological events, contractile function, membrane integrity and energy metabolism. In particular, a novel theory involving phosphatidylinositol turnover and Ca2+-dependent ATPase activation has been advanced regarding the mechanism and control of calcium entry into the cardiac cell upon excitation. Alterations in the regulation of calcium metabolism through the interaction of a number of separate, elements may affect calcium distribution in the cell and thereby may change cardiac function and metabolism. The part calcium plays in the genesis of pathological states in the myocardium is discussed in the light of research employing various experimental protocols. Intracellular calcium overload and deficiency are postulated to contribute to cardiac contractile failure and cell death through a number of distinct mechanisms. It is now a real challenge to understand the precise nature of processes associated with the occurrence of intracellular calcium overload or intracellular calcium deficiency in order to achieve proper management of cardiac disorders.ZusammenfassungEs ist allgemein anerkannt, daß Calcium von besonderer Bedeutung für die Funktion der Myokardzelle ist. Trotzdem ist über die genaue Natur der Calcium-Wirkung sowie auch über die mögliche Bedeutung von Calcium für das Absterben einer Myokardzelle wenig bekannt. Fortschritte in der Erforschung der Calcium-Bewegungen im Herzen ermöglichen neue Vorstellungen über die Rolle des Calciums unter physiologischen und pathophysiologischen Bedingungen. Offensichtlich bestehen enge Beziehungen zwischen Calcium-Bewegungen und elektrophysiologischen Abläufen, kontraktiler Funktion, Membranintegrität und Energiemetabolismus. Insbesondere wurde eine neue Theorie entwickelt, die den giemetabolismus. Insbesondere wurde eine neue Theorie entwickelt, die den Inositphosphatid-Umsatz und die Aktivierung der Ca-abhängigen ATPase berücksichtigt im Hinblick auf die Mechanismen und die Kontrolle des Calcium-Eintritts in die Zelle bei Erregung. Änderungen in der Regulierung des Calcium-Stoffwechsels können die Ca-Verteilung in der Zelle beeinflussen und dadruch Herzfunktion und Stoffwechsel verändern. Die Rolle, die Calcium bei der Entwicklung pathologischer Zustände im Myokard spielt, wird im Lichte der Forschungsergebnisse bei Verwendung unterschiedlicher experimenteller Ansätze diskutiert. Es wird postuliert, daß Überladung der Zelle mit Calcium und Calcium-Mangel der Zelle zum kontraktilen Versagen des Herzens und zum Zelltod beitragen durch eine Anzahl definierter Mechanismen. Im Hinblick auf eine sachgerechte Behandlung kardialer Störungen stellt sich daher die Aufgabe, die genaue Natur der Prozesse zu klären, die mit Calcium-Überbeladung oder Calcium-Mangel einhergehen.

Cardiac alpha- and beta-adrenergic receptor alterations in diabetic cardiomyopathy

SummaryThe effect of chronic experimental diabetes on the adrenergic receptors in the rat heart was investigated. Diabetes was induced by streptozotocin (65 mg/kg; i.v.) administration, animals were sacrificed 8 weeks later, and positive as well as negative dF/dt values were determined in isolated papillary muscle preparations. Stimulation of the contractile force generation by isoproterenol and methoxamine was attenuated in diabetic preparations. Beta-and alpha-adrenergic receptor bindings were determined in cardiac membranes by employing3H-dihydroalprenolol and3H-dihydroergocryptine respectively. Reduced number of beta- and alpha-receptor binding sites without changes in the affinity constants were observed in diabetic myocardium. Such a decrease in alpha- and beta-receptor density in the heart may account for the depressed contractile responsiveness to adrenergic stimuli in diabetic cardiomyopathy.ZusammenfassungEs wurde der Einfluß eines chronischen, experimentellen Diabetes auf die adrenergen Rezeptoren des Rattenherzens untersucht. Diabetes wurde durch Streptozotocin (65 mg/kg i.v.) erzeugt. Die Untersuchungen wurden 8 Wochen nach Verabreichung durchgeführt. Es wurden positive und negative dF/dt-Werte (Geschwindigkeit der Kraftentwicklung) von isolierten Papillarmuskeln bestimmt. Die durch Isoproterenol und Methoxamin gesteigerte Kraftentwicklung war bei Ratten mit Diabetes vermindert. Die Bindungseigenschaften von Beta-und Alpha-rezeptoren in den Membranen des Herzens wurden mit Hilfe von3H-dihydroalprenolol und3H-dihydroergocryptin bestimmt. Im diabetischen Myokard war die Zahl der Beta- und Alpharezeptor-Bindungsstellen vermindert, nicht jedoch die Affinitätskonstanten. Die verringerte Beta- und Alpharezeptoren-Dichte im Herz könnte für die verminderte Ansprechbarkeit der Mechanik auf adrenerge Reize bei der diabetischen Kardiomyopathie verantwortlich sein.

Cardiac myofibrillar ATPase activity in diabetic rats

Abstract Diabetes was induced by an intravenous injection of 65 mg/kg streptozotocin and hearts were removed 8 weeks later for the isolation of myofibrils. The basal ATPase activity of myofibrils from diabetic hearts was significantly lower than the controls. Although Ca 2+ -stimulated ATPase activity was also depressed in diabetic myocardium, the dependency of diabetic myofibrils on free calcium concentration was not different from that of control. The basal and Ca 2+ -stimulated ATPase activities in diabetic rats demonstrated a greater sensitivity to KCl than control preparations. The myofibrillar basal ATPase, unlike Ca 2+ -stimulated ATPase, in diabetic animals exhibited a greater sensitivity to ethylene glycol. These results support the view regarding the presence of some subtle structural and conformational changes in diabetic myofibrils.

The cardiovascular effects of flaxseed and its omega-3 fatty acid, alpha-linolenic acid

Preventing the occurrence of cardiovascular disease (CVD) with nutritional interventions is a therapeutic strategy that may warrant greater research attention. The increased use of omega (ω)-3 fatty acids is a powerful example of one such nutritional strategy that may produce significant cardiovascular benefits. Marine food products have provided the traditional dietary sources of ω-3 fatty acids. Flaxseed is an alternative to marine products. It is one of the richest sources of the plant-based ω-3 fatty acid, alpha-linolenic acid (ALA). Based on the results of clinical trials, epidemiological investigations and experimental studies, ingestion of ALA has been suggested to have a positive impact on CVD. Because of its high ALA content, the use of flaxseed has been advocated to combat CVD. The purpose of the present review was to identify the known cardiovascular effects of flaxseed and ALA and, just as importantly, what is presently unknown.

Oxidative status of lipoproteins in coronary disease patients

Oxidized low-density lipoprotein (LDL) may play an important role in atherogenesis. The oxidative status of isolated LDL and very low-density lipoprotein (VLDL) were investigated in 23 patients with proven coronary disease and in 23 healthy asymptomatic control subjects. Oxidized cholesterol (4-cholesten-3-one and 20 alpha-OH cholesterol) was identified in LDL and VLDL from both groups. The content of cholesterol and 4-cholesten-3-one in LDL from patients was significantly increased in comparison with values from the control subjects. Lipid peroxidation, as assessed by malondialdehyde (MDA) formation, was barely detectable in native LDL and VLDL from the two groups. However, after incubation with a free radical-producing system, MDA levels in LDL from patients were significantly higher than those in control subjects. Lysine reactivity in LDL after incubation with an oxidizing agent, CuSO4, was similar between groups. However, lysine reactivity to CuSO4 in VLDL from patients was less than that in control subjects. Our results suggest that LDL levels from patients with coronary disease have an elevated oxidized cholesterol content and are more susceptible to peroxidative modification. Conversely, the LDL apoprotein does not appear to have been oxidatively modified in these patients. The data are consistent with a role for oxidized LDL in coronary artery disease and indicate that the LDL lipid may be an important oxidation site.

Beneficial Effects of Verapamil in Diabetic Cardiomyopathy

It has been suggested that the occurrence of an intracellular Ca2+ overload may result in the development of diabetic cardiomyopathy, which is associated with depletion of high-energy phosphate stores and a derangement of ultrastructure and cardiac dysfunction. Accordingly, the effects of verapamil, a Ca2+ antagonist, on cardiac function, ultrastructure, and high-energy phosphate stores in the myocardium were evaluated in rats made diabetic by an intravenous injection of streptozocin (65 mg/kg). Four weeks after the induction of diabetes, the animals were treated with three doses (2, 4, or 8 mg kg−1 day−1) of verapamil for 4 wk until they were used for the measurement of different parameters. Untreated diabetic animals had slower heart rates, depressed rate of contraction and rate of relaxation, lower peak left ventricular systolic pressure, and elevated left ventricular diastolic pressure. All of these changes were significantly improved in diabetic rats receiving verapamil treatment. The beneficial effects of verapamil were more evident with higher doses (8 mg · kg−1 · day−1) than with the lower doses (2 mg · kg−1 · day−1). The diabetic animals also showed alterations in myocardial high-energy phosphate stores and exhibited evidence of ultrastructural damage; these abnormalities were improved by verapamil treatment without affecting their hyperglycemic status. Our results demonstrate that verapamil is capable of preventing diabetes-induced myocardial changes and support the involvement of Ca2+ in the cardiac pathology during diabetes.

A Comparison of Fish Oil, Flaxseed Oil and Hempseed Oil Supplementation on Selected Parameters of Cardiovascular Health in Healthy Volunteers

Objective: The impact of dietary polyunsaturated fatty acids (PUFAs) of the n-6 and n-3 series on the cardiovascular system is well documented. To directly compare the effects of three dietary oils (fish, flaxseed and hempseed) given in concentrations expected to be self-administered in the general population on specific cardiovascular parameters in healthy volunteers. Design: 86 healthy male and female volunteers completed a 12 week double blinded, placebo controlled, clinical trial. They were randomly assigned to one of the four groups. Subjects were orally supplemented with two 1 gm capsules of placebo, fish oil, flaxseed oil or hempseed oil per day for 12 weeks. Results: Plasma levels of the n-3 fatty acids docosahexanoic acid and eicosapentanoic acid increased after 3 months supplementation with fish oil. Alpha linolenic acid concentrations increased transiently after flaxseed supplementation. However, supplementation with hempseed oil did not significantly alter the concentration of any plasma fatty acid. The lipid parameters (TC, HDL-C, LDL-C and TG) did not show any significant differences among the four groups. Oxidative modification of LDL showed no increase in lag time over the 12 wk period. None of the dietary interventions induced any significant change in collagen or thrombin stimulated platelet aggregation and no increase in the level of inflammatory markers was observed. Conclusion: From a consumers perspective, ingesting 2 capsules of any of these oils in an attempt to achieve cardiovascular health benefits may not provide the desired or expected result over a 3 month period.

Dietary Vaccenic Acid Has Antiatherogenic Effects in LDLr−/− Mice

Epidemiological evidence has associated dietary trans fatty acids (TFA) with heart disease. TFA are primarily from hydrogenated fats rich in elaidic acid, but dairy products also contain naturally occurring TFA such as vaccenic acid. Our purpose in this study was to compare the effects of consuming a commercially hydrogenated vegetable shortening rich in elaidic TFA (18:1t9) or a butter rich in vaccenic TFA (18:1t11) in the absence and presence of dietary cholesterol on atherosclerosis. LDL receptor deficient (LDLr(-/-)) mice were fed 1 of 8 experimental diets for 14 wk with the fat content replaced by: regular (pork/soy) fat (RG), elaidic shortening (ES), regular butter (RB), vaccenic butter (VB), or an atherogenic diet containing 2% cholesterol with RG (CH+RG), ES (CH+ES), RB (CH+RB), or VB (CH+VB). Serum cholesterol levels were elevated with cholesterol feeding (P < 0.001), whereas serum triglyceride levels were higher only in the CH+RB (P < 0.001) and CH+VB (P < 0.001) groups compared with the other 6 groups. Serum cholesterol and triglyceride levels were significantly lower in the CH+VB group than in the CH+RB group (P < 0.001). Atherosclerosis was stimulated by dietary ES compared with RG (P = 0.021), but CH+ES did not stimulate atherosclerosis beyond CH+RG alone. In contrast, VB did not induce an increase in atherosclerotic plaque formation compared with the RG and RB diets and the CH+VB diet reduced atherosclerosis compared with the other diets containing cholesterol (P < 0.01). In summary, consuming a hydrogenated elaidic acid-rich diet stimulates atherosclerosis, whereas a vaccenic acid-rich butter protects against atherosclerosis in this animal model.

Regulation of intracellular Ca2+ in the heart during diabetes

Cardiovascular disease is a significant medical problem. The diabetic population is even more susceptible to cardiovascular complications and heart failure than non-diabetic patients. Atherosclerotic complications, a neuropathy and microvascular lesions have all been implicated causally in the accelerated cardiovascular disease during diabetes. However, one mechanism which may participate in the abnormalities in heart performance demonstrated during diabetes and may also contribute to heart failure in the diabetic is a derangement in the capacity of the myocardial cell to regulate its [Ca2+]. The purpose of this treatise is to identify the current controversies and conclusions available regarding the specific defects in Ca2+ flux thought to contribute to these cardiac defects during diabetes mellitus.