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PubMed2001

Model of cardiovascular injury in magnesium deficiency.

Magnesium deficiency is known to produce cardiovascular lesions. It is, however, not clear as to what constitutes magnesium deficiency - reduced serum levels, reduced tissue levels or reduced intracellular levels of the ionic form of the element. This article cites evidence in support of a hypothesis that a fall in serum magnesium levels may trigger a temporal sequence of events involving vasoconstriction, hemodynamic alterations and vascular endothelial injury to produce pro-inflammatory, pro-oxidant and pro-fibrogenic effects, resulting in initial perivascular myocardial fibrosis which, in turn, would cause myocardial damage and replacement fibrosis. Further, angiotensin II may be the prime mover of the pathogenetic cascade in magnesium deficiency. Importantly, such a mechanism of cardiovascular injury would be independent of a reduction in myocardial or vascular tissue levels of magnesium.

Cardiovascular Diseases↗
PubMed1997

Animal models of cardiovascular disease for pharmacologic drug development and testing: appropriateness of comparison to the human disease state and pharmacotherapeutics.

For proper drug development, targeting and testing the use of suitable animal models that are well controlled with regard to duration, degree, and stage of the disease are vitally needed. Furthermore reliable phenotyping and genotyping with regard to functional physiology as well as cellular biochemistry and molecular biology are vital to early decision making in drug discovery, development, and successful clinical development. The use of animal models allows the design of clinical trials without the complication of having to impose "accepted treatment modalities" on top of investigative agents. With the availability of human myocardium for study as a result of cardiac transplantation programs, experimental findings previously reported in several animal models of heart disease have been questioned with regard to suitability for comparison to the human condition. With the development and application of sophisticated techniques and biochemical assays to the study of heart tissue several adaptive changes have been identified and labeled "markers of heart failure." Several animal models share some of these adaptive changes in common with failing human myocardium, but not others. The goal of this report is to point out similarities and differences reported to date in failing and nonfailing human myocardium to that reported in animal models of human heart disease. This discussion indicates important dissimilarities found in several key animal models that have resulted in the development of cardioactive agents and therapeutic interventions for the treatment of human heart disease and the unexpected outcomes. Although focusing on heart failure, a vital goal of this report is to emphasize some key principles supporting the need for clear, comprehensive, and unbiased evaluation of animal models currently in use to study any disease condition, as well as the need for further model development and study in open collaborative efforts.

Animals↗
PubMed2006

Artificial neural network based model for cardiovascular risk stratification in hypertension.

This study was to develop an objective method to stratify cardiovascular risk in hypertension. Stratification for cardiovascular risk is crucial in deciding treatment strategy for hypertension but has yielded undesirable results in clinic due to its low accuracy which is caused by physicians' subjective experience and the uncertainty of patients' statements. Our model proposed herein overcomes these disadvantages by applying artificial neural network based on a classic back propagation net. The model input is derived from the clinical investigation. The target output is the stratification level of total cardiovascular risk, which is learned from the guidelines of hypertension treatment. Study in 348 normotensive and hypertensive subjects showed that the results of model stratification are consistent with the standard stratification suggested by hypertension guidelines in 81.61% cases. The results confirm the accuracy of the model and demonstrate its ability in risk evaluation for hypertension.

Algorithms↗
PubMed2004

The mouse as a model of cardiovascular adaptations to microgravity.

There are a multitude of physiological adaptations to microgravity, involving the cardiovascular, neuromuscular, and neuroendocrine systems. Some of these adaptations lead to cardiovascular deconditioning on return to normal gravity, posing a threat to human functional integrity after long-term spaceflight. Animal models of microgravity, e.g., tail suspension in rats, have yielded important information regarding the mechanism of these adaptations and have been useful in the design of countermeasures. The mouse could potentially be a useful experimental model, given its small size (smaller and lighter payload) and the powerful tools of experimental mouse genetics, which allow us to dissect mechanisms on a gene-specific basis. We show that the mouse demonstrates a wide range of cardiovascular responses to simulated microgravity, including alterations in heart rate, exercise capacity, peripheral arterial vasodilatory responsiveness, and baroreflex response. These responses are qualitatively similar to many of those demonstrated in humans during spaceflight and in rats using tail suspension, although there are some important differences. Thus the mouse has value as a model for studies of cardiovascular changes during microgravity; however, investigators must maintain an appreciation of important species differences.

Adaptation, Physiological↗
PubMed2006

Hereditary hypertriglyceridemic rat: a suitable model of cardiovascular disease and metabolic syndrome?

Hypertriglyceridemia and hypertension seem to be very important cardiovascular risk factors. The Prague hereditary hypertriglyceridemic (hHTG) rat was developed as a model of human hypertriglyceridemia. It was demonstrated that these rats are not obese, they are hypertensive and insulin resistant and they have some disturbances in glucose metabolism. Several QTLs were identified for blood pressure, its particular components (dependent on major vasoactive systems) and plasma triglycerides throughout the genome of hHTG rats by using of F(2) hybrids strategy. It is evident that hHTG rats are a suitable model for the study of metabolic disturbances in relation to blood pressure as well as for the search of genetic determinants of these abnormalities. Numerous abnormalities of blood pressure regulation as well as alterations in the structure and function of cardiovascular apparatus (heart, conduit and resistance arteries) were found in hHTG rats. A special attention was paid to possible changes in the efficiency of various vasoactive systems such as nitric oxide, renin-angiotensin-aldosterone system and sympathetic nervous system, which seem to contribute substantially to cardiovascular and/or metabolic abnormalities observed in Prague hereditary hypertriglyceridemic rats.

Animals↗
PubMed2005

Pharmacokinetic-pharmacodynamic modelling of the cardiovascular effects of drugs - method development and application to magnesium in sheep.

BACKGROUND: There have been few reports of pharmacokinetic models that have been linked to models of the cardiovascular system. Such models could predict the cardiovascular effects of a drug under a variety of circumstances. Limiting factors may be the lack of a suitably simple cardiovascular model, the difficulty in managing extensive cardiovascular data sets, and the lack of physiologically based pharmacokinetic models that can account for blood flow changes that may be caused by a drug. An approach for addressing these limitations is proposed, and illustrated using data on the cardiovascular effects of magnesium given intravenously to sheep. The cardiovascular model was based on compartments for venous and arterial blood. Blood flowed from arterial to venous compartments via a passive flow through a systemic vascular resistance. Blood flowed from venous to arterial via a pump (the heart-lung system), the pumping rate was governed by the venous pressure (Frank-Starling mechanism). Heart rate was controlled via the difference between arterial blood pressure and a set point (Baroreceptor control). Constraints were made to pressure-volume relationships, pressure-stroke volume relationships, and physical limits were imposed to produce plausible cardiac function curves and baseline cardiovascular variables. "Cardiovascular radar plots" were developed for concisely displaying the cardiovascular status. A recirculatory kinetic model of magnesium was developed that could account for the large changes in cardiac output caused by this drug. Arterial concentrations predicted by the kinetic model were linked to the systemic vascular resistance and venous compliance terms of the cardiovascular model. The kinetic-dynamic model based on a training data set (30 mmol over 2 min) was used to predict the results for a separate validation data set (30 mmol over 5 min). RESULTS: The kinetic-dynamic model was able to describe the training data set. A recirculatory kinetic model was a good description of the acute kinetics of magnesium in sheep. The volume of distribution of magnesium in the lungs was 0.89 L, and in the body was 4.02 L. A permeability term (0.59 L min-1) described the distribution of magnesium into a deeper (probably intracellular) compartment. The final kinetic-dynamic model was able to predict the validation data set. The mean prediction error for the arterial magnesium concentrations, cardiac output and mean arterial blood pressure for the validation data set were 0.02, 3.0 and 6.1%, respectively. CONCLUSION: The combination of a recirculatory model and a simple two-compartment cardiovascular model was able to describe and predict the kinetics and cardiovascular effects of magnesium in sheep.

Animals↗
PubMed1994

[Control system for a complete artificial heart based on a mean value model of the cardiovascular system].

The reliable use of an artificial heart in patients requires a control strategy that is able to monitor and realistically regulate the different loads of the cardiovascular system. The model outlined in the following article was created in an interdisciplinary environment with heart specialists and automation engineers. A control system for an artificial heart, in the form of a peristaltic pump, was created with the help of a load-dependent mean-value model of the cardiovascular system. The resistance of the arterioles in the systemic vascular system RA was chosen as the parameter for the adaptation of the cardiac output. This parameters can be easily and accurately estimated through the measurement of pressures and flows, and it is a very good indicator for the load of the organism. The results, obtained through simulation of the overall system, show a very fast and accurate adaptation of the cardiac output to the needs of the body at changing loads over a large range of workloads. At the same time, the protection of the lungs from excessive pressure is ensured by balance control of the outputs of the two halves of the artificial heart. The control system outlined here needs only pressure and flow sensors, which can be integrated into the pump housing.

Cardiac Output↗
PubMed2003

Chronic cholestasis and cardiac mitochondrial function in Wistar rats: a model for cardiovascular alterations in chronic liver disease?

OBJECTIVES: A growing number of reports in the literature have been correlating cardiovascular alterations with the presence of chronic liver disease, such as cirrhosis and cholestasis. The objective of this work was to compare mitochondrial bioenergetics and calcium loading capacity in the hearts of rats injected with alpha-naphthylisothiocyanate (ANIT), a compound used to induce cholestasis in animal models. METHODS: Female Wistar rats (n = 12) were randomly divided into two groups. One of the groups was injected with six weekly doses of ANIT. Each group was evaluated in terms of mitochondrial bioenergetic capacity and susceptibility to the mitochondrial permeability transition (MPT), a deleterious phenomenon associated with oxidative stress and excessive mitochondrial calcium accumulation. RESULTS: Our data showed unequivocally that cardiac mitochondria of rats chronically injected with ANIT lost their ability to accumulate calcium, in a cyclosporin A sensitive manner. This was reflected in a higher calcium-dependent swelling rate and amplitude (p < 0.01). The RCI value, an index of mitochondrial integrity, was also lower in the ANIT-treated group (p < 0.05). CONCLUSIONS: This suggests that during cholestasis development, cardiac mitochondria lose their normal ability to control cytosolic calcium due to increased susceptibility to the MPT. Our results may suggest an explanation for the occurrence of cardiomyopathies associated with cholestatic disease, which may persist even in the absence of serum markers for liver disease.

1-Naphthylisothiocyanate↗
PubMed2001

[Genetically modified animal models in cardiovascular research].

It is a basic tenet of molecular and clinical medicine that specific protein complements underlie cell and organ function. Since cellular and ultimately organ function depend upon the polypeptides that are present, it is not surprising that when function is altered changes in the protein pools occur. In the heart, numerous examples of contractile protein changes correlate with functional alterations, both during normal development and during the development of numerous pathologies. Similarly, different congenital heart diseases are characterized by certain shifts in the motor proteins. To understand these relationships, and to establish models in which the pathogenic processes can be studied longitudinally, it is necessary to direct the heart to stably synthesize, in the absence of other peliotropic changes, the candidate protein. Subsequently, one can determine if the protein's presence causes the effects directly or indirectly with the goal being to define potential therapeutic targets. By affecting the heart's protein complement in a defined manner, one has the means to establish both mechanism and the function of the different mutated proteins of protein isoforms. Gene targeting and transgenesis in the mouse provides a means to modify the mammalian genome and the cardiac motor protein complement. By directing expression of an engineered protein to the heart, one is now able to effectively remodel the cardiac protein profile and study the consequences of a single genetic manipulation at the molecular, biochemical, cytological and physiologic levels, both under normal and stress stimuli.

Animals↗
PubMed1984

Neuromuscular diseases as models of cardiovascular regulation during exercise.

This article reviews the research performed to date on the cardiovascular responses to exercise in patients with neuromuscular diseases and lesions affecting the transmission of afferent impulses from skeletal muscle. These studies have provided important information about the roles of central command and reflexes from skeletal muscle afferents in circulatory control. Few animal models of neuromuscular diseases are available. Studies of patients with specific defects in skeletal muscle energy metabolism are particularly valuable because the local metabolic state participates in both systemic and local cardiovascular regulation. In patients with certain muscle metabolic defects (e.g., McArdle's disease, carnitine deficiency) cardiac output is normal at rest but increases excessively in relation to oxygen uptake during exercise. The excessive increase in cardiac output during exercise can be totally or partially normalized by increasing the availability of substrate to exercising muscle. These studies provide unique insights into the specific metabolic factors which are involved in cardiovascular regulation.

Afferent Pathways↗
PubMed2006

Deficiencies of cardiovascular risk prediction models for type 1 diabetes.

OBJECTIVE: Cardiovascular risk prediction models are available for the general population (Framingham) and for type 2 diabetes (U.K. Prospective Diabetes Study [UKPDS] Risk Engine) but may not be appropriate in type 1 diabetes, as risk factors including younger age at diabetes onset and presence of diabetes complications are not considered. Therefore, our objective was to examine the accuracy of Framingham and UKPDS models for predicting coronary heart disease (CHD) in a type 1 diabetic cohort. RESEARCH DESIGN AND METHODS: Ten-year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, a prospective cohort study of 658 subjects with childhood-onset type 1 diabetes diagnosed between 1950 and 1980 first seen in 1986-1988, were analyzed. EDC study data were used to calculate the 10-year probability of CHD (fatal CHD, nonfatal myocardial infarction, or Q-waves) applying to the Framingham and UKPDS equations. RESULTS: Mean age at CHD onset was 39 years. When fatal/nonfatal myocardial infarction and CHD death were modeled, both the UKPDS and Framingham models showed significant lack of calibration (P < 0.0001) but moderate discrimination (0.76 UKPDS, 0.77 Framingham men, and 0.88 Framingham women). Both the UKPDS and Framingham models underestimated probability of events in highest risk deciles. CONCLUSIONS: Currently available CHD models poorly predict events in type 1 diabetes. Future research should focus on determining the risk factors accounting for the lack of fit and developing prediction models specific to this high-risk group.

Adult↗
PubMed1997

A model for the design and evaluation of algorithms for closed-loop cardiovascular therapy.

Developing a clinically useful closed-loop drug delivery system can be extremely time consuming and costly. One approach to reducing the time and cost associated with developing closed-loop systems is to reduce the number of animal experiments and perform an extensive set of simulation studies. Through simulations, a closed-loop controller's performance can be evaluated over a complete spectrum of the patient population, including boundary conditions. Simulation studies are repeatable, offering significant advantages in comparing modifications in control algorithms. Finally, simulation studies can be performed in a fraction of the time required for animal studies, at a fraction of the cost. We have developed a simulator, that included a nonlinear pulsatile-flow cardiovascular model, a physiological regulatory mechanism, and the pharmacology of four frequently titrated cardiovascular drugs. This simulator has already been used in the design and evaluation of two closed-loop algorithms-a self-tuning regulator (STR) and a multiple model adaptive controller (MMAC)-for blood pressure control during and after cardiac surgery.

Algorithms↗
PubMed2006

Pharmacokinetic-pharmacodynamic (PK-PD) modeling of cardiovascular effects of metoprolol in spontaneously hypertensive rats: a microdialysis study.

The present work addressed possible alterations in the pharmacokinetics and the in vivo pharmacodynamic of metoprolol (MET) in spontaneously hypertensive (SH) rats and Wistar Kyoto (WKY) animals by means of the microdialysis technique. The correlation between MET unbound plasma concentrations and its pharmacological effects, such as heart rate and blood pressure change, was also examined in SH and WKY rats by the application of a PK-PD model. MET dialysate concentrations and its chronotropic and blood pressure effect were determined during 3 h after the administration of 3 and 10 mg.kg(-1) of the drug. A PK-PD model with a separate effect compartment was used to analyse the data. A good correlation between plasma MET concentrations and its hypotensive and chronotropic effect was found in all experimental groups. Although a greater maximal effect (E(max)) for the antihypertensive effect of MET was observed in SH rats (WKY: E(max): -17+/-1 mmHg; SH: E(max): -28+/-4 mmHg; P<0.05 versus WKY rats), no differences were found in the concentration yielding half-maximal response (IC(50)) comparing SH (IC(50): 583+/-146 ng x ml(-1)) and WKY animals (IC(50): 639+/-187 ng x ml(-1)). The bradycardic effect of MET was greater in SH rats (E(max): -29+/-1%, P<0.05 versus WKY rats) than in WK animals (E(max): -22+/-2%), but no differences were observed in the IC(50) comparing both experimental groups (WKY: IC(50): 187+/-53 ng x ml(-1); SH: IC(50): 216+/-62 ng x ml(-1)). Pharmacokinetic analysis shows that the volume of distribution of MET was greater in SH rats (Vd: 3.4+/-0.5 l, P<0.05 versus WKY rats) with regard to Wistar Kyoto (WKY) animals (Vd: 1.9+/-0.2 l). The results suggest that the pharmacokinetic behaviour of metoprolol are modified in SH rats, resulting in an increased volume of distribution. A greater maximal efficacy to the hypotensive effect of metoprolol was observed in SH rats, suggesting participation of beta-adrenoceptors in the maintenance of the hypertension. Also, a greater chronotropic response to metoprolol was found in the hypertensive group compared with WKY animals, suggesting that, at least in part, the greater cardiac effect of metoprolol explained the enhanced hypotensive response of the beta blocker in the SH animals.

Adrenergic beta-Antagonists↗