Rediscovery of Otto Frank's contribution to science.

In the late 19th century, German physiologist Otto Frank (1865-1944) embarked on a near life-long research program of laying down the mathematical, methodological, and theoretical foundations in order to understand and define the performance of the heart and circulatory system in all their complexity. The existence of the "Frank-Starling law" testifies to this. Two of his seminal publications have been translated into English previously, introducing Frank's research on the dynamics of the heart and the arterial pulse to a wider audience.

The Hyponatremia Epidemic: A Frontier Too Far?

Hyponatremia is the most common electrolyte abnormality and is often neglected, especially in elderly and seemingly terminal patients. Hyponatremia can be asymptomatic or can cause symptoms ranging from nausea and lethargy to convulsions and coma. This condition has become increasingly common over time with a similar time course to the increase in adoption of low salt diets.

Update on the important new drug target in cardiovascular medicine - the vascular glycocalyx.

We reviewed this subject in 2009, pointing out that, to the process of atherothrombosis, glycocalyx dysfunction and damage must be added to the previous known causitive factors. Glycocalyx dysfunction is possibly the very first step in the process of atherothrombosis, being a protective layer between the endothelial cells and the blood. We emphasise the unique feature of glycocalyx mediated vasodilatation in that it is initiated purely by mechanical changes, i.

The important new drug target in cardiovascular medicine--the vascular glycocalyx.

The process of atherothrombosis is known to involve endothelial pathology (first drug target), plaque formation (second drug target) and thrombosis (third drug target). However it has recently been postulated that, even before endothelial pathology occurs, the very first step in the process of atherothrombosis is dysfunction of the arterial glycocalyx that lies between the endothelial cells and the blood [1]. So there are really four drug targets, and perhaps the arterial glycocalyx will become the most important for future early prevention of people at risk.

Dilatation in the femoral vascular bed does not cause retrograde relaxation of the iliac artery in the anaesthetized pig.

Aim: We tested the hypothesis that dilatation of a feeding artery may be elicited by transmission of a signal through the tissue of the arterial wall from a vasodilated peripheral vascular bed.

Methods: In eight pentobarbital anaesthetized pigs, acetylcholine (ACh, an endothelium-dependent vasodilator) was injected intra-arterially above (upstream) and below (downstream) a test segment of the left iliac artery, the diameter of which was measured continuously by sonomicrometry.

Results: Under control conditions, ACh injections upstream and downstream of the test segment caused dilatation.

Hypothesis: arterial glycocalyx dysfunction is the first step in the atherothrombotic process.

We present evidence that the 0.5 microm thick gel layer, lining the inner wall of healthy blood vessels, the glycocalyx, is the first line of defence against atherothrombotic disease. All blood vessel linings are coated with this gel, a highly negatively charged structure, rich in anionic sites mostly represented by the sialic acid moieties of glycoproteins and the sulphate and carboxyl groups of heparan-sulphate proteoglycans.

Regional sympathetic denervation affects the relation between canine local myocardial blood flow and oxygen consumption.

Myocardial blood flow and oxygen consumption are heterogeneously distributed. Perfusion and myocardial oxygen consumption are closely correlated in the normal heart. It is unknown how this metabolism-perfusion relation is influenced by sympathetic denervation.

Basal and hyperaemic myocardial blood flow in regionally denervated canine hearts: an in vivo study with positron emission tomography.

Purpose: Positron emission tomography (PET) studies in patients with diabetic autonomic neuropathy (DAN) have demonstrated the impact of this disease on cardiac sympathetic innervation and myocardial blood flow (MBF). To investigate the effects of selective partial sympathetic denervation of the left ventricle (LV) on baseline and hyperaemic MBF, we measured myocardial presynaptic catecholamine re-uptake (uptake-1), beta-adrenoceptor (beta-AR) density and MBF non-invasively by means of PET in a canine model of regional sympathetic denervation.

Methods: In 11 anaesthetised dogs, the sympathetic nerves of the free wall and septum of the LV were removed by means of dissection and phenol painting.

The antiplatelet drug target in atherosclerotic diseases.

The aim of this review is (1) to give a rationale for anti-platelet therapy based on mechanisms of platelet rich arterial thrombosis, (2) to point out the pitfalls involved in monitoring therapy with platelet function tests and (3) to outline the potential clinical applications of such therapy based on the various modes of action of anti-platelet drugs. The primary event in arterial thrombosis is platelet-mediated, either due to increased shear or exposed collagen, followed by fibrin-rich thrombosis. Anti-platelet therapy needs to be monitored but most platelet function tests, now in use, do not reflect in vivo function; the anticoagulant used for blood samples removes extra-cellular calcium ions, platelets are often separated before the test, or very high doses of agonist are used: all of these can give misleading results.

Differential inhibition by hyperglycaemia of shear stress- but not acetylcholine-mediated dilatation in the iliac artery of the anaesthetized pig.

Clinical hyperglycaemia affects vascular endothelial function, but the effect on shear stress-induced arterial dilatation has not yet been established. We hypothesized that hyperglycaemia would inhibit this response via impaired glycocalyx mechanotransduction. Experiments were carried out in the anaesthetized pig in which pressure, blood flow and diameter of the left iliac artery were measured at two sites: proximal (d1) and distal (d2).

The beat-to-beat decay of cardiac contractility from highly potentiated levels is bi-exponential.

In order to determine the mode of beat-to-beat decay of contractility from very high levels, we studied the beat-by-beat decay of cardiac contractility following potentiation. Such decay curves are normally analysed using a mono-exponential decay function, which assumes that a fixed fraction of activator calcium ions is recirculated from one beat to the next. We postulated that there might be deviations from such a mono-exponential expression at high levels of contractility.

Chronic catecholamine depletion switches myocardium from carbohydrate to lipid utilisation.

Purpose: Chronic cardiac transplantation denervation (i.e., global sympathetic denervation with myocardial catecholamine depletion, plus parasympathetic denervation) is known to inhibit myocardial oxidation of glucose.

Thrombosis in one coronary artery causes generalized coronary vasoconstriction in a dog model of unstable angina.

We investigated the effect of thrombosis in one coronary artery upon the vascular resistance of another coronary artery. In previous investigations, using an animal model of unstable angina, we have observed increased resistance downstream from thrombus within a left circumflex coronary artery (LCx) stenosis and vasoconstriction of collateral vessels from the left anterior descending artery (LAD) supplying the distal LCx vascular bed. In the present paper, we induced thrombosis within a stenosis of the LCx of 16 beagle dogs, and observed the changes in blood flow to the myocardium supplied by the LAD using the radioactive microsphere technique.

Measurement of coronary collateral flow and resistance in the presence of an open critical stenosis, and the response to intra-arterial thrombosis.

Objective: (1) Can one measure coronary collateral flow around an open critical stenosis? (2) Does intracoronary platelet thrombosis affect native coronary collateral vessels?

Methods: We measured regional myocardial blood flow by the radioactive microsphere technique in seven anaesthetised dogs with an ultrasonic flowmeter on the circumflex branch of the left coronary artery (LCx). Measurements were made (a) in a control period, (b) after induction of a tight stenosis on the LCx, and (c) after additional arterial damage at the stenosis to induce intraluminal thrombosis. Collateral flow was calculated from LCx tissue flow(in ml/min/g tissue) minus LCx flowmeter flow which is in ml/min.

Chronic cardiac denervation affects the speed of coronary vascular regulation.

Objective: We tested the hypothesis that the rate of adaptation of coronary metabolic vasodilatation and autoregulation is modulated by the cardiac nerves.

Methods: Anaesthetised dogs (seven innervated (control) and seven with denervated hearts) were subjected to controlled pressure perfusion of the left main coronary artery. Heart rate was controlled by pacing.

Downstream resistance effects of intracoronary thrombosis in the stenosed canine coronary artery.

Objective: The presence is well established in unstable angina of intracoronary thrombosis in a stenosed epicardial coronary artery. The effects of the thrombus formation on the distal microcirculation are however still unclear.

Methods: We adapted the Folts canine model of left circumflex coronary arterial stenosis and intracoronary thrombosis by the insertion of a pressure catheter distal to the stenosis and by the use of 15 microns radioactive microspheres for measurement of regional myocardial blood flow.

Protein changes observed in pacing-induced heart failure using two-dimensional electrophoresis.

Rapid ventricular pacing in dogs results in a low output cardiomyopathic state which is similar to idiopathic dilated cardiomyopathy in man. However, the pathophysiological mechanisms which cause this failure following pacing are unknown. Five dogs underwent rapid ventricular pacing.

Depletion of endogenous dopamine stores and shift in beta-adrenoceptor subtypes in cardiac tissue following five weeks of chronic denervation.

Surgical ablation of extrinsic cardiac nerve fibers results in a chronically denervated state of the left ventricle of the heart. The present study was performed to elucidate the effect of a period of 5 weeks of chronic denervation on cardiac catecholamine levels in general and dopamine in particular. Moreover, the possible effect on cardiac beta-adrenoceptor subtypes was investigated.

Metabolic alterations in the chronically denervated dog heart.

Objective: Previous studies have shown that chronic cardiac denervation impairs myocardial glucose oxidation. To investigate this further we tested whether the tissue content of glucose transporters, activity of glycolytic enzymes or metabolic capacity of pyruvate dehydrogenase were altered. Moreover, we investigated whether the decline in glucose utilization was associated with an upregulation of proteins and enzymes involved in fatty acid handling.

Beneficial effect of the calcium-sensitizing drug EMD 57033 in a canine model of dilated heart failure.

1. Pacing-induced heart failure was studied in eight dogs. Heart failure was induced by right ventricular pacing at 250-260 beats/min for 6 weeks.