Renocardiac syndromes: physiopathology and treatment stratagems.

PURPOSE OF REVIEW: Bidirectional inter-organ interactions are essential for normal functioning of the human body; however, they may also promote adverse conditions in remote organs. This review provides a narrative summary of the epidemiology, physiopathological mechanisms and clinical management of patients with combined renal and cardiac disease (recently classified as type 3 and 4 cardiorenal syndrome). Findings are also discussed within the context of basic research in animal models with similar comorbidities. SOURCES OF INFORMATION: Pertinent published articles were identified by literature search of PubMed, MEDLINE and Google Scholar. Additional data from studies in the author's laboratory were also consulted. FINDINGS: The prevalence of renocardiac syndrome throughout the world is increasing in part due to an aging population and to other risk factors including hypertension, diabetes and dyslipidemia. Pathogenesis of this disorder involves multiple bidirectional interactions between the kidneys and heart; however, participation of other organs cannot be excluded. Our own work supports the hypothesis that the uremic milieu, caused by kidney dysfunction, produces major alterations in vasoregulatory control particularly at the level of the microvasculature that results in impaired oxygen delivery and blood perfusion. LIMITATIONS: Recent clinical literature is replete with articles discussing the necessity to clearly define or characterize what constitutes cardiorenal syndrome in order to improve clinical management of affected patients. Patients are treated after onset of symptoms with limited available information regarding etiology. While understanding of mechanisms involved in pathogenesis of inter-organ crosstalk remains a challenging objective, basic research data remains limited partly because of the lack of animal models. IMPLICATIONS: Preservation of microvascular integrity may be the most critical factor to limit progression of multi-organ disorders including renocardiac syndrome. More fundamental studies are needed to help elucidate physiopathological mechanisms and for development of treatments to improve clinical outcomes.

OBJECTIFS DE LA RÉVISION: Les interactions bidirectionnelles entre organes adjacents sont essentielles au bon fonctionnement du corps humain mais sont aussi susceptibles de provoquer des conditions adverses sur des organes plus éloignés. Cette revue offre un compte rendu sommaire de l'épidémiologie, des mécanismes physiopathologiques et du traitement clinique des patients atteints à la fois d'insuffisance rénale et de cardiopathie, ou tel que récemment désignés, atteints du syndrome cardiorénal de type 3 ou de type 4. La revue examine également des résultats obtenus en recherche fondamentale en utilisant des modèles animaux présentant des cas similaires de comorbidité. SOURCES: Les articles pertinents ont été répertoriés à la suite d'une recherche dans la littérature sur PubMed, MEDLINE et « Google Scholar ¼. Des données complémentaires provenant  d'études du laboratoire de recherche de l'auteur ont aussi été consultées. CONSTATATIONS: Le vieillissement de la population en plus de facteurs de risque incluant l'hypertension, le diabète et la dyslipidémie augmente en partie la prévalence du syndrome cardiorénal à travers le monde. La pathogenèse de ce désordre implique de multiples interactions bidirectionnelles entre le cœur et les reins; cependant, la participation d'organes périphériques n'est tout de même pas à exclure. Nos travaux soutiennent l'hypothèse selon laquelle l'environnement urémique résultant de la dysfonction rénale serait responsable d'altérations majeures dans la régulation de la pression, particulièrement au niveau des microvaisseaux. En résultent une perfusion sanguine altérée et une distribution insuffisante d'oxygène vers les organes. LIMITES DE L'ÉTUDE: La littérature clinique récente comporte de nombreux articles traitant de la nécessité d'identifier et de caractériser de façon plus élaborée les causes du syndrome cardiorénal dans la perspective d'améliorer le traitement clinique des patients qui en sont atteints. Par contre, puisqu'il existe encore très peu d'informations sur l'étiologie du syndrome cardiorénal, les patients ne sont pris en charge qu'après son apparition. Qui plus est, la compréhension des mécanismes impliqués dans la pathogenèse résultant des interactions entre organes demeure un objectif difficile à atteindre, en partie parce que la recherche fondamentale est limitée étant donné la rareté des modèles animaux pour cette pathologie. CONSÉQUENCES: À la lumière des données disponibles à ce jour, il apparait que la préservation de l'intégrité du système vasculaire, particulièrement au niveau des microvaisseaux, est un facteur-clé pour restreindre le développement de désordres impliquant plusieurs organes tel le syndrome cardiorénal. Davantage d'études en recherche fondamentale sont requises pour faire la lumière sur les mécanismes physiopathologiques de ce syndrome et développer des traitements efficaces pour en améliorer les résultats cliniques.

Nitric oxide bioavailability affects cardiovascular regulation dependent on cardiac nerve status.

The sympathetic nervous system and nitric oxide (NO) contribute to regulation of vascular tone, blood flow regulation and cardiac function. Intrinsic cardiac neurons are tonically influenced by locally released NO and exogenous NO donors; however, the role of intact central neural connections remains controversial. We investigated the effects of S-nitroso-N-acetylpenicillamine (SNAP) administered into an intracoronary artery near the ventral interventricular ganglionated plexus (VIVGP) to evaluate distribution of myocardial blood flow (MBF) and ventricular function in normal and acute cardiac decentralized dogs. MBF was measured with microspheres during infusion of SNAP (100µM, IC) after systemic administration of 7-nitroindazole (nNOS blocker) followed by N(ω)-nitro-L-arginine methyl ester (LN; non-selective NOS blocker). Cardiac dynamics were not significantly affected by cardiac decentralization; several of these parameters (aortic systolic and diastolic pressures) were significantly increased after systemic administration of LN. Overall SNAP administered to the VIVGP increased blood flow in the anterior LV wall (vs. posterior LV wall) without affecting other cardiodynamic factors. In cardiac decentralized dogs subepicardial blood flow to the anterior LV wall during LN+SNAP was diminished resulting in a significantly higher inner:outer blood flow ratio (index of blood flow uniformity across the LV wall). LV function was not affected by acute cardiac decentralization; however, LV ejection fraction decreased markedly after LN (reduced NO bioavailability). These results validate earlier claims that reduced NO bioavailability imposes an upper limit on myocardial blood flow regulation and its transmural distribution. These effects are exacerbated after disconnection of intrinsic cardiac neurons from intact central neuron connections.

Modulation of nitric oxide affects myocardial perfusion-contraction matching in anaesthetized dogs with recurrent no-flow ischaemia.

Myocardial perfusion and contraction are closely coupled; however, the effect of recurrent no-flow ischaemia on perfusion-contraction matching remains to be established. In the present studies, we examined the influence of modulating nitric oxide availability on perfusion-contraction matching after recurrent no-flow ischaemia in acute open-chest, anaesthetized dogs. The following three groups were studied: (1) saline; (2) L-NAME (10 mg kg(-1) I.V.); and (3) enalaprilat (1.5 mg kg(-1) I.V.). Regional myocardial blood flow was measured with microspheres and contractile function with piezoelectric crystals to determine systolic wall thickening. Dogs underwent four cycles of 5 min acute ischaemia and 5 min coronary reperfusion; area at risk was similar for all groups. In all dogs, ischaemic zone contractile function was depressed after recurrent no-flow ischaemia despite increased myocardial blood flow during reperfusion; contractile function was further depressed during L-NAME and was partly restored with enalaprilat. Within the ischaemic region, blood flow in subendocardial and subepicardial layers increased significantly compared with baseline during each reperfusion period independently of treatment. Our findings suggest that reduced NO availability can significantly impair myocardial perfusion-contraction matching, which is partly restored by administration of an NO donor.

Effect of estrogen replacement therapy on distribution of myocardial blood flow in female anesthetized rabbits.

Estrogen replacement therapy reduces risk of cardiovascular events by altering coronary vasoregulation and distribution of blood flow. Vessel reactivity and blood flow distribution were assessed in anesthetized female rabbits in the following groups: 1) sham, 2) ovariectomy, 3) ovariectomy + 17beta-estradiol, and 4) ovariectomy + dehydroepiandrosterone. After a 2-wk treatment, cardiac hemodynamics, vascular reserve, and blood flow were evaluated during the following infusions: 1) NaCl, or vehicle (0.5 ml/min), 2) acetylcholine (2 mg/kg), 3) isoproterenol (2 mg. kg(-1). min(-1)), and 4) chromonar (8 mg/kg). In hearts from ovariectomized rabbits, autoregulatory blood flow was preserved despite lower diastolic perfusion pressures (55 +/- 8 vs. 64 +/- 8 mmHg in sham) and rate-pressure product (14.4 +/- 0.8 vs. 19.3 +/- 0.8 beats/min. mmHg x 10(-3)). Estrogen replacement therapy restored coronary pressure and reserve, and all drugs increased vascular conductance. In conclusion, in hearts from ovariectomized rabbits, vascular reserve declined because coronary pressure was lower; however, blood flow was preserved at a higher level than expected for oxygen demand. Estrogen replacement therapy restores myocardial oxygen supply-demand indices and returns coronary pressure-flow data to levels observed in animals with intact ovaries.

Effect of angiotensin inhibition on the coronary artery lower pressure limit in anesthetized dogs.

The renin-angiotensin system plays a critical role in regulating vasoconstriction and vasodilatation that can influence myocardial blood flow and its transmural distribution. We tested the hypothesis that angiotensin inhibition can induce a leftward shift of the coronary autoregulatory pressure-flow relation and preserve distribution of myocardial blood flow at lower coronary perfusion pressures. We established circumflex artery pressure-flow relations under baseline conditions and after intracoronary enalaprilat or losartan potassium. Thereafter, transmural myocardial blood flow was measured at baseline and at the lower coronary pressure limit (LPL). With enalaprilat, the LPL was shifted leftward from 48 +/- 6 mmHg at baseline to 43 +/- 3 mmHg (P = 0.026); with losartan, the LPL was shifted leftward from 48 +/- 10 mmHg at baseline to 41 +/- 5 mmHg (P = 0.027). The leftward shift occurred while cardiac hemodynamics and MVO2 were maintained at control levels. These results indicate that angiotensin inhibition extends the range of coronary autoregulation to lower LPL while preserving myocardial blood flow distribution, a physiologic effect that might explain the lower incidence of coronary events in treated patients.

Myocardial blood flow regulation relative to left ventricle pressure and volume in anesthetized dogs.

The influence of left ventricle pressure and volume changes on coronary blood flow was investigated in eight anesthetized dogs. Coronary artery pressure-flow relationships were determined at two levels of left ventricular pressure and volume. The distribution of blood flow within the myocardium was also determined when these relationships varied. Reducing left ventricle pressures and volumes increased heart rate. Rate-pressure product, diastolic coronary pressure, myocardial O2 consumption, total, subendocardial and subepicardial flow decreased. Hematocrit and blood gas data were unchanged. The pressure-flow relationships were shifted leftward (p = 0.001) but the range of autoregulation was not altered. At low left ventricle pressures and volumes, the lower coronary artery pressure limit was shifted leftward (from 75 to 45 mm Hg (1 mm Hg = 133.3 Pa)), while total, subendocardial, and subepicardial blood flow did not change compared with the control. Below the lower coronary artery pressure limit, subendocardial but not subepicardial flow decreased, resulting in maldistribution of flow across the left ventricular wall. When coronary pressure was reset between control and the lower coronary artery pressure limit, subendocardial flow was restored. These results show that the lower coronary artery pressure limit can be shifted leftward while the distribution of blood flow across the left ventricular wall is preserved.

Influence of baseline lipids on effectiveness of pravastatin in the CARE Trial. Cholesterol And Recurrent Events.

OBJECTIVES: We sought to assess the influence of baseline lipid levels on coronary event rates and the effectiveness of pravastatin therapy in the Cholesterol And Recurrent Events (CARE) study. BACKGROUND: The CARE study cohort provided a relatively unique opportunity to examine the relation between lipid levels and clinical events in a post-myocardial infarction (MI) population with relatively low cholesterol and low density lipoprotein (LDL) cholesterol values. METHODS: There were 4,159 patients with a previous infarct and a total cholesterol level <240 mg/dl, LDL cholesterol level 115 to 174 mg/dl and triglyceride level <350 mg/dl randomly allocated to placebo (n=2,078) or pravastatin 40 mg/day (n=2,081). Time to either coronary death or nonfatal MI (primary end point) or to the secondary end point, which included undergoing a coronary revascularization procedure, was determined as a function of baseline lipids (total, LDL, high density lipoprotein [HDL] cholesterol and triglyceride levels). RESULTS: Quartile analysis indicated important effects for LDL cholesterol, in which a higher LDL was associated with greater cardiac event rates (in the placebo group, every 25-mg/dl increment in LDL was associated with a 28% increased risk [5% to 56%, p=0.015]) in the primary event. The differential event rates with respect to baseline LDL cholesterol for placebo and pravastatin groups reduced the difference in clinical outcomes at lower LDL cholesterol levels. In both the placebo and pravastatin groups, an inverse relation between baseline HDL cholesterol and cardiac events was observed (10 mg/dl lower baseline HDL cholesterol level was associated with a 10% [0% to 19%, p=0.046] increase in coronary death or nonfatal MI). CONCLUSIONS: Within the LDL cholesterol levels in CARE (115 to 174 mg/dl), baseline values influenced both the risk of events in the placebo group as well as the clinical effectiveness of pravastatin therapy.

A reappraisal of exercise electrocardiographic indexes of the severity of ischemic heart disease: angiographic and scintigraphic correlates.

OBJECTIVES: We explored how the exercise electrocardiographic (ECG) indexes generally presumed to signify severe ischemic heart disease (IHD) correlate with coronary angiographic and scintigraphic myocardial perfusion findings. BACKGROUND: In exercise testing, it is generally assumed that the early onset of ST segment depression and its occurrence at a low rate-pressure product (ischemic threshold); the amount of maximal ST segment depression; and a horizontal or downsloping ST segment and its prolonged recovery after exercise signify more severe IHD. However, the relation of these indexes to coronary angiographic and exercise myocardial perfusion findings in patients with IHD is unclear. METHODS: We prospectively carried out a symptom-limited 12-lead Bruce protocol thallium-201 single-photon emission computed tomographic (SPECT) exercise test in 66 consecutive subjects with stable angina, > or = 70% stenosis of at least one coronary artery, normal rest ECG and left ventricular wall motion and a prior positive exercise ECG. The above ECG indexes, vessel disease (VD), a VD score and the quantitative thallium-SPECT measures of the extent, maximal deficit and redistribution gradient of the perfusion abnormality were characterized. RESULTS: Maximal ST segment depression could not differentiate the number of diseased vessels; was not related to VD score, maximal thallium deficit or redistribution gradient; but was related to the extent of perfusion abnormality (r = 0.29, 95% confidence interval [CI] 0.08 to 0.52, p = 0.02). Time of onset of ST segment depression correlated inversely only with VD (r = -0.22, 95% CI -0.44 to -0.05, p < 0.05), whereas the ischemic threshold had low inverse correlation only with VD score (r = -0.25, 95% CI -0.47 to -0.01, p < 0.05) and the redistribution gradient (r = -0.33, 95% CI -0.53 to -0.10, p < 0.01). A horizontal or downsloping compared with an upsloping ST segment did not demonstrate more severe angiographic and scintigraphic disease. Recovery time did not correlate with angiographic and scintigraphic findings, and correlations between angiographic and scintigraphic findings were also low or absent. CONCLUSIONS: In this homogeneous study group, the exercise ECG indexes did not necessarily signify more severe IHD by angiographic and scintigraphic criteria. Lack of concordance between the exercise ECG, angiography and myocardial scintigraphy suggests that these diagnostic modalities examine different facets of myocardial ischemia, underscoring the need for caution in the interpretation of their results.

Left ventricular intramyocardial pressure determination using two different solid-state micromanometric pressure sensors.

Intramyocardial tissue pressure can influence distribution of ventricular blood flow and dynamics during the cardiac cycle. Left ventricular ventral wall subepicardial and subendocardial tissue pressures were measured simultaneously using two different types of solid-state micromanometers (5F Millar model SPR-230 and Konigsberg Instruments model P19 pressure transducers) and compared with left ventricular cavity pressure. Systolic pressures recorded by Millar and Konigsberg transducers were similar when the sensor surfaces faced the left ventricular cavity either in the endocardium or epicardium. Diastolic pressures in the epicardium were higher than left ventricular cavity pressure. When Millar and Konigsberg transducer were placed in the epicardium, with the pressure sensors facing epicardially, the output signal of the Millar transducer was out of phase with the signal of the Konigsberg transducer and left ventricular chamber pressure outputs. Results indicate that output signals for intramyocardial pressures vary depending on the direction of the Millar or Konigsberg pressure sensor in the left ventricular wall. Thus, pressure output signals vary depending on configuration of the sensor surface, relative flexibility of the connecting cables, and orientation of the sensor surface with respect to left ventricular anatomy.

Effect of 3-aminotriazole on hyperthermia-mediated cardioprotection in rabbits.

Hyperthermia-induced cardioprotection during myocardial ischemia may involve increased activity of antioxidative enzymes. In this study we investigated the effects of 3-amino-1,2,4-triazole (3-AT), an irreversible catalase inhibitor, in heat-shocked (HS) rabbits subjected to ischemia-reperfusion injury. Rabbits underwent whole body hyperthermia at 42 degrees C for 15 min. Twenty-four hours later, rabbits were administered either saline vehicle or 3-AT (1 or 2 g/kg i.p.) 30 min before undergoing 30 min of regional coronary occlusion and 3 h reperfusion. Controls did not undergo whole body hyperthermia and were given either saline or 3-AT. Heart rate and left ventricular pressure were recorded continuously during these experiments. Infarct area (tetrazolium staining) was normalized to anatomic risk zone size (microsphere autoradiography). Expression of HSP 71 was verified using Western blot analysis; myocardial catalase activity was determined in tissue biopsies. Infarct size was significantly reduced in HS rabbits (25.1 +/- 2.8%, P = 0.2; means +/- SE) compared with controls (53.6 +/- 4.7%). Treatment with 1 g/kg 3-AT attenuated HS-mediated cardioprotection (36.9 +/- 4.9%, P = 0.063 vs. HS); protection was abolished with 2 g/kg 3-AT (48.9 +/- 6.6%). Myocardial catalase activities were higher in tissue biopsies from HS rabbits (47.0 +/- 4.5 U/mg protein, P < or = 0.02) compared with controls (33.4 +/- 1.9 U/mg protein); catalase activities were significantly reduced in rabbits treated with 3-AT. In conclusion, whole body hyperthermia increases expression levels of HSP 71; myocardial catalase activity is also significantly increased. Myocardial protection is HS rabbits subjected to ischemia-reperfusion injury was reversed with 3-AT. These data suggest that increased intracellular activities of catalase and possibly other antioxidant enzymes is an important mechanism for hyperthermia-mediated cellular protection.

Chemical modulation of in situ intrinsic cardiac neurones influences myocardial blood flow in the anaesthetised dog.

OBJECTIVE: The aim was to determine whether modulation of intrinsic cardiac neurones influences the distribution of myocardial blood flow in canine anaesthetised open chest experimental preparations. METHODS: Intrinsic cardiac neurones were modified by locally applied nicotine (100 micrograms) or bradykinin (50 micrograms) while changes were recorded in cardiac haemodynamics and myocardial blood flow (radiolabelled microspheres). Right and left ventricular intramyocardial tissue pressures were measured with high fidelity microtip transducers. RESULTS: Control injections of saline (vehicle; 0.1 ml) into active loci did not produce cardiovascular responses. Nicotine modulation of intrinsic cardiac neurones did not change coronary artery conductance, but total myocardial blood flow [116(SEM 17) v 532(97) ml.min-1.100 g-1; p = 0.001 v baseline] and oxygen consumption [7.92(1.10) v 20.14(1.86) ml.min-1.100 g-1; p = 0.001] increased in direct relation to heart rate-blood pressure product changes. Locally administered bradykinin increased coronary artery conductance [2.62(0.39) v 4.71(1.07) ml.min-1.100 g-1.mm Hg-1], total myocardial blood flow, to 263(72) ml.min-1.100 g-1, and oxygen consumption, to 14.9(4.4) ml.min-1.100 g-1; however, heart rate-blood pressure product did not change. CONCLUSIONS: These results support earlier findings that intrinsic neurones are involved in cardiac regulation. Furthermore, modification of intrinsic cardiac neurones by nicotine or bradykinin significantly alters the distribution of myocardial blood flow, possibly because of increased myocardial metabolism.

Prognostic value of neurohumoral activation in patients with an acute myocardial infarction: effect of captopril.

OBJECTIVES: This study attempted to evaluate whether neurohumoral activation at the time of hospital discharge in postinfarction patients helps to predict long-term prognosis and whether long-term therapy with the angiotensin-converting enzyme inhibitor captopril modifies this relation. BACKGROUND: Neurohumoral activation persists at the time of hospital discharge in a large number of postinfarction patients. The Survival and Ventricular Enlargement (SAVE) study demonstrated that the angiotensin-converting enzyme inhibitor captopril improves survival and decreases the development of severe heart failure in patients with left ventricular dysfunction (left ventricular ejection fraction < or = 40%) but no overt postinfarction heart failure. METHODS: In 534 patients in the SAVE study, plasma neurohormone levels were measured a mean of 12 days after infarction. Patients were then randomized to receive captopril or placebo and were followed up for a mean (+/- SD) of 38 +/- 6 months (range 24 to 55). The association between activation of plasma neurohormones at baseline and subsequent cardiovascular mortality or the development of heart failure was assessed with and without adjustment for other important prognostic factors. RESULTS: By univariate analysis, activation of plasma renin activity and aldosterone, norepinephrine, atrial natriuretic peptide and arginine vasopressin levels were related to subsequent cardiovascular events, whereas epinephrine and dopamine levels were not. By multivariate analysis, only plasma renin activity (relative risk 1.6, 95% confidence interval [CI] 1.0 to 2.5) and atrial natriuretic peptide (relative risk 2.2, 95% CI 1.3 to 3.8) were independently predictive of cardiovascular mortality, whereas the other neurohormones were not. Only plasma renin activity and aldosterone, atrial natriuretic peptide and arginine vasopressin were independent predictors of the combined end points of cardiovascular mortality, development of severe heart failure or recurrent myocardial infarction. Except for 1-year cardiovascular mortality, the use of captopril did not significantly modify these relations. CONCLUSIONS: Neurohumoral activation at the time of hospital discharge in postinfarction patients is an independent sign of poor prognosis. This is particularly true for plasma renin activity and atrial natriuretic peptide. Except for 1-year cardiovascular mortality, captopril does not significantly modify these relations.

Acute tamponade alters subendo- and subepicardial pressure-flow relations differently during vasodilation.

Instantaneous diastolic left coronary artery pressure-flow relations (PFR) shift during acute tamponade as pressure surrounding the heart increases. Coronary pressure at zero flow (Pf = 0) on the linear portion of the PFR is the weighted mean of the different myocardial waterfall pressures, the distribution of which varies across the left ventricular wall during diastole. However, instantaneous PFR measured in large epicardial coronary arteries cannot be used to estimate Pf = 0 in the different myocardial tissue layers. During coronary vasodilatation in a capacitance-free model, myocardial PFR differs from subendocardium to subepicardium. Therefore, we studied the effects of acute tamponade during maximal pharmacology induced coronary vasodilatation on myocardial PFR in in situ anesthetized dogs. Tamponade reduced cardiac output, aortic pressure, and coronary blood flow. Results demonstrate that different mechanisms influence distribution of myocardial blood flow during tamponade. Subepicardial vascular resistance is unchanged and the extrapolated Pf = 0 is increased, thereby shifting PFR to a higher intercept on the pressure axis. Subendocardial vascular resistance is increased while the extrapolated Pf = 0 remains unchanged. Results indicate that in the setting of acute tamponade with coronary vasodilatation different mechanisms regulate the distribution of myocardial blood flow: in the subepicardium only outflow pressure increases, whereas in the subendocardium only vascular resistance increases.

Microsphere and dilution measurements of flow and interstitial space in dog heart.

The effects of coronary flow on cardiac capillary permeability-surface area products and interstitial spaces were examined at rest and after hemodilution in the canine heart. Multiple-indicator-dilution experiments and left atrial injections of microspheres were carried out in closed-chest anesthetized animals at rest and after plasma expansion with dextran. Plasma expansion was utilized to produce a large increase in coronary perfusion compared with control conditions. Values for plasma flow per unit interstitial space, derived from analysis of the indicator-dilution data, were found to correlate closely with average vascular plasma flow per gram, calculated from the cardiac microsphere data; the one reflects the other. With an increase in flow, cardiac capillary permeability-surface area product values were found to increase substantially, whereas the average sucrose extravascular or cardiac interstitial spaces remained stable. Consequently the dilution parameter, flow per unit interstitial space, which is independent of tracer loss, provided a good reflection of flow per weight of tissue in the heart, without the additional requirement for a flow probe.

Timely administration of AICA riboside reduces reperfusion injury in rabbits.

OBJECTIVE: Agents which promote increased interstitial adenosine levels may be cardioprotective. The aim of this study was to evaluate the ability of 5-amino-1-beta-D- ribofuranosylimidazole-4-carboxamide (AICAr), an adenosine regulating agent, to limit infarct size when given before ischaemia, before coronary reperfusion, or postreperfusion in a rabbit preparation of ischaemia-reperfusion injury. METHODS: The left coronary artery was occluded for 30 min and subsequently the ischaemic bed was reperfused for 180 min. Infarct size and risk zone size were delineated by tetrazolium staining and microsphere autoradiography, respectively. Four groups were studied: controls (n = 13), AICAr (2.5 mg.kg-1.min-1 intravenously for 5 min followed by 0.5 mg.kg-1.min-1 for 60 min) beginning either 5 min before coronary occlusion (n = 11), 5 min before coronary reperfusion (n = 11), or at 25 min coronary reperfusion (n = 10). Lignocaine was not given in these experiments. RESULTS: Infarct size, normalised to risk zone, was significantly reduced with AICAr given 5 min before coronary reperfusion, at 35.0(SEM 4.4)% v 51.8(3.9)% in controls; p = 0.03. Cardioprotection was not observed when AICAr was given either 5 min before coronary occlusion [44.2(4.8)%] or 25 min postreperfusion [45.9(3.2)%]. CONCLUSIONS: These findings support the hypothesis that adenosine regulating agents, such as AICAr, can modulate infarct size in this rabbit preparation of ischaemia-reperfusion injury.

Myocardial tissue pressure and blood flow during coronary sinus pressure modulation in anesthetized dogs.

To determine whether coronary sinus outflow pressure (Pcs) or intramyocardial tissue pressure (IMP) is the effective back pressure in the different layers of the left ventricular (LV) myocardium, we increased Pcs in 14 open-chest dogs under maximal coronary artery vasodilation. Circumflex arterial (flowmeter), LV total, and subendocardial and subepicardial (15-microns radioactive spheres) pressure-flow relationships (PFR) and IMP (needle-tip pressure transducers) were recorded during graded constriction of the artery at two diastolic Pcs levels (7 +/- 3 vs. 23 +/- 4 mmHg). At high Pcs, LV, aortic and diastolic circumflex arterial pressure, heart rate, myocardial oxygen consumption, and lactate extraction were unchanged; IMP in the subendocardium did not change (130/19 mmHg), whereas IMP in the subepicardium increased by 17 mmHg during systole and 10 mmHg during diastole (P < or = 0.001), independently of circumflex arterial pressure. Increasing Pcs did not change the slope of the PFR; however, coronary pressure at zero flow increased in the subepicardium (P < or = 0.008), whereas in the subendocardium it remained unchanged at 24 +/- 3 mmHg. Thus Pcs can regulate IMP independently of circumflex arterial pressure and consequently influence myocardial perfusion, especially in the subepicardial tissue layer of the LV.

Improved high-performance liquid chromatographic assay for the stereoselective determination of mexiletine in plasma.

A simple and sensitive high-performance liquid chromatographic procedure for resolution of mexiletine enantiomers has been developed. Proteins from plasma samples containing RS-mexiletine were precipitated with a mixture of barium hydroxide and zinc sulphate before extraction under alkaline conditions with diethyl ether. Organic extracts were evaporated to dryness, and the residues reconstituted with 0.03 M hydrochloric acid (20 microliters). Derivatization with o-phthalaldehyde N-acetyl-L-cysteine reagent was performed after alkalinization with 0.1 M sodium borate. An aliquot of the resulting solution was injected onto a reversed-phase C18 column and resolution of mexiletine diastereoisomeric derivatives was achieved with a mobile phase consisting of methanol-50 mM sodium acetate (65:35), at a flow-rate of 1 ml/min. The retention times of S-(+)- and R-(-)-mexiletine diastereoisomeric peaks were 14 and 15 min, respectively. Product elution was monitored by fluorescence detection using excitation and emission wavelengths fixed at 350 and 445 nm, respectively. Calibration curves were linear over the concentration range 2.5-500 ng/ml for each enantiomer (r greater than 0.99). The assay is shown to be suitable for pharmacokinetic studies after administration of a single oral dose of 200 mg of RS-mexiletine hydrochloride to healthy volunteers.

Influence of debrisoquine phenotype and of quinidine on mexiletine disposition in man.

Mexiletine is a low clearance drug which undergoes extensive metabolism in man. In vitro studies with human liver microsomes have suggested that major oxidation pathways of mexiletine are predominantly catalyzed by the genetically determined debrisoquine 4-hydroxylase (cytochrome P450IID6) activity. In this study, we investigated the role of debrisoquine polymorphism and the effects of low dose quinidine, a selective inhibitor of cytochrome P450IID6, on the disposition of mexiletine. Fourteen healthy volunteers, 10 with the extensive metabolizer (EM) and 4 with the poor metabolizer (PM) phenotype, received a single 200-mg dose of mexiletine hydrochloride orally on two occasions (1 week apart), once alone and once under steady-state conditions for quinidine (50 mg QID). During the phase mexiletine alone, total clearance, nonrenal clearance and partial metabolic clearance of mexiletine to hydroxymethylmexiletine, to m-hydroxymexiletine and to p-hydroxymexiletine were decreased in PM compared to EM (all P less than .05). In EM, quinidine decreased mexiletine total clearance from 621 +/- 298 to 471 +/- 214 ml/min (mean +/- S.D.; P less than .05) and mexiletine nonrenal clearance from 583 +/- 292 to 404 +/- 188 ml/min (P less than .05). Moreover, quinidine increased mexiletine elimination half-life in EM from 9 +/- 1 to 11 +/- 2 h (P less than .05). In these subjects, partial metabolic clearance to hydroxymethylmexiletine, m-hydroxymexiletine and p-hydroxymexiletine were decreased by quinidine coadministration 5-, 4- and 7-fold, respectively, whereas partial metabolic clearance to N-hydroxymexiletine was unaffected. Changes induced by quinidine in EM were correlated to their debrisoquine metabolic ratio. Thus, genetically determined or pharmacologically induced modulation of cytochrome P450IID6 activity represents a major determinant of mexiletine disposition.

Prognosis in patients with a strongly positive exercise electrocardiogram.

In patients with a strongly positive exercise electro-cardiogram, the workload achieved during the test allows the identification of subsets with good or poor survival rates. To determine whether the same criteria also predict acute ischemic heart events such as unstable angina and myocardial infarction, fatal and nonfatal acute manifestations were documented in 241 patients medically treated during an 8-year follow-up. All patients had a Bruce protocol treadmill exercise test with ST-segment depression greater than or equal to 2 mm and coronary angiographic studies. There were 52 deaths; of these 44 were due to coronary artery disease. There were 41 episodes of unstable angina and 21 myocardial infarcts documented as first morbid events. As expected, survival improved with increased workload achieved; patients terminating their exercise at stage I (5.1 METs) had an 8-year survival rate of 45 +/- 9% while those reaching stage IV or more (10 METs) had a survival rate of 93 +/- 6%. In a multivariate analysis, the duration of exercise and the number of narrowed coronary arteries and of left ventricular segment abnormalities correlated significantly with survival. In contrast, nonfatal acute events occurred in about 20 to 35% of patients whatever the stage of the exercise test. Furthermore, neither variables during the exercise test nor angiographic findings predicted nonfatal events. Thus, although the workload achieved did identify patients with different mortality rates, it failed to predict subsets of patients with different morbid event rates.

Effect of N-acetylcysteine on tissue necrosis during acute myocardial infarction in rabbits.

This study examined whether N-acetylcysteine, a low molecular weight compound used clinically to replenish glutathione, could limit tissue necrosis during acute myocardial infarction in hearts with minimal coronary collateral flow. Fifty rabbits underwent 45 mins ischemia with and without coronary reperfusion for 3h. Four groups were studied. Saline or N-acetylcysteine (140 mg/kg) was administered intravenously 10 mins before occlusion and continued for 35 mins after occlusion. The area at risk of necrosis was assessed with fluorescent particles and the area of tissue necrosis was defined using triphenyltetrazolium chloride staining. No differences were observed for tissue necrosis expressed as a percentage of the risk zone size (mean +/- SEM, 46.7 +/- 8.2% versus 46.3 +/- 8.2%) for saline and N-acetylcysteine treated rabbits subjected to 45 mins coronary occlusion. Tissue necrosis in rabbits with 45 mins ischemia followed by 3 h reperfusion was not significantly reduced with N-acetylcysteine treatment (36.4 +/- 5.1%) compared to untreated controls (36.5 +/- 6.4%). Risk zone size and hemodynamic parameters were similar between the treatment groups. Thus, treatment before and during short term coronary occlusion did not limit tissue necrosis during acute myocardial infarction.