Comparison of the telephone-Montreal Cognitive Assessment (T-MoCA) and Telephone Interview for Cognitive Status (TICS) as screening tests for early Alzheimer's disease.

INTRODUCTION: Remote screening for cognitive impairment associated with Alzheimer's disease (AD) has grown in importance with the expected rise in prevalence of AD in an aging population and with new potential treatment options. METHODS: The Telephone Interview for Cognitive Status (TICS) and new telephone adaptation of the Montreal Cognitive Assessment (T-MoCA) were administered to participants independently classified through in-person clinical evaluation as cognitively normal (CN; n = 167), mild cognitive impairment (MCI; n = 25), or dementia (n = 23). Cerebrospinal fluid AD biomarkers were measured (n = 79). RESULTS: TICS and T-MoCA were highly correlated (r = 0.787; P < 0.001): groups differed on both (CN

Exploration of potential mechanisms of hepatitis C virus resistance in exposed uninfected intravenous drug users.

A rare outcome following exposure to hepatitis C virus (HCV) is a lack of observable infection as clinically measured by HCV RNA- or HCV-recognizing antibodies. The population who exhibit this trait is termed exposed uninfected (EU). Increasing evidence has refined characterization of these individuals, distinct from those who become infected but spontaneously clear HCV. Study of the EU population is highly pertinent for the discovery of antiviral mechanisms of resistance that can reveal antiviral therapeutic strategies. This review provides an overview of similarities and differences of the EU population relative to spontaneous resolvers and the majority whom develop chronic HCV infection, and focusses on possible mechanisms of resistance including innate and adaptive immunity, genetics and lipid interactions.

The Role of Prevotella Species in Female Genital Tract Infections.

Female genital tract infections (FGTIs) include vaginal infections (e.g., bacterial vaginosis [BV]), endometritis, pelvic inflammatory disease [PID], and chorioamnionitis [amniotic fluid infection]. They commonly occur in women of reproductive age and are strongly associated with multiple adverse health outcomes including increased risk of HIV/sexually transmitted infection acquisition and transmission, infertility, and adverse birth outcomes such as preterm birth. These FGTIs are characterized by a disruption of the cervicovaginal microbiota which largely affects host immunity through the loss of protective, lactic acid-producing Lactobacillus spp. and the overgrowth of facultative and strict anaerobic bacteria. Prevotella species (spp.), anaerobic Gram-negative rods, are implicated in the pathogenesis of multiple bacterial FGTIs. Specifically, P. bivia, P. amnii, and P. timonensis have unique virulence factors in this setting, including resistance to antibiotics commonly used in treatment. Additionally, evidence suggests that the presence of Prevotella spp. in untreated BV cases can lead to infections of the upper female genital tract by ascension into the uterus. This narrative review aims to explore the most common Prevotella spp. in FGTIs, highlight their important role in the pathogenesis of FGTIs, and propose future research in this area.

Tracing TET1 expression in prostate cancer: discovery of malignant cells with a distinct oncogenic signature.

BACKGROUND: Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) is involved in DNA demethylation and transcriptional regulation, plays a key role in the maintenance of stem cell pluripotency, and is dysregulated in malignant cells. The identification of cancer stem cells (CSCs) driving tumor growth and metastasis is the primary objective of biomarker discovery in aggressive prostate cancer (PCa). In this context, we analyzed TET1 expression in PCa. METHODS: A large-scale immunohistochemical analysis of TET1 was performed in normal prostate (NOR) and PCa using conventional slides (50 PCa specimens) and tissue microarrays (669 NOR and 1371 PCa tissue cores from 371 PCa specimens). Western blotting, RT-qPCR, and 450 K methylation array analyses were performed on PCa cell lines. Genome-wide correlation, gene regulatory network, and functional genomics studies were performed using publicly available data sources and bioinformatics tools. RESULTS: In NOR, TET1 was exclusively expressed in normal cytokeratin 903 (CK903)-positive basal cells. In PCa, TET1 was frequently detected in alpha-methylacyl-CoA racemase (AMACR)-positive tumor cell clusters and was detectable at all tumor stages and Gleason scores. Pearson's correlation analyses of PCa revealed 626 TET1-coactivated genes (r > 0.5) primarily encoding chromatin remodeling and mitotic factors. Moreover, signaling pathways regulating antiviral processes (62 zinc finger, ZNF, antiviral proteins) and the pluripotency of stem cells were activated. A significant proportion of detected genes exhibited TET1-correlated promoter hypomethylation. There were 161 genes encoding transcription factors (TFs), of which 133 were ZNF-TFs with promoter binding sites in TET1 and in the vast majority of TET1-coactivated genes. CONCLUSIONS: TET1-expressing cells are an integral part of PCa and may represent CSCs with oncogenic potential.

A study of the structure of the crystalline bacterial biofilms that can encrust and block silver Foley catheters.

The aim of this study was to examine the structure of the crystalline bacterial biofilms that encrust and block silver/hydrogel-coated latex catheters. Scanning electron microscopy was used to examine the crystalline deposits that were found encrusting catheters obtained from six patients undergoing long-term catheterization in a community setting. Large populations of bacilli and cocci were seen on all catheters developing on a basal foundation layer of crystalline material. These observations show that in patients prone to catheter encrustation, crystalline material formed in the urine can cover the surfaces of silver catheters. Extensive bacterial biofilms then develop on the crystals, shielded from the underlying silver. It is suggested that if antimicrobials are to be incorporated into catheters to prevent encrustation, they must diffuse out from the catheter surface and reduce the viable cell populations of the urease producing bacteria that elevate the urinary pH and trigger crystal formation.

Alpha adrenergic contributions to dysrhythmia during myocardial ischemia and reperfusion in cats.

Alpha compared to beta adrenergic contributions to dysrhythmias induced by left anterior descending coronary occlusion and by reperfusion were assessed in chloralose-anesthetized cats (n = 96). Alpha receptor blockade with either phentolamine or prazosin significantly reduced the number of premature ventricular complexes during coronary reperfusion (321 +/- 62-14 +/- 10 premature ventricular complexes, P less than 0.001), abolished early ventricular fibrillation (from 25% in controls to 0%), and prevented the increase in idioventricular rate seen with coronary reperfusion. However, beta-receptor blockade was without effect. Ventricular dysrhythmias induced by coronary occlusion alone (without reperfusion) were attenuated markedly by alpha-receptor blockade under conditions in which perfusion (measured with radiolabeled microspheres) within ischemic zones was not affected. Alternative sympatholytic interventions including pretreatment with 6-hydroxydopamine to deplete myocardial norepinephrine from 8.8 +/- 1.4 to 0.83 +/- 0.2 ng/mg protein and render the heart unresponsive to tyramine (120 microgram/kg) attenuated dysrhythmias induced by both coronary occlusion and reperfusion in a fashion identical to that seen with alpha-receptor blockade. Although efferent sympathetic activation induced by left stellate nerve stimulation increased idioventricular rate from 66 +/- 6 to 144+/- 7 beats/min (P less than 0.01) before coronary occlusion, this response was blocked by propranolol but not by phentolamine. In contrast, during reperfusion the increase in idioventricular rate induced by left stellate nerve stimulation (to 203 +/- 14) was not inhibited by propranolol but was abolished by phentolamine (79 +/- 10). Intracoronary methoxamine (0.1 microM) in animals depleted of myocardial catecholamines by 6-hydroxydopamine pretreatment did not affect idioventricular rate before coronary occlusion. However, early after coronary reperfusion, methoxamine increased idioventricular rate from 33 +/- 7 to 123 +/- 21 beats/min (P less than 0.01). Thus, enhanced alpha-adrenergic responsiveness occurs during myocardial ischemia and appears to be primary mediator of the electrophysiological derangements and resulting malignant dysrhythmias induced by catecholamines during myocardial ischemia and reperfusion.

Hepatitis C virus and atherosclerosis: A legacy after virologic cure?

Hepatitis C virus (HCV) is a major pathogen with approximately 3% of the world's population (over 170 million) infected. Epidemiological studies have shown HCV is associated with an increased risk of cardiovascular and cerebrovascular mortality as well as peripheral arterial disease. This is despite HCV inducing an ostensibly favourable lipid profile with accompanying low classical risk score for atherosclerosis (AS). We discuss possible factors involved in the aetiopathogenesis of atherosclerosis in chronic HCV and hypothesise that an important mechanism underlying the development of AS is the presence of circulating low-density immune complexes that induce an inflammatory response. We suggest that HCV particles may be inducing an antibody response to lipoproteins present in the lipoviral particles and sub-viral particles - a concept similar to the more general 'autoantibody' response to modified LDL. After virologic cure some AS risk factors will recede but an increase in serum cholesterol could result in progression of early atherosclerotic lesions, leaving a legacy from persistent HCV infection that has clinical and therapeutic implications.

Regions of alpha-amino-5-methyl-3-hydroxy-4-isoxazole propionic acid receptor subunits that are permissive for the insertion of green fluorescent protein.

The green fluorescent protein can be fused to the ends of a mature glutamate receptor subunit to produce functional, fluorescent receptors. However, there are good reasons to search for internal regions of receptor subunits that can tolerate green fluorescent protein insertion. First, internal insertions of green fluorescent protein may produce functional, fluorescent subunits that traffic more correctly. Second, fluorescent proteins inserted near interacting surfaces of subunits could potentially create reagents suitable for fluorescence resonance energy transfer measurements. Finally, internal green fluorescent protein insertions could potentially produce subunits capable of signaling conformational changes through intrinsic changes in fluorescence intensity. To identify regions of receptor subunits that are permissive for green fluorescent protein insertion, we used a series of recombinant transposons to create fluorescent protein insertions in three alpha-amino-5-methyl-3-hydroxy-4-isoxazole propionic acid receptor subunits. A combined analysis of the relative fluorescence intensity and glutamate-gated ion channel function of 69 different green fluorescent protein fusion proteins identified permissive zones for the creation of bright and fully functional receptor subunits in the C-terminal portion of the amino terminal domain, the intracellular tail of the carboxy terminal domain, and within the pore-forming regions of the channel.

Modulation of crystalline Proteus mirabilis biofilm development on urinary catheters.

The crystalline biofilms formed by Proteus mirabilis can seriously complicate the care of patients undergoing long-term bladder catheterization. The generation of alkaline urine by the bacterial urease causes calcium and magnesium phosphates to precipitate from urine and accumulate in the catheter biofilm, blocking the flow of urine from the bladder. The pH at which these salts crystallize from a urine sample, the nucleation pH (pH(n)), can be elevated by diluting the urine and by increasing its citrate content. The aim of this study was to examine whether manipulation of pH(n) in these ways modulated the rate at which crystalline biofilm developed. Experiments in laboratory models of the catheterized bladder infected with P. mirabilis showed that when the bladder was supplied with a concentrated urine (pH(n) 6.7) at a low fluid output (720 ml per 24 h), catheters blocked at 19-31 h. Diluting this urine 1:4 increased the pH(n) to 7.5 and models supplied with this urine at 2880 ml per 24 h took 110-137 h to block. When models were supplied with urine containing citrate at 1.5 mg ml(-1) or above (pH(n) 8.3-9.1), the catheters drained freely for the full 7 day experimental period. Scanning electron microscopy revealed that the catheter biofilms that developed in urine with high pH(n) values were devoid of crystalline formations. These observations should encourage a clinical trial to examine the effect of increasing a patient's fluid intake with citrate-containing drinks on the encrustation and blockage of catheters.

Postnatal developmental changes in the electrophysiological properties of cat right ventricular papillary muscles.

Cellular electrophysiological properties of cat right ventricular papillary muscles were studied during postnatal development using intracellular microelectrodes. Animals were studied in the neonatal period (less than 75 h of age), in infancy (16 to 18 days old) and in adult life (1.8 to 2.3 kg body weight). Resting membrane potential, action potential amplitude, Vmax and action potential duration increased significantly with age. The age related changes in action potential duration were independent of stimulation frequency. Conduction velocity was measured using two simultaneous impalements and increased significantly with age. Exposure to low [Ca]o (0.2 mmol X litre-1) caused a prolongation in action potential duration which was greater in infant and adult than neonatal myocardium, and was greatest at low stimulation frequencies. High [Ca]o shortened action potential duration and this was also greater in infant and adult tissue. Action potential duration was prolonged by low [K]o (0.5 mmol X litre-1) and shortened by high [K]o. Both of these effects appeared to be independent of age. Exposure to ouabain, 10(-8) and 10(-7) mol X litre-1 caused a dose related shortening of action potential duration. This effect was significantly greater in adult and infant than neonatal myocardium. The results indicate that the electrophysiological properties of the cat myocardium continue to develop during early postnatal life. These findings are discussed in relation to changes in morphology and transmembrane ionic gradients occurring at this time.

Direct effect of acebutolol on force generation in immature and adult myocardium.

The effect of acebutolol on active isometric force generation has been studied in isolated papillary muscle preparations from adult cats and kittens less than 24 h old. Statistically significant reduction in active force occurred at a concentration of 0.27 mmol-litre-1 in the adult preparations and at 1.34 mmol-litre-1 in the infant ones. At 2.86 mmol-litre-1 active force had fallen to 43.4%+/-2.2 (SEM) of the control value in the adults and to 52.4%+/-3.3(SEM) in the infants. These results suggest that the infant myocardium is no more sensitive to the negative inotropic effect of acebutolol than is the adult myocardium.

Postnatal maturation of noradrenaline uptake and release in cat papillary muscles.

Catecholamine uptake and release have been studied in isolated right ventricular papillary muscles from kittens aged less than 24 hours, 16 to 18 days and 28 to 32 days. Under the age of 24 h catecholamine uptake (uptake I) does not appear to be functioning and at this age there is a significantly lower response to tyramine. These results suggest that myocardial sympathetic innervation continues to mature, in the cat, after birth.

Arrhythmias and cellular electrophysiological changes during myocardial "ischaemia" and reperfusion.

Action potentials and ECGs were recorded from isolated guinea pig hearts during low flow (10% of control) and zero flow myocardial "ischaemia" and during subsequent reperfusion. During myocardial "ischaemia" ventricular tachycardia and ventricular fibrillation were significantly more frequent during low flow, than zero flow "ischaemia" (P less than 0.01). Reperfusion arrhythmias required a minimum ischaemic period of 10 to 15 min, were most frequent following 20 to 30 min of "ischaemia", being fewer following 60 min of "ischaemia" (P less than 0.05). The degree of "ischaemia" had little effect on reperfusion arrhythmias following 20 to 30 min of "ischaemia". Both types of "ischaemia" reduced action potential amplitude, Vmax, and duration, and increased conduction time. During low flow "ischaemia", electrophysiological change reached a nadir at 12 +/- 3 (mean +/- SEM) min, and in all cases spontaneous electrophysiological recovery in action potentials and conduction time preceded ventricular arrhythmias, which occurred at 18 +/- 3 min. In contrast during zero flow "ischaemia" electrophysiological changes were more marked and no recovery was observed. Refractory periods were initially prolonged by both forms of "ischaemia", followed by a marked shortening. The initial prolongation was more marked and subsequent shortening less during zero than low flow "ischaemia". Reperfusion induced electrophysiological recovery in all hearts; however reperfusion VF was preceded by further shortening of action potential duration and refractory period. These results indicate that residual flow during myocardial "ischaemia" is associated with spontaneous electrophysiological recovery and more frequent ventricular arrhythmias. The severity of "ischaemia" is less important than its duration for the development of reperfusion arrhythmias.

Effects of sotalol on arrhythmias and electrophysiology during myocardial ischaemia and reperfusion.

Isolated, buffer perfused guinea pig hearts were used to study the effects of sotalol on arrhythmias and electrophysiology during 30 min of myocardial ischaemia, induced by reducing coronary flow to 10% of control, and subsequent reperfusion. Action potentials were recorded using the floating microelectrode technique and arrhythmias were noted and defined by extracellular electrical records. Sotalol 10(-4) mol X litre-1 reduced the incidence of ventricular arrhythmias during myocardial ischaemia and reperfusion. Prior to the onset of ischaemia sotalol reduced action potential amplitude and Vmax, and prolonged action potential duration, refractory period, and conduction time, and increased pacing threshold. During myocardial ischaemia the effect of sotalol on action potential duration disappeared, and that on refractory period was diminished. The effect of sotalol on action potential amplitude and Vmax was reduced during the early (2 to 12 min) part of ischaemia, but later, at the onset of arrhythmias, tended to reemerge, while the effect on QRS width was exaggerated. Thus the cellular electrophysiological effects of sotalol on normal myocardium provided a poor guide to the mechanism of its antiarrhythmic action in ischaemic tissue.

The effects of diadenosine polyphosphates on the cardiovascular system.

Diadenosine polyphosphates are members of a group of dinucleoside polyphosphates that are ubiquitous, naturally occurring molecules. They form a recently identified class of compounds derived from ATP and consist of two adenosine molecules bridged by up to six phosphate groups. These compounds are stored in high concentrations in platelet dense granules and are released when platelets become activated. Some of the compounds promote platelet aggregation, while others are inhibitory. Possible roles as neurotransmitters, extracellular signalling molecules or 'alarmones' secreted by cells in response to physiologically stressful stimuli have been postulated. Recent studies suggest a role for these compounds in atrial and synaptic neurotransmission. Studies using isolated mesenteric arteries indicate an important role of phosphate chain length in determining whether diadenosine polyphosphates produce vasodilation or vasoconstriction, but in the coronary circulation, diadenosine polyphosphates generally produce vasodilation via mechanisms thought to involve release of NO or prostacyclin (PGI2). They produce cardiac electrophysiological effects by altering ventricular refractoriness at submicromolar concentrations and reduce heart rate. Mechanisms involving KATP channels have been proposed in addition to the involvement of P1- and P2-purinergic receptors and the specific diadenosine polyphosphate receptor identified on isolated cardiac myocytes. Clinical evidence suggests a role for diadenosine polyphosphates in hypertensive patients and those with the Chédiak-Higashi syndrome. This review outlines the effects of these compounds on the cardiovascular system and considers their potential involvement in mediating the pathophysiological effects associated with platelet activation during myocardial ischaemia.

Postnatal ultrastructural changes in the cat myocardium: a morphometric study.

In order to understand more clearly the basis for our previously observed postnatal age related changes in the mechanical performance of the cat myocardium we have carried out a quantitative ultrastructural analysis of right ventricular papillary muscles obtained from adult cats (1.8 to 2.3 kg), infant cats (16 days of age), and neonatal kittens (less than 72 hours old). Volume fractions were calculated for myofibrils, sarcoplasm, mitochondria, lipid, sarcoplasmic reticulum (SR), golgi, and nuclei. The myofibril content of neonatal fibres was significantly less than that of the infant or adult groups (P less than 0.05 and 0.005 respectively). In addition the infant fibres contained a smaller volume of myofibrils than the adult ones (P less than 0.001). The mitochondrial content of the neonatal fibres was also significantly less than that of either the infants' (P less than 0.005) or adults' (P less than 0.001). These data provide an anatomical basis for the progressive age related increase in mechanical performance of the cat myocardium, in postnatal life.

Effects of myocardial catecholamine depletion on cellular electrophysiology and arrhythmias during ischaemia and reperfusion.

The effect of myocardial catecholamine depletion on cellular electrophysiology and arrhythmias was assessed in Langendorff perfused guinea pig hearts during ischaemia and reperfusion. Myocardial noradrenaline was reduced to 0.17 +/- 0.04 microgram X g-1 by intracardiac injection of 6-hydroxydopamine (450 mg X kg-1 in six doses over 20 days) compared with 1.5 +/- 0.2 microgram X g-1 in vehicle injected controls. Myocardial catecholamine depletion significantly reduced the incidence of ventricular tachycardia and fibrillation during 30 min of global ischaemia and subsequent reperfusion. Myocardial catecholamine depletion prolonged action potential duration and refractory period during control perfusion and blunted ischaemia induced reduction in action potential amplitude, Vmax, and duration, but accentuated the prolongation in conduction time and QRS width. Catecholamine depletion abolished or attenuated reperfusion induced shortening of action potential duration and refractory period. Catecholamine depletion increased myocardial glycogen levels from 2.47 +/- 0.3 mg X g-1 wet weight to 4.39 +/- 0.3 mg X g-1; fasting animals for 48 h prior to study reversed this with no attenuation of the electrophysiological or antiarrhythmic action. These results provide further evidence that release of endogenous myocardial catecholamines contributes to the electrophysiological changes and arrhythmias associated with myocardial ischaemia and reperfusion.

Hypertrophy causes delayed conduction in human and guinea pig myocardium: accentuation during ischaemic perfusion.

OBJECTIVE: The aim was to investigate why cardiac hypertrophy causes increased vulnerability to arrhythmias during myocardial ischaemia. METHODS: The electrophysiological basis for this increased vulnerability was studied in isolated perfused guinea pig hearts obtained 50 and 150 d after aortic constriction, and in sham operated controls. Cellular electrophysiology, conduction, and refractory periods were examined during control perfusion and during low flow (coronary flow reduced to 10% of control) and zero flow ischaemia. ECGs in patients with left ventricular hypertrophy and in controls matched for age and heart rate were also studied. RESULTS: Aortic constriction increased heart weight:body weight ratio by 33% at 50 d and by 69% at 150 d. Action potentials were unchanged in hypertrophied hearts. Significant conduction delay occurred in 150 d hypertrophied hearts [conduction time index 23(SEM 4) ms v 18(3) ms, p < 0.001; QRS width 40(1) ms v 35(1) ms, p < 0.01], but not in 50 d hypertrophied hearts. Conduction delay was also present in humans with left ventricular hypertrophy [QRS width 96(13) ms v 87(8) ms, p < 0.01]. Although the QTc interval was increased in humans, at 422(23) ms v 411(17) ms in controls, p < 0.05, this could be explained by the increased QRS duration. During ischaemia, ventricular arrhythmias tended to occur earlier in hypertrophied hearts. Hypertrophy was also associated with a greater increase in conduction delay. Ischaemia reduced action potential duration and refractory periods; the reduction in action potential duration was attenuated by hypertrophy (p < 0.01), although the reverse was apparent during low flow ischaemia at 50 d. CONCLUSIONS: Delayed conduction is an important feature of severe cardiac hypertrophy in guinea pigs and man. Hypertrophy is associated with accentuated conduction delay and altered repolarisation during ischaemia.

Beta(2)-adrenergic receptor overexpression driven by alpha-MHC promoter is downregulated in hypertrophied and failing myocardium.

OBJECTIVE: The alpha-myosin heavy chain (alpha-MHC) promoter is frequently used to direct cardiac specific transgene expression. We studied whether transgene expression controlled by this promoter was altered under conditions of cardiac hypertrophy and failure. METHODS: Transgenic (TG) mice overexpressing human beta(2)-adrenergic receptors (beta(2)AR) and wild type (WT) controls were subjected to thoracic aortic constriction (TAC) or sham operation and studied at 1, 3 and 8 weeks after surgery. RESULTS: Sham operated TG mice had higher heart rates and left ventricular (LV) contractility than WT (all P<0.01), demonstrating enhanced betaAR activation. TAC at 1, 3 and 8 weeks produced progressive LV hypertrophy which was similar between WT and TG mice. Evidence of heart failure was more marked in TG mice with a greater increase in weights of the right ventricle and lungs and a higher prevalence of atrial thrombus (P<0.05 in each case). In hypertrophied TG hearts, endogenous alpha-MHC mRNA transcripts in LV were maintained at 1 and 3 weeks, but were reduced by approximately 40% relative to the sham-operated group at 8 weeks after TAC. Transgene expression, measured as human beta(2)AR mRNA, was reduced by 45% at 1 and 3 weeks and by 70% at 8 weeks after TAC. beta(2)AR binding sites were reduced by 35, 47 and 65%, respectively, at 1, 3 and 8 weeks. CONCLUSION: Cardiac hypertrophy and failure cause downregulation of the endogenous alpha-MHC as well as cardiac specific overexpression of the transgene directed by an alpha-MHC promoter.

Myocardial ischaemia induces platelet activation with adverse electrophysiological and arrhythmogenic effects.

OBJECTIVE: The aim was to investigate how platelet activation during myocardial ischaemia can induce electrophysiological and arrhythmogenic effects, and examine the involvement of different platelet membrane receptors in producing these effects. METHODS: Transmembrane action potentials and electrograms were recorded from isolated, Langendorff perfused guinea pig hearts during normal perfusion, global myocardial ischaemia, and reperfusion during infusion of human platelets. Platelet reactivity was altered by treating platelets with forskolin, aspirin, the platelet activating factor (PAF) receptor antagonist BN 52021, the thromboxane A2 (TP) receptor antagonist GR 32191B, and the alpha 2 adrenoceptor antagonist yohimbine. Myocardial catecholamine depletion was induced by treatment with 6-hydroxydopamine. RESULTS: Platelet infusion had no electrophysiological effects during normal perfusion, but during ischaemia it enhanced the reduction in action potential duration at 95% repolarisation [APD95, 110(SEM 3) ms v 121(5) ms, p < 0.05, at 15 min] and increased the incidence of ventricular arrhythmias (from 56% to 94%, p = 0.04) compared to hearts receiving buffer but no platelets. The reductions in APD95 and the arrhythmogenic effects were attenuated when forskolin treated, aspirin treated or GR 32191B treated platelets were infused (VF: 50% v 94%, p = 0.03; 50% v 94%, p = 0.02; 22% v 94%, p < 0.001, respectively). Similar results were obtained when normal platelets were infused into catecholamine depleted hearts (VF: 60% v 94%, p = 0.0549). These differences were associated with inhibited aggregatory responses to thrombin (for forskolin treated platelets) and the thromboxane mimetic U44069 (for GR 32191B treated platelets). Yohimbine was antiarrhythmic in the presence and absence of platelets, suggesting direct myocardial effects, but BN 52021 had no antiarrhythmic effects. CONCLUSIONS: Myocardial ischaemia causes platelet activation resulting in electrophysiological and arrhythmogenic effects. PAF receptor antagonism does not prevent these effects, but inhibition of platelet reactivity, platelet thromboxane receptor antagonism, and myocardial catecholamine depletion are effective. These findings suggest that the arrhythmogenic effects of platelet activation during myocardial ischaemia are principally mediated by a thromboxane dependent mechanism, while catecholamine release has a contributory role.