The clinical and geographical characteristics, health-seeking behaviours of ST-segment elevation myocardial infarction patients with their total ischaemic time and short-term cardiac mortality outcomes: a local geographical perspective from a developing country.

INTRODUCTION: Ischaemic heart disease including ST-segment elevation myocardial infarction (STEMI) is the leading cause of death among Malaysians. Total ischaemic time (TIT) which consists of patient delay and systemic delay is a strong predictor of cardiovascular outcome in STEMI. Primary percutaneous coronary intervention (PPCI) is superior to medical thrombolysis in improving STEMI patients' survival outcomes. Our study aims to provide an insight into the clinical and geographical characteristics of STEMI patients, their health-seeking behaviour, TIT, interventions received and short-term cardiac mortality outcomes in the effort to improve the existing coronary care service. MATERIALS AND METHODS: This is a descriptive study looking into patients who were diagnosed with STEMI and presented to or were referred to Sarawak Heart Centre between 1st July 2022 and 31st December 2022. RESULTS: A total of 183 patients were recruited and 33.3% were <50 years old. The majority were in a different division during symptom onset from where the local PPCI centre is located and some underwent one or two transits before arrival at the revascularisation centre. More presented outof- hour and they were more likely to present within the PPCI window. The median TIT for the study population was 3.3 hours. The short-term cardiac mortalities were 9.3% and only the Killip class was found to have a significant association. In this study, TIT was not significantly associated with short-term mortalities but those who died had a longer median TIT. CONCLUSION: A local STEMI network should be set up using the 'Hub-and-Spoke' model in a staged-wise approach to reduce TIT given that PPCI is now the gold standard of treatment alongside continuous effort in patient education.

Factors associated with in-hospital mortality among infective endocarditis patients.

INTRODUCTION: Despite recent advancements in the diagnosis and management of infective endocarditis (IE), it is associated with substantial morbidity and mortality. Our study objective is to determine the factors associated with in-hospital mortality in IE patients among the local population. MATERIALS AND METHODS: All IE patients who were diagnosed with definite or possible IE and were treated at Sarawak Heart Centre from 1st January 2020 to 31st December 2022 were recruited. We examined the demographic features of the subjects and the factors that contributed to in-hospital mortality. Multivariate logistic regression was used to analyse the associated factors and in-hospital mortality. RESULTS: Our study population comprised a total of 37 patients with a mean age of 46.4 years and male predominance. The in-hospital mortality rate of IE in this study was 44.4%. Haemodynamic instability and anaemia were found to be strong predictors of IE survival outcome, with an odds ratio of 51.5 and 35.7 respectively. Patients with vascular phenomenon and heart failure were at 10.5- and 6.0-times higher odds of dying, however, these two associations were found to be not statistically significant. CONCLUSION: The in-hospital mortality due to IE in our study was among the highest in developing countries. Factors of hypotension and optimal response to individual hemodynamic parameters may confer lower mortality. While anaemia is demonstrable as a risk factor for inpatient mortality, a target has yet to be reasonably established.

The association of the dietary approach to stop hypertension (DASH) diet with blood pressure, glucose and lipid profiles in Malaysian and Philippines populations.

BACKGROUND AND AIM: Despite a growing body of evidence from Western populations on the health benefits of Dietary Approaches to Stop Hypertension (DASH) diets, their applicability in South East Asian settings is not clear. We examined cross-sectional associations between DASH diet and cardio-metabolic risk factors among 1837 Malaysian and 2898 Philippines participants in a multi-national cohort. METHODS AND RESULTS: Blood pressures, fasting lipid profile and fasting glucose were measured, and DASH score was computed based on a 22-item food frequency questionnaire. Older individuals, women, those not consuming alcohol and those undertaking regular physical activity were more likely to have higher DASH scores. In the Malaysian cohort, while total DASH score was not significantly associated with cardio-metabolic risk factors after adjusting for confounders, significant associations were observed for intake of green vegetable [0.011, standard error (SE): 0.004], and red and processed meat (-0.009, SE: 0.004) with total cholesterol. In the Philippines cohort, a 5-unit increase in total DASH score was significantly and inversely associated with systolic blood pressure (-1.41, SE: 0.40), diastolic blood pressure (-1.09, SE: 0.28), total cholesterol (-0.015, SE: 0.005), low-density lipoprotein cholesterol (-0.025, SE: 0.008), and triglyceride (-0.034, SE: 0.012) after adjusting for socio-demographic and lifestyle groups. Intake of milk and dairy products, red and processed meat, and sugared drinks were found to significantly associated with most risk factors. CONCLUSIONS: Differential associations of DASH diet and dietary components with cardio-metabolic risk factors by country suggest the need for country-specific tailoring of dietary interventions to improve cardio-metabolic risk profiles.

Facts and challenges in respiratory neurobiology.

Respiratory neurobiology has been a lead discipline in the field of neuroscience for almost a century. Despite this, research studies on the fundamental synaptic and cellular processes underlying the generation and modulation of breathing movements suffered a significant decline during the last decade. We still believe that respiratory neurobiology is one of the most exciting and imperative fields of neuroscience. With the first white paper concerned with the central control of breathing, we want to celebrate the global importance of breathing research.

Viscerosensory input drives angiotensin II type 1A receptor-expressing neurons in the solitary tract nucleus.

Homeostatic regulation of visceral organ function requires integrated processing of neural and neurohormonal sensory signals. The nucleus of the solitary tract (NTS) is the primary sensory nucleus for cranial visceral sensory afferents. Angiotensin II (ANG II) is known to modulate peripheral visceral reflexes, in part, by activating ANG II type 1A receptors (AT1AR) in the NTS. AT1AR-expressing NTS neurons occur throughout the NTS with a defined subnuclear distribution, and most of these neurons are depolarized by ANG II. In this study we determined whether AT1AR-expressing NTS neurons receive direct visceral sensory input, and whether this input is modulated by ANG II. Using AT1AR-GFP mice to make targeted whole cell recordings from AT1AR-expressing NTS neurons, we demonstrate that two-thirds (37 of 56) of AT1AR-expressing neurons receive direct excitatory, visceral sensory input. In half of the neurons tested (4 of 8) the excitatory visceral sensory input was significantly reduced by application of the transient receptor potential vallinoid type 1 receptor agonist, capsaicin, indicating AT1AR-expressing neurons can receive either C- or A-fiber-mediated input. Application of ANG II to a subset of second-order AT1AR-expressing neurons did not affect spontaneous, evoked, or asynchronous glutamate release from visceral sensory afferents. Thus it is unlikely that AT1AR-expressing viscerosensory neurons terminate on AT1AR-expressing NTS neurons. Our data suggest that ANG II is likely to modulate multiple visceral sensory modalities by altering the excitability of second-order AT1AR-expressing NTS neurons.

Functional and neurochemical characterization of angiotensin type 1A receptor-expressing neurons in the nucleus of the solitary tract of the mouse.

Angiotensin II acts via two main receptors within the central nervous system, with the type 1A receptor (AT1AR) most widely expressed in adult neurons. Activation of the AT1R in the nucleus of the solitary tract (NTS), the principal nucleus receiving central synapses of viscerosensory afferents, modulates cardiovascular reflexes. Expression of the AT1R occurs in high density within the NTS of most mammals, including humans, but the fundamental electrophysiological and neurochemical characteristics of the AT1AR-expressing NTS neurons are not known. To address this, we have used a transgenic mouse, in which the AT1AR promoter drives expression of green fluorescent protein (GFP). Approximately one-third of AT1AR-expressing neurons express the catecholamine-synthetic enzyme tyrosine hydroxylase (TH), and a subpopulation of these stained for the transcription factor paired-like homeobox 2b (Phox2b). A third group, comprising approximately two-thirds of the AT1AR-expressing NTS neurons, showed Phox2b immunoreactivity alone. A fourth group in the ventral subnucleus expressed neither TH nor Phox2b. In whole cell recordings from slices in vitro, AT1AR-GFP neurons exhibited voltage-activated potassium currents, including the transient outward current and the M-type potassium current. In two different mouse strains, both AT1AR-GFP neurons and TH-GFP neurons showed similar AT1AR-mediated depolarizing responses to superfusion with angiotensin II. These data provide a comprehensive description of AT1AR-expressing neurons in the NTS and increase our understanding of the complex actions of this neuropeptide in the modulation of viscerosensory processing.

Respiratory modulation of sympathetic nerve activity is enhanced in male rat offspring following uteroplacental insufficiency.

Sympathetic nerve activity to the cardiovascular system displays prominent respiratory-related modulation which leads to the generation of rhythmic oscillations in blood pressure called Traube-Hering waves. An amplification of this respiratory modulation of sympathetic activity is observed in hypertension of both genetic, the spontaneously hypertensive rat, and induced, chronic intermittent hypoxia or maternal protein restriction during gestation, origin. Male offspring of mothers with uteroplacental insufficiency, induced by bilateral uterine vessel ligation at 18 days of gestation, are also hypertensive in adulthood. In this study we examined whether these male offspring display altered respiratory modulation of sympathetic activity at pre-hypertensive ages compared to controls. Respiratory, cardiovascular and sympathetic parameters were examined using the working heart-brainstem preparation in 35 day old male rats that had reduced birth weight due to uteroplacental insufficiency. Whilst all respiratory parameters were not different between groups, we observed an enhanced respiratory-related burst of thoracic sympathetic nerve activity and amplified Traube-Hering waves in the growth-restricted group. This group also showed an increased sympathetic and bradycardic response to activation of peripheral chemoreceptors. The observations add support to the view that altered respiratory modulation of sympathetic activity represents a common mechanism involved in the development of several forms of hypertension.

Identification of CNS neurons with polysynaptic connections to both the sympathetic and parasympathetic innervation of the submandibular gland.

Coordinated modulation of sympathetic and parasympathetic nervous activity is required for physiological regulation of tissue function. Anatomically, whilst the peripheral sympathetic and parasympathetic pathways are separate, the distribution of premotor neurons in higher brain regions often overlaps. This co-distribution would enable coordinated regulation and might suggest individual premotor neurons could project to both sympathetic and parasympathetic outflows. To investigate this one submandibular gland was sympathectomized. One of two isogenic strains of the pseudorabies virus, expressing different fluorophores, was injected into the cut sympathetic nerve and the other into the submandibular gland. Independent labeling of the peripheral sympathetic and parasympathetic pathways was observed. Dual-labeled neurons were observed in many CNS regions known to be involved in regulating salivary function. We propose these observations highlight a common pattern of organization of the CNS, providing the anatomical framework for the fine control of organ function required for homeostatic regulation and the coordination of organ responses to enable complex behaviors.

Carotid intima media thickness and high sensitivity C-reactive protein as markers of cardiovascular risk in a malaysian population.

INTRODUCTION: Carotid intima media thickness (CIMT) being a cost effective and easily performed technique is useful in the detection of subclinical atherosclerosis and has been shown to be a prognosticator of cardiovascular events. The primary objective of this study was to obtain the distribution of CIMT measurements, highly sensitive C reactive protein (hs-CRP) and assessing health awareness and attitudes of the Malaysian population at cardiovascular disease (CVD) risk and not receiving lipid lowering agents. Secondarily the study sought to assess the significance of the relationship between these measurements against various patient characteristics. METHODS: Measurements of CIMT are obtained by ultrasonography of 12 sites within the common carotid artery was recorded for 123 subjects from a single centre tertiary hospital of Malaysia who had two or more CVD risk factors but were not receiving lipid lowering therapy. CVD risk factors and lipid and glucose profiles were analyzed with respect to distribution of CIMT and high-sensitivity Creactive protein (hs-CRP) values. RESULTS: The mean-max CIMT was 0.916±0.129mm (minimum 0.630mm, maximum 1.28mm) and the mean-mean CIMT was 0.743±0.110mm (minimum 0.482mm, maximum 1.050mm) and mean hs-CRP was 0.191mg/dL (minimum 0.030mg/dL, maximum 5.440mg/dL). Multivariate analyses confirmed a significant association between increasing CIMT and increasing age, total and low density lipoprotein cholesterol while log-transformed hs-CRP levels showed significant association with increasing body mass index, waist circumference, high blood glucose and triglyceride levels. Our patients had good health awareness on CVD. CONCLUSION: Newly defined CIMT measurements and hs-CRP levels may be useful adjunctive tools to screen for atherosclerosis in the Malaysian population. It may help in refining risk stratification on top of traditional clinical assessment.

Prevalence of asymptomatic atrial fibrillation in malaysian patients with hypertension.

Atrial fibrillation (AF) is usually asymptomatic and often associated with established cardiovascular risk factors such as hypertension. The prevalence atrial fibrillation in patients admitted to Malaysian hospitals has been determined, but asymptomatic atrial fibrillation (AAF) in hypertensive patients in the primary care setting is not established. This study reports the prevalence of AAF in hypertensive patients in Malaysia, in a primary care setting. The overall prevalence of AAF was 0.75% with no differences between the gender. The prevalence of AAF increases with age - in the age groups of 30-39, >40-49, >50-59, >60-69, 70-79 and >80 years old were 0%, 0.17%, 0.35%, 2.32%, 2.59%, and 0% respectively. Hypertensive patients with age of ≥ 61 year old were associated with a probability of 10.6 times higher for AAF. We suggest the age threshold to screen for AAF to be age of 60. It is estimated that there are 49,029 Malaysians with AAF in 2010. A large population is at risk of AAF-related complications. There is justification for an even greater emphasis on diagnostic, primary and secondary prevention strategies.

Species differences in respiratory rhythm generation in rodents.

We examined the role of riluzole (RIL)- and flufenamic acid (FFA)-sensitive mechanisms in respiratory rhythmogenesis in rats and hamsters using the in situ arterially perfused preparation. Based on the hypothesis that respiratory networks in animals capable of autoresuscitation would have a greater prevalence of membrane mechanisms that promote endogenous bursting, we predicted that older (weaned) hamsters (a hibernating species) would be more sensitive to the blockade of RIL- and FFA-sensitive mechanisms than age-matched rats and that younger (preweaned) rats would behave more like hamsters. Consistent with this, we found that respiratory motor output in weaned hamsters [>21 days postnatal (P21)] was highly sensitive to RIL (0.2-20 muM), while in young rats (P12-14) it was less so (only affected at higher concentrations of RIL), and weaned rats were not affected at all. On the other hand, respiratory motor output was equally reduced by FFA (0.25-25 muM) in both young and weaned rats but was unaffected in weaned hamsters. Coapplication of RIL and FFA (RIL + FFA) produced greater inhibition of respiration in both young and weaned rats compared with either drug alone. In contrast, in weaned hamsters, FFA coapplication offset the inhibitory effect of RIL alone. Increasing respiratory drive with hypercapnia/acidosis ameliorated the respiratory inhibition produced by RIL + FFA in weaned rats but had no effect in young rats. Data from the present study indicate that respiratory rhythmogenesis in young rats is more dependent on excitatory RIL-sensitive and FFA-sensitive mechanisms than older rats and that fundamental differences exist in the respiratory rhythmogenic mechanisms between rats and hamsters.

Cardiovascular diagnostics mining on Borneo island: from labour-intensive to prototype.

Mining for medical data poses different challenges compared with mining other types of data. The wide range of imaging modalities of medical data leads to data integration and compatibility issues. The analysis of imaging modalities is further complicated by the different format and attributes used by the different imaging equipment by different vendors. Human factors such as interest of adapting data mining into diagnosis and planning process raised the difficulty of engaging the users into the development of a practical and useful data miner. Requirement engineering technique prototyping further enhanced the engagement of users towards the data-miner. Data from different equipment and different vendors are also merged for efficient data analysis and subsequently charting and reporting. We have also successfully engaged the medical doctors into believing the data miner's capability after they reviewed and walkthrough the prototype.

Expression of Group I metabotropic glutamate receptors on phenotypically different cells within the nucleus of the solitary tract in the rat.

Group I metabotropic glutamate receptors (mGluRs) are G-coupled receptors that modulate synaptic activity. Previous studies have shown that Group I mGluRs are present in the nucleus of the solitary tract (NTS), in which many visceral afferents terminate. Microinjection of selective Group I mGluR agonists into the NTS results in a depressor response and decrease in sympathetic nerve activity. There is, however, little evidence detailing which phenotypes of neurons within the NTS express Group I mGluRs. In brainstem slices, we performed immunohistochemical localization of Group I mGluRs and either glutamic acid decarboxylase 67 kDa isoform (GAD67), neuronal nitric oxide synthase (nNOS) or tyrosine hydroxylase (TH). Fluoro-Gold (FG, 2%; 15 nl) was microinjected in the caudal ventrolateral medulla (CVLM) of the rat to retrogradely label NTS neurons that project to CVLM. Group I mGluRs were distributed throughout the rostral-caudal extent of the NTS and were found within most NTS subregions. The relative percentages of Group I mGluR expressing neurons colabeled with the different markers were FG (6.9+/-0.7) nNOS (5.6+/-0.9), TH (3.9+/-1.0), and GAD67 (3.1+/-1.4). The percentage of FG containing cells colabeled with Group I mGluR (13.6+/-2.0) was greater than the percent colabeled with GAD67 (3.1+/-0.5), nNOS (4.7+/-0.5), and TH (0.1+/-0.08). Cells triple labeled for FG, nNOS, and Group I mGluRs were identified in the NTS. Thus, these data provide an anatomical substrate by which Group I mGluRs could modulate activity of CVLM projecting neurons in the NTS.

Targeted deletion of neurokinin-1 receptor expressing nucleus tractus solitarii neurons precludes somatosensory depression of arterial baroreceptor-heart rate reflex.

Neurokinin-1 receptor (NK1-R) expressing neurons are densely distributed throughout the nucleus tractus solitarii (NTS). However, their fundamental role in arterial baroreflex function remains debated. Previously, our group has shown that activation of contraction-sensitive somatic afferents evoke substance P (SP) release in the NTS and resets the arterial baroreflex via activation of a GABAergic NTS circuit. Based on these findings, we hypothesized that modulation of arterial baroreflex function by somatic afferents is mediated by NK1-R dependent inhibition of barosensitive NTS circuits. In the present study, SP-conjugated saporin toxin (SP-SAP) was used to ablate NK1-R expressing NTS neurons. Contraction-sensitive somatic afferents were activated by electrically-evoked muscle contraction and the arterial baroreceptor-heart rate reflex was assessed by constructing reflex curves using a decerebrate, arterially-perfused preparation. Baseline baroreflex sensitivity was significantly attenuated in SP-SAP-treated rats compared with control rats receiving either unconjugated SAP or vehicle. Muscle contraction significantly attenuated baroslope in SAP and vehicle-treated animals and shifted the baroreflex curves to higher systemic pressure. In contrast, somatic afferent stimulation failed to alter baroslope or shift the baroreflex curves in SP-SAP-treated animals. Moreover, when reflex sensitivity was partially restored in SP-SAP animals, somatic stimulation failed to attenuate baroreflex bradycardia. In contrast, SP-SAP and somatic stimulation failed to blunt the reflex bradycardia evoked by the peripheral chemoreflex. Immunohistochemistry revealed that pretreatment with SP-SAP significantly reduced the number of NK1-R expressing neurons in the caudal NTS, while sparing NK1-R expressing neurons rostral to the injection site. This was accompanied by a significant reduction in the number of glutamic acid decarboxylase (GAD67) expressing neurons at equivalent levels of the NTS. These findings indicate that immunolesioning of NK1-R expressing NTS neurons selectively abolishes the depressive effect of somatosensory input on arterial baroreceptor-heart rate reflex function.

Immunoreactive localisation of P2Y1 receptors within the rat and human nodose ganglia and rat brainstem: comparison with [alpha 33P]deoxyadenosine 5'-triphosphate autoradiography.

The present study employed standard peroxidase immunohistochemistry to map the distribution of P2Y(1) receptors in the rat brainstem and nodose ganglia and characterised the binding profile of [alpha(33)P]dATP. Binding of [alpha(33)P]dATP was fully displaceable by adenosine 5'-triphosphate (ATP), and was found on both human and rat nodose ganglia, and throughout the rat brainstem, including the nucleus tractus solitarius and ventrolateral medulla. [Alpha(33)P]dATP binding in the human nodose ganglia was significantly displaced by both 2-methylthio ATP and alpha,beta-methylene ATP, but not by uridine 5'-triphosphate, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid, 8,8'-(carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino))bis(1,3,5-naphtalenetrisulfonic) acid (NF279) or N-ethylcarboxamidoadenosine. [Alpha(33)P]dATP binding in the rat nodose ganglia and brainstem was significantly displaced by only 2-methylthio ATP, suggesting that [alpha(33)P]dATP is binding to P2Y receptors in the rat. Binding of [alpha(33)P]dATP was also significantly displaced by alpha,beta-methylene adenosine 5'-diphosphate, suggesting a component of the binding is to endogenous ecto-5'-nucleotidase, however, almost all binding could be displaced by a combination of receptor agonists (2-methylthio ATP, uridine 5'-triphosphate and alpha,beta-methylene ATP), suggesting preferential binding to receptors. Immunoreactivity to P2Y(1) receptor (P2Y(1)-IR) exhibited similar distribution patterns to [alpha(33)P]dATP binding, with a clear topographic profile. Particularly dense P2Y(1)-IR labeling was evident in cells and fibres of the dorsal vagal complex. Immunolabeling was also present in the dorsal motor nucleus of the vagus and nucleus ambiguus, indicating the possibility of P2Y(1) receptors on vagal efferents. Unilateral vagal ligation was also performed to examine the transport of P2Y(1) receptor, using both immunohistochemistry and [alpha(33)P]dATP autoradiography. Accumulations of both P2Y(1)-IR and [alpha(33)P]dATP binding were apparent adjacent to both ligatures, suggesting bi-directional transport of P2Y(1) receptors along the rat vagus nerve. This current study represents the first description of P2Y(1) receptor distribution within the rodent brainstem and nodose ganglion and also characterises [alpha(33)P]dATP binding to P2Y receptors.

Axonal transport of NADPH-diaphorase and [(3)H]nitro-L-arginine binding, but not [(3)H]cGMP binding, by the rat vagus nerve.

Previous studies have shown that the NO(ccirf)-cGMP pathway may be functionally relevant in the nodose ganglion and at afferent terminations of the vagus nerve. The technique of unilateral vagal ligations, using double ligatures, was combined with the techniques of NADPH-diaphorase histochemistry, as an index of nitric oxide synthase (NOS) activity, and autoradiography using the radioligands [(3)H]nitro-L-arginine and [(3)H]cGMP, to examine axonal transport of NOS and cGMP-dependent effectors by the rat vagus nerve. A population of perikarya in the nodose ganglia was NADPH-diaphorase positive, and binding of both [(3)H]nitro-L-arginine and [(3)H]cGMP was found on the nodose ganglia. Following vagal ligation, NADPH-diaphorase reactivity accumulated proximal to the proximal ligature and distal to the distal ligature. Vagus nerve transection beyond the distal ligature eliminated NADPH-diaphorase reactivity at the distal ligature. Similarly, [(3)H]nitro-L-arginine binding was found over the nodose ganglion; and after vagal ligation, an accumulation of [(3)H]nitro-L-arginine binding was seen adjacent to the proximal ligature, though little binding was found adjacent to the distal ligature. No accumulation of [3H]cGMP binding was found adjacent to either the proximal or the distal ligatures. These findings suggest that the rat vagus nerve bidirectionally transports NOS, the enzyme involved in biosynthesis of NO(ccirf) by nitroxidergic nerves. As anticipated, [(3)H]nitro-L-arginine, a competitive inhibitor of the amino acid precursor for NO(ccirf), binds only to a centrifugally transported moiety that we conjecture is NOS, while cGMP apparently is not subject to transport. These data further support the use of NO(&z.ccirf;) in transmission at vagal afferent terminals.