Heat Stress: A Serious Disruptor of the Reproductive Physiology of Dairy Cows.

Global warming is a significant threat to the sustainability and profitability of the dairy sector, not only in tropical or subtropical regions but also in temperate zones where extreme summer temperatures have become a new and challenging reality. Prolonged exposure of dairy cows to high temperatures compromises animal welfare, increases morbidity, and suppresses fertility, resulting in devastating economic losses for farmers. To counteract the deleterious effects of heat stress, cattl e employ various adaptive thermoregulatory mechanisms including molecular, endocrine, physiological, and behavioral responses. These adaptations involve the immediate secretion of heat shock proteins and cortisol, followed by a complex network of disrupted secretion of metabolic and reproductive hormones such as prolactin, ghrelin, ovarian steroid, and pituitary gonadotrophins. While the strategic heat stress mitigation measures can restore milk production through modifications of the microclimate and nutritional interventions, the summer fertility records remain at low levels compared to those of the thermoneutral periods of the year. This is because sustainment of high fertility is a multifaceted process that requires appropriate energy balance, undisrupted mode of various hormones secretion to sustain the maturation and fertilizing competence of the oocyte, the normal development of the early embryo and unhampered maternal-embryo crosstalk. In this review, we summarize the major molecular and endocrine responses to elevated temperatures in dairy cows, as well as the impacts on maturing oocytes and early embryos, and discuss the consequences that heat stress brings about in dairy cattle fertility.

Feeding Flaxseed and Lupins during the Transition Period in Dairy Cows: Effects on Production Performance, Fertility and Biochemical Blood Indices.

Flaxseed and lupin seed were offered as an alternative dietary approach in dairy cows, through the partial substitution of soybean meal. Milk production and fertility traits were investigated. A total of 330 animals were allocated into two groups, treated (n = 176) and control (n = 154). From each group, 30 animals were selected for hematological and cytological studies. The experimental feeding period lasted for 81 days (25 days prepartum and 56 days postpartum). The control ration (group C) contained corn, barley, soybean meal, rapeseed cake, corn silage and lucerne hay; whereas, in the treatment group (group T), 50% of the soybean meal was replaced by an equal mixture of flaxseed and lupins. The two rations were formulated to be isonitrogenous and isoenergetic. Milk samples were analyzed for chemical composition, somatic cell count (SCC) content and total colony forming units (CFU). Blood samples were collected, and serum was analyzed for non-esterified fatty acids (NEFA), acute phase proteins (haptoglobin and serum amyloid) and lipid oxidation indices, namely thiobarbituric-acid-reactive substances (TBARS) and catalase activity. To assess polymorphonuclear neutrophils (PMN) numbers, endometrial samples from each cow were collected on days 21 and 42. No difference was recorded between groups in milk yield (p > 0.05). In multiparous cows, NEFA (mMol/L) concentrations were significantly lower in group T than in group C on day 14 (p > 0.009) and on day 42 (p = 0.05), while no difference was detected in the group of primiparous cows. At all time points, serum TBARS and catalase values were similar in both groups (p > 0.05). Multiparous cows in group T expressed the first postpartum estrus and conceived earlier than cows in group C (p ≤ 0.05). Between days 21 to 42 postpartum, the PMN reduction rate was higher in group T animals (p ≤ 0.05). Acute phase protein levels were in general lower in group T animals, and at specific time points differed significantly from group C (p ≤ 0.05). It was concluded that the partial replacement of soybean meal by flaxseed and lupins had no negative effect on milk yield or milk composition, and improved cow fertility; which, along with the lower cost of flaxseed and lupins mixture, may increase milk production profitability.

Composition, Organoleptic Characteristics, Fatty Acid Profile and Oxidative Status of Cow's Milk and White Cheese after Dietary Partial Replacement of Soybean Meal with Flaxseed and Lupin.

The effect of partial substitution of soybean meal by equal quantities of flaxseed and lupins in diets of Holstein dairy cows and heifers was investigated. A total of 6 animals (30 multiparous and 30 primiparous) were allocated into two equal groups in a randomised block design and fed control (group CO) or modified (group FL) TMR diets from three weeks prior to calving until day 40 postpartum. The TMR of group CO contained corn, barley, soybean meal, rapeseed cake, corn silage, and Lucerne hay, whereas in group FL equal quantities of whole flaxseed and lupins were used to replace 50% of the soybean meal in the TMR. All animals were fed twice daily with a daily allowance of 24 kg dry matter intake per animal. Milking was carried out three times daily and milk yield was recorded during every milking. Milk samples were analysed for chemical composition and SCC content. White cheeses were manufactured from bulk milk of each group at industrial level. Bulk milk and white cheese were analysed for chemical composition and fatty acid profile; cheese was also assessed for its organoleptic properties. Results indicate that milk yield did not differ among groups. Lipid oxidation values were similar among the groups, for both milk and cheese. However, FL inclusion resulted in lower (p < 0.05) protein carbonyls and higher (p < 0.05) phenolic compounds in both milk and cheese samples. Milk from the FL group had decreased palmitic (p < 0.05) and myristic (p < 0.05) and increased oleic (p < 0.05) and linolenic acid (p < 0.05) when compared to group CO. White cheese from group FL showed a decrease in saturated fatty acids (SFA) (p < 0.05), an increase in monounsaturated fatty acids (MUFA) (p < 0.05), and a higher increase in polyunsaturated fatty acids (PUFA) (p < 0.05) when compared with that of group CO. The white cheese of cows fed diets with flaxseed and lupins showed compositional and organoleptic properties quite similar to control group cheese; aroma, texture, and color were acceptable and desirable in both cheeses. However, increased levels of n-3 polyunsaturated fatty acids were found in the cheese of FL fed animals. The substitution of soybean meal by flaxseed and lupins in diets of Holstein cows warrants further investigation, especially towards the production of cheese that meet the consumers' demand for novel and healthier dairy products.

Genetic diversity and thermotolerance in Holstein cows: Pathway analysis and marker development using whole-genome sequencing.

Heat stress causes extensive losses in the dairy sector, due to negative effects on milk production and reproduction. Cows have evolved a series of protective mechanisms, (physiological, biochemical, behavioural) to cope with the thermostressing environments, which have allowed the preservation of productive and reproductive potential of specific animals during summer; these animals are considered thermotolerant and could be used to design programs of selective breeding. These programs, targeting the generations of a population of heat-resistant animals, would increase the frequency of the desired phenotypes, tackling the financial losses on one hand and reducing the carbon footprints of the dairy sector on the other. The development of genomics techniques has enabled genome wide variant calling, to detect SNPs associated with the desired phenotypes. In this study, we used a comparative genomics approach to detect genetic variation associated with thermotolerance and to design molecular markers for characterizing the animals as tolerant/sensitive. A total of 40 cows from each group were split in four sequencing pools and a whole-genome sequencing approach was used. Results and conclusion: Genome-wide genetic variation between groups was characterized and enrichment analysis revealed specific pathways which participate in the adaptive mechanisms of thermotolerance, implicated into systemic and cellular responses, including the immune system functionality, Heat Stress and Unfolded Protein Response. The markers made a promising set of results, as specific SNPs in five genes encoding for Heat Shock Proteins were significantly associated with thermotolerance.

Oviductal epithelial cells transcriptome and extracellular vesicles characterization during thermoneutral and heat stress conditions in dairy cows.

In this study, the transcriptome of oviductal epithelial cells and certain characteristics of their extracellular vesicles of dairy cows were described under thermoneutral and heat stress conditions. Twenty cows were compared in springtime at THI = 65.6 ± 0.90 and in summertime at THI = 78.36 ± 2.73. During each season, the estrous cycles of the cows were synchronized, and on day 3 of the ensuing cycle, a blood sample was collected for progesterone determination, while their oviducts were collected after slaughter. Epithelial cells and oviductal fluid were collected from the oviduct ipsilateral and contralateral to the corpus, respectively. For the gene expression study, a comparative transcriptomic approach, using RNASeq, was performed on cells collected from the ipsilateral and the contralateral oviducts. The size and the concentration of extracellular vesicles (EVs) at both seasons were analyzed using Transmission Electron Microscopy and Nanoparticle tracking analysis and specific proteins were detected by Western blotting. Progesterone concentration was higher during the thermoneutral period. Between seasons, divergent expression of genes related to immune system, contractility, gamete protection and lncRNAs was found. The size and the concentration of the EVs did not differ between seasons, however, the concentration in the ipsilateral oviduct tended to be lower (p = 0.09) from the contralateral one in the summer, but not in the spring. Our results show for the first time that HS could be involved with alterations in the oviductal cells' gene expression and in the changes in concentration of EVs in the oviductal lumen. Our results imply that the altered oviductal environment during HS could be associated with the suppressed summer fertility in dairy cows.

The Effects of Heat Shock Protein 70 Addition in the Culture Medium on the Development and Quality of In Vitro Produced Heat Shocked Bovine Embryos.

The aims of the present study were to examine the effects of HSP70 addition in the in vitro culture medium of day 3 embryos on their developmental competence and quality. Bovine oocytes (n = 1442) were in vitro matured, inseminated and cultured for the first two days according to standardized methods. The presumptive zygotes were randomly allocated in three experimental groups: Control, C (embryos cultured at 39 °C throughout the culture period), group C41 (temperature was raised to 41 °C from the 48th to 72nd h post insemination (p.i.) and then it returned at 39 °C for the remaining culture period), and group H41 (the temperature modification was the same as in C41 and during heat exposure, HSP70 was added in the culture medium). Cleavage and embryo yield were assessed 48 h p.i. and on days 7, 8, 9, respectively and gene expression in day 7 blastocysts was assessed by RT-PCR. Blastocyst yield was the highest in group C39; and higher in group H41 compared to group C41. From the gene expression analyses, altered expression of 11 genes was detected among groups. The analysis of the orchestrated patterns of gene expression differed between groups. The results of this study confirm the devastating effects of heat stress on embryo development and provide evidence that HSP70 addition at the critical stages can partly counterbalance, without neutralizing, the negative effects of the heat insult on embryos, acting mainly through mechanisms related to energy deployment.

Ultrasonographic findings of the corpus luteum and the gravid uterus during heat stress in dairy cattle.

The objectives of this study were to assess alterations in, echogenic appearance, size and blood flow in the corpus luteum, the placentomes and the blood flow in umbilical and uterine arteries that heat stress can cause in cooled pregnant dairy cows. Pregnant cows were allocated in two groups and the gravid uteri, along with the ipsilateral corpora lutea were examined during the winter (group W, n = 9) or the summer (group S, n = 10). The grey-scale ultrasound and colour flow imaging of the corpus luteum and placentome were performed. In addition, the umbilical and uterine artery diameters and haemodynamic parameters in the vessels were calculated. At the time of ultrasonographic examination, cortisol concentrations were higher, and progesterone levels tended to be lower in group S compared to group W. The grey-scale ultrasound evaluation of corpora lutea and placentomes was lower in group S compared to group W. The diameter of umbilical artery and the blood volume in the vessel were less in group S than in group W. We infer that heat stress affects foetal blood supply and possibly the structure of placentomes and corpora lutea, but it differently affects the blood flow characteristics in the umbilical and uterine arteries.

Heat Shock Protein 70 Improves In Vitro Embryo Yield and Quality from Heat Stressed Bovine Oocytes.

Heat shock protein 70 (HSP70) is a chaperon that stabilizes unfolded or partially folded proteins, preventing inappropriate inter- and intramolecular interactions. Here, we examined the developmental competence of in vitro matured oocytes exposed to heat stress with or without HSP70. Bovine oocytes were matured for 24 h at 39 °C without (group C39) or with HSP70 (group H39) and at 41 °C for the first 6 h, followed by 16 h at 39 °C with (group H41) or without HSP70 (group C41). After insemination, zygotes were cultured for 9 days at 39 °C. Cleavage and embryo yield were assessed 48 h post insemination and on days 7, 8, 9, respectively. Gene expression was assessed by RT-PCR in oocytes, cumulus cells and blastocysts. In C41, blastocysts formation rate was lower than in C39 and on day 9 it was lower than in H41. In oocytes, HSP70 enhanced the expression of three HSP genes regardless of incubation temperature. HSP70 at 39 °C led to tight coordination of gene expression in oocytes and blastocysts, but not in cumulus cells. Our results imply that HSP70, by preventing apoptosis, supporting signal transduction, and increasing antioxidant protection of the embryo, protects heat stressed maturing bovine oocyte and restores its developmental competence.

Developmental competence of heat stressed oocytes from Holstein and Limousine cows matured in vitro.

The negative effects of heat stress on dairy cattle's fertility have been extensively studied, but the relevant knowledge for beef cattle is rather limited. The aims of this study were to investigate the effects of HS during in vitro maturation on the developmental potential of oocytes derived from Limousine and Holstein cows and to estimate the effect of the differential gene expression of important genes in oocytes, cumulus cells and blastocysts in the growth competence between the breeds. In seven replicates, cumulus oocyte complexes from Holstein and Limousine cows were matured for 24 hr at 39°C (controls C; Hol_39, Lim_39) or at 41°C from hour 2 to hour 8 of IVM (treated T; Hol_41, Lim_41), fertilized, and presumptive zygotes were cultured for 9 days at 39°C. Cleavage and embryo formation rates were evaluated 48 hr post-insemination and on days 7, 8 and 9, respectively. From all groups, subsets of cumulus cells, oocytes and blastocysts were analysed for the relative expression of genes related to metabolism, stress, apoptosis and placentation. No difference was detected in cleavage rate or in blastocyst formation rate among the control groups. In both breeds, heat stress reduced blastocyst yield, but at all days the suppression was higher in Limousines. In Holsteins, altered gene expression was detected in cumulus cells (G6PD, GLUT1) and blastocysts (PLAC8), while in Limousines, differences were found in oocytes (G6PD, HSP90AA1), in cumulus cells (CPT1B, HSP90AA1, SOD2) and blastocysts (DNMT, HSP90AA1, SOD2). It appears that Holstein COCs are more tolerant than Limousine COCs, possibly due to compulsory, production driven selection.

Early embryo losses, progesterone and pregnancy associated glycoproteins levels during summer heat stress in dairy cows.

Objectives of this study were to characterize the effects of heat stress on pregnancy associated glycoproteins (PAG) and progesterone and its involvement in embryo survival. In trial 1, blood samples collected from days 29 to 36 post insemination were examined for the comparison of PAG concentrations between winter (n = 3721) and summer (n = 2388). In trial 2, embryo losses were assessed in winter (n = 144) and in summer (n = 133), in days 31 or 32 of pregnancy. Pregnancy diagnosis was carried out by ultrasonography on days 24 or 25, and it was repeated a week later; in the second occasion PAG concentration was also determined. In trial 3 the PAG and progesterone concentrations were assessed in days 33 to 36 in winter and summer. In trial 1 PAG levels did not differ between winter and summer, the conception rate and the proportion of uncertain pregnancies were higher in winter than summer. The likelihood of pregnancy was 10 to 15% higher in winter. In trial 2, the embryo death rate was higher in summer, but the PAG levels of cows that had embryo loss in summer were higher than those in winter. In both seasons, lower PAG levels were associated with higher risk of pregnancy loss, while embryo death was five times more likely to occur in summer than in winter and lower PAG concentrations were positively associated with higher risk of embryo loss. In trial 3, mean PAG levels were higher and of progesterone were lower during the summer than during the winter. We infer that despite the devastating effects of heat stress on cows' fertility, those early embryos that survive under continuous heat stress can form a well-functioning placenta; hence, the high embryo mortality rate observed during the summer months could be mainly attributed to luteal insufficiency.

Intracoronary Administration of Allogeneic Cardiosphere-Derived Cells Immediately Prior to Reperfusion in Pigs With Acute Myocardial Infarction Reduces Infarct Size and Attenuates Adverse Cardiac Remodeling.

BACKGROUND: Allogeneic cardiosphere-derived cells (CDCs) exert cardioprotective effects when administered intracoronarily after reperfusion in animal models of acute myocardial infarction (AMI). The "no-reflow" phenomenon develops rapidly post-reperfusion and may undermine the efficacy of cell therapy, due to poor cell delivery in areas of microvascular obstruction (MVO). We hypothesized that CDC-induced cardioprotection would be enhanced by cell administration prior to reperfusion, when microvasculature is still relatively intact, to facilitate widespread cell delivery within the ischemic area. METHODS AND RESULTS: We studied 81 farm pigs; 55 completed the specified protocols. A dose-optimization study in infarcted pigs demonstrated that the doses of 5 million and 10 million CDCs are the maximum safe doses that can be administered intracoronarily at 5 minutes prior to and at 5 minutes post-reperfusion, respectively, without aggravating MVO. Quantification of acute cell retention by polymerase chain reaction demonstrated that cell delivery prior to reperfusion resulted in higher cardiac cell retention compared to delivery post-reperfusion. We then performed a randomized, placebo-controlled study to assess the long-term efficacy of intracoronary infusion of 5 million allogeneic CDCs, delivered at 5 minutes prior to reperfusion, in a porcine model of AMI. The CDC therapy resulted in decreased scar size, improved regional systolic function, and attenuation of adverse cardiac remodeling (manifested as preserved global systolic function, preserved end-systolic volume, and decreased interstitial fibrosis) compared to placebo at 30 days post-MI. CONCLUSIONS: Dose-optimized intracoronary infusion of allogeneic CDCs prior to reperfusion in a porcine model of AMI is feasible, safe and confers long-term benefits.

A study on stress response and fertility parameters in phenotypically thermotolerant and thermosensitive dairy cows during summer heat stress.

It is well documented that heat stress (HS) causes subfertility in dairy cows. However, during the last ten years we have been observing that, under high temperature-humidity index (THI ≥ 75), despite the overall reduced fertility, some cows conceive at the first artificial insemination (AI). Here, we examined distinctive features of cows with conserved fertility under severe HS. From the databases of three herds, 167 lactating Holstein cows were selected; group TT cows (n = 57) conceived in the previous summer (THI ≥ 75) at the 1st AI, and group TS (n = 110) failed to conceive at the same period after at least 2 consecutive AIs. The animals calved in spring, and in August, blood samples were collected during a hot day (THI ≥ 81) for the determination of cortisol and HSP70 concentrations. In one farm, the validity of fertility data of the previous year was re-examined. In 28 cows from group TT and in 39 cows from group TS, the conception rate was examined during July and August. In 6 cows from each group (TT and TS) the oestrous cycles were synchronized, ovulation was induced with GnRH (THI = 80), and the concentration of the pre-ovulatory LH surge was determined in 9 blood samples. The progesterone concentration in the ensuing cycle was determined in blood samples collected every other day. Overall, cortisol and HSP70 were significantly lower in TT group compared to TS. More (p < .05) animals from group TT conceived at the first AI compared with those from group TS. The induced pre-ovulatory LH surge peaked at higher level (p < .002) in group TT than in group TS, while no difference was recorded among groups either in mean progesterone concentrations or in the duration of the ensuing oestrous cycle. These results are highly suggestive that thermotolerance in some dairy cows is an inherent characteristic, warranting further genetic investigation.

Short term temperature elevation during IVM affects embryo yield and alters gene expression pattern in oocytes, cumulus cells and blastocysts in cattle.

Heat stress causes subfertility in cattle by inducing alterations in steroidogenic capacity, follicular function and ovulation defects, which eventually negatively affect oocyte quality and embryo survival. Here, the effects of short, moderate temperature elevation during IVM, on embryo yield, and on the expression of various genes was evaluated. In 8 replicates, cumulus oocyte complexes (COCs) were matured for 24 h at 39 °C (controls n = 605) or at 41 °C from hour 2 to hour 8 of IVM (treated, n = 912), fertilized, and presumptive zygotes were cultured for 9 days at 39 °C. Cleavage and embryo formation rates were evaluated 48 h post insemination and on days 7, 8, 9 respectively. Cumulus cells, oocytes and blastocysts from 5 replicates were snap frozen for the relative expression analysis of genes related to metabolism, thermal and oxidative stress response, apoptosis, and placentation. In treated group, cleavage and embryo formation rates were statistically significantly lower compared with the control (cleavage 86.7% vs 74.2%; blastocysts: day 7, 29.9% vs 19.7%, day 8, 34.2% vs 22.9% and day 9 35.9% vs 24.5%). Relative mRNA abundance of three genes in cumulus cells (HSP90AA1, CPT1B, G6PD) and three genes in blastocysts (DNMT3A, PLAC8, GPX1) indicated significantly different expression between groups (p < 0.05)., The expression of G6PD, SOD2, GXP1 in oocytes and PTGS2 in blastocysts tended to differ among groups (0.05

Safety and efficacy of global intracoronary administration of cardiosphere-derived cells or conditioned medium immediately after coronary reperfusion in rats.

OBJECTIVE: Cardiosphere-derived cells (CDCs) have been shown to reduce infarct size after myocardial infarction (MI). In the present study we investigated the safety and efficacy of global intracoronary administration (GIA) of CDCs or CDC-conditioned medium (CM) immediately after reperfusion in a rat model of ischemia-reperfusion. METHODS: CDCs were grown from myocardial biopsies obtained from male Wistar Kyoto rats (WKY). Female WKY rats underwent MI for 45minutes, followed by reperfusion for 1hour. Infarcted rats were randomized to receive GIA of CDCs (CDC group), CM (CM group) or vehicle (control group) immediately after the onset of reperfusion. Cell retention was quantified by PCR for the male specific SRY gene; area at risk (AR) and no reflow area (NR) were measured by histopathology. Cardiac function was evaluated by echocardiography at 1 and 2 months post-MI. RESULTS: Cell retention at 1hour after GIA was 25.1% ±5.1. The myocardial AR and NR (measured at 1 hour post-reperfusion) were similar between groups [AR: 28.8% ±7.4 of LV mass in control vs 27.2% ±8 in CM vs 27% ±7 in CDCs group. NR: 7.0% ±3.3 in control vs 7.3% ±3.8 in CM vs 7.1% ±3.6 in CDCs]. One and 2 months post-MI, systolic function and LV volumes did not differ between control and CM groups. CONCLUSION: Intracoronary administration of CDCs during the acute phase of MI, at the beginning of reperfusion, does not aggravate microvascular obstruction and results in high cell retention. Delivery of CM in the acute phase of MI did not confer long-term cardiac functional benefits.

Salutary Effects of the PULVAD, a Novel Implantable Counterpulsation Assist Device, on Cardiac Mechanoenergetics.

The Pressure Unloading Left Ventricular Assist Vevice (PULVAD) is a novel implantable counterpulsation LVAD, designed to provide ventricular unloading with augmentation of LV performance and retention of pulsatility. We assessed the effects of the PULVAD on hemodynamics and LV mechanoenergetics in seven farm pigs with acute ischemic heart failure. The PULVAD was implanted in the thorax and was connected to the ascending aorta. The PULVAD was pneumatically driven by a standard intra-aortic balloon pump console and was electrocardiogram-synchronized to provide LV pressure unloading along with diastolic aortic pressure augmentation. Hemodynamics, indices of LV mechanoenergetics, and coronary blood flow were measured without and after brief PULVAD support. PULVAD support decreased LV afterload and improved LV mechanical performance (increased ejection fraction, stroke volume, cardiac output and maximum elastance). The PULVAD concurrently reduced LV energy consumption (decreased stroke work and pressure-volume area) and optimized LV energetic performance (improved the ratio of stroke work to pressure-volume area). PULVAD support increased mean coronary blood flow, through dramatic augmentation of diastolic blood flow. In conclusion, the PULVAD unloads the failing LV, optimizes LV mechanoenergetics, and augments coronary blood flow. These salutary effects of short-term PULVAD support provide the foundation for long-term testing.

Pharmacologic inhibition of the mitochondrial Na+/Ca2+ exchanger protects against ventricular arrhythmias in a porcine model of ischemia-reperfusion.

BACKGROUND: The mitochondrial Na+/Ca2+ exchanger (mNCX) has been implicated in the pathogenesis of arrhythmogenicity and myocardial reperfusion injury, rendering its inhibition a potential therapeutic strategy. We examined the effects of CGP-37157, a selective mNCX inhibitor, on arrhythmogenesis, infarct size (IS), and no reflow area (NRA) in a porcine model of ischemia-reperfusion. METHODS: Forty pigs underwent myocardial ischemia for 60 minutes, followed by 2 hours of reperfusion. Animals were randomized to receive intracoronary infusion of 0.02 mg/kg CGP-37157 or vehicle, either before ischemia (n=17) or before reperfusion (n=17). Animals were monitored for arrhythmias. Myocardial area at risk (AR), IS, and NRA were measured by histopathology. RESULTS: AR, NRA, and IS were comparable between groups. Administration of CGP-37157 before ischemia resulted in the following: (a) suppression of ventricular tachyarrhythmias (events/pig: 1.5±1.1 vs 3.5±1.9, p=0.014), (b) easier cardioversion of ventricular tachyarrhythmias (defibrillations required for cardioversion of each episode: 2.6±2.3 vs 6.2±2.1, p=0.006), and (c) decreased maximal depression of the J point (0.75±0.27 mm vs 1.75±0.82 mm, p=0.007), compared to controls. Administration of CGP-37157 before reperfusion expedited ST-segment resolution; complete ST-segment resolution within 30 minutes of reperfusion was observed in 7/8 CGP-37157-treated animals versus 1/9 controls (p=0.003). CONCLUSIONS: In a porcine model of myocardial infarction, intracoronary administration of CGP-37157 did not decrease IS or NRA. However, it suppressed ventricular arrhythmias, decreased depression of the J point during ischemia and expedited ST-segment resolution after reperfusion. These findings motivate further investigation of pharmacologic mNCX inhibition as a potential therapeutic strategy to suppress arrhythmias in the injured heart.

Comparison of the effects of ramipril versus telmisartan in reducing serum levels of high-sensitivity C-reactive protein and oxidized low-density lipoprotein cholesterol in patients with type 2 diabetes mellitus.

The effect of ramipril (an angiotensin [AT]-converting enzyme inhibitor), telmisartan (an AT-II type 1 receptor blocker), or their combination on inflammation and lipid peroxidation was assessed in 37 patients with type 2 diabetes who were free of coronary artery disease. All regimens were associated with a significant reduction of C-reactive protein and oxidized low-density lipoprotein cholesterol serum levels (p <0.001). These results further enlighten the mechanisms underlying the cardiovascular beneficial effect of renin-AT system inhibition.