Improved Long-term Survival with Remote Limb Ischemic Preconditioning in a Rat Fixed-Pressure Hemorrhagic Shock Model.

PURPOSE: We investigated whether bilateral, lower limb remote ischemic preconditioning (RIPC) improved long-term survival using a rat model of hemorrhagic shock/resuscitation. METHODS: Rats were anesthetized, intubated and ventilated, and randomly assigned to RIPC, induced by inflating bilateral pressure cuffs around the femoral arteries to 200 mmHg for 5 min, followed by 5-min release of the cuffs (repeated for 4 cycles), or control group (cuffs were inflated to 30 mmHg). Hemorrhagic shock was induced by withdrawing blood to a fixed mean blood pressure of 30 mmHg for 30 min, followed by 30 min of resuscitation with shed blood. Rats remained anesthetized for 1 h during which hemodynamics were monitored then they were allowed to survive for 6 weeks. RESULTS: The percentage of estimated total blood volume withdrawn to maintain a level of 30 mmHg was similar in both groups. RIPC significantly increased survival at 6 weeks: 5 of 27 (19%) rats in the control group and 13 of 26 (50%; p = 0.02) rats in the RIPC group survived. Blood pressure was higher in the RIPC group. The diastolic internal dimension of the left ventricle, an indicator of circulating intravascular blood volume, was significantly larger in the RIPC group at 1 h after initiation of resuscitation compared to the control group (p = 0.04). Left ventricular function assessed by fractional shortening was comparable in both groups at 1 h after initiation of resuscitation. Blood urea nitrogen (BUN) was within normal range in the RIPC group (17.3 ± 1.2 mg/dl) but elevated in the control group (22.0 ± 1.7 mg/dl) at 48 h after shock. CONCLUSIONS: RIPC significantly improved short-term survival in rats that were subjected to hemorrhagic shock, and this benefit was maintained long term. RIPC led to greater circulating intravascular blood volume in the early phase of resuscitation and improved BUN.

Cardioprotection: Where to from here?

The size of the myocardial infarction remains an important therapeutic target, because heart attack size correlates with mortality and heart failure. In this era, myocardial infarct size is reduced primarily by timely reperfusion of the infarct related coronary artery. Whereas numerous pre-clinical studies have shown that certain pharmacologic agents and therapeutic maneuvers reduce myocardial infarction size greater than reperfusion alone, very few of these therapies have translated to successful clinical trials or standard clinical use. In this review we discuss both the recent successes as well as recent disappointments, and describe some of the newer potential therapies from the preclinical literature that have not yet been tested in clinical trials.

Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease.

Mice with homozygous null mutations in the HDL receptor (scavenger receptor class B, type I, or SR-BI) and apolipoprotein E (apoE) genes [SR-BI/apoE double KO (SR-BI(-/-)/apoE(-/-) or dKO) mice] spontaneously develop occlusive, atherosclerotic coronary artery disease (CAD) and die prematurely (50% mortality at 42 d of age). Using microarray mRNA expression profiling, we identified genes whose expression in the hearts of dKO mice changed substantially during disease progression [at 21 d of age (no CAD), 31 d of age (small myocardial infarctions), and 43 d of age (extensive myocardial infarctions) vs. CAD-free SR-BI(+/-)/apoE(-/-) controls]. Expression of most genes that increased >sixfold in dKO hearts at 43 d also increased after coronary artery ligation. We examined the influence and potential mechanism of action of apolipoprotein D (apoD) whose expression in dKO hearts increased 80-fold by 43 d. Analysis of ischemia/reperfusion-induced myocardial infarction in both apoD KO mice and wild-type mice with abnormally high plasma levels of apoD (adenovirus-mediated hepatic overexpression) established that apoD reduces myocardial infarction. There was a correlation of apoD's ability to protect primary cultured rat cardiomyocytes from hypoxia/reoxygenation injury with its potent ability to inhibit oxidation in a standard antioxidation assay in vitro. We conclude that dKO mice represent a useful mouse model of CAD and apoD may be part of an intrinsic cardioprotective system, possibly as a consequence of its antioxidation activity.

MicroRNA-26a regulates pathological and physiological angiogenesis by targeting BMP/SMAD1 signaling.

RATIONALE: The rapid induction and orchestration of new blood vessels are critical for tissue repair in response to injury, such as myocardial infarction, and for physiological angiogenic responses, such as embryonic development and exercise. OBJECTIVE: We aimed to identify and characterize microRNAs (miR) that regulate pathological and physiological angiogenesis. METHODS AND RESULTS: We show that miR-26a regulates pathological and physiological angiogenesis by targeting endothelial cell (EC) bone morphogenic protein/SMAD1 signaling in vitro and in vivo. MiR-26a expression is increased in a model of acute myocardial infarction in mice and in human subjects with acute coronary syndromes. Ectopic expression of miR-26a markedly induced EC cycle arrest and inhibited EC migration, sprouting angiogenesis, and network tube formation in matrigel, whereas blockade of miR-26a had the opposite effects. Mechanistic studies demonstrate that miR-26a inhibits the bone morphogenic protein/SMAD1 signaling pathway in ECs by binding to the SMAD1 3'-untranslated region, an effect that decreased expression of Id1 and increased p21(WAF/CIP) and p27. In zebrafish, miR-26a overexpression inhibited formation of the caudal vein plexus, a bone morphogenic protein-responsive process, an effect rescued by ectopic SMAD1 expression. In mice, miR-26a overexpression inhibited EC SMAD1 expression and exercise-induced angiogenesis. Furthermore, systemic intravenous administration of an miR-26a inhibitor, locked nucleic acid-anti-miR-26a, increased SMAD1 expression and rapidly induced robust angiogenesis within 2 days, an effect associated with reduced myocardial infarct size and improved heart function. CONCLUSIONS: These findings establish miR-26a as a regulator of bone morphogenic protein/SMAD1-mediated EC angiogenic responses, and that manipulating miR-26a expression could provide a new target for rapid angiogenic therapy in ischemic disease states.

Bendavia, a mitochondria-targeting peptide, improves postinfarction cardiac function, prevents adverse left ventricular remodeling, and restores mitochondria-related gene expression in rats.

AB We evaluated the post-myocardial infarction (MI) therapeutic effects of Bendavia. Two hours after coronary artery ligation, rats were randomized to receive chronic Bendavia treatment (n = 28) or water (n = 26). Six weeks later, Bendavia significantly reduced scar circumference (39.7% +/- 2.2%) compared with water treatment (47.4% +/- 0.03%, P = 0.024) and reduced left ventricular (LV) volume by 8.9% (P = 0.019). LV fractional shortening was significantly improved by Bendavia (28.8% +/- 1.7%) compared with water treatment (23.8% +/- 1.8%, P = 0.047). LV ejection fraction was higher with Bendavia (55.3% +/- 1.4%) than water treatment (49.3% +/- 1.4%, P = 0.005). Apoptosis, within the MI border zone, was significantly less in the Bendavia group (32% +/- 3%, n = 12) compared with the water group (41% +/- 2%, n = 12; P = 0.029). Bendavia reversed mitochondrial function-related gene expression in the MI border, which was largely reduced in water-treated rats. Bendavia improved complex-I and -IV activity, and reduced production of reactive oxygen species and cytosolic cytochrome c level in the peri-infarcted region. Bendavia improved post-MI cardiac function, prevented infarct expansion and adverse LV remodeling, and restored mitochondria-related gene expression, complex-I and -IV activity, and reduced reactive oxygen species and cardiomyocyte apoptosis in the noninfarcted MI border.

Effects of Electronic Cigarette Vaping on Cardiac and Vascular Function, and Post-myocardial Infarction Remodeling in Rats.

The effect of electronic cigarette (E-cig) vaping on cardiac and vascular function during the healing phase of myocardial infarction (MI), and post-MI remodeling was investigated. Sprague Dawley rats were subjected to left coronary artery ligation to induce MI. One week later, rats were randomized to receive either 12 weeks of exposure to purified air (n = 37) or E-cig vapor (15 mg/ml of nicotine) (n = 32). At 12 weeks, cardiac and vascular function, and post-MI remodeling were assessed. Baseline blood flow in the femoral artery did not differ between groups, but peak reperfusion blood flow was blunted in the E-cig group (1.59 ± 0.15 ml/min) vs. the air group (2.11 ± 0.18 ml/min; p = 0.034). Femoral artery diameter after reperfusion was narrower in the E-cig group (0.54 ± 0.02 mm) compared to the air group (0.60 ± 0.02 mm; p = 0.023). Postmortem left ventricular (LV) volumes were similar in the E-cig (0.69 ± 0.04 ml) and air groups (0.73 ± 0.04 ml; p = NS); and myocardial infarct expansion index did not differ between groups (1.4 ± 0.1 in E-cig group versus 1.3 ± 0.1 in air group; p = NS). LV fractional shortening by echo did not differ between groups at 12 weeks (E-cig at 29 ± 2% and air at 27 ± 1%; p = NS). Exposure to E-cig during the healing phase of MI was associated with altered vascular function with reduced femoral artery blood flow and diameter at reperfusion, but not with worsened LV dilation or worsened cardiac function.

Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity.

Immunoglobulin light chain (LC) amyloidosis (AL) results from overproduction of circulating amyloidogenic LC proteins and subsequent amyloid fibril deposition in organs. Mortality in AL amyloidosis patients is highly associated with a rapidly progressive AL cardiomyopathy, marked by profound impairment of diastolic and systolic cardiac function and significant early mortality. While myocardial fibril deposition contributes to the severe diastolic dysfunction seen in AL cardiomyopathy patients, the degree of fibril deposition has not been found to correlate with prognosis. Previously, we and others showed a direct cardiotoxic effect of amyloidogenic LC proteins (AL-LC), which may contribute to the pathophysiology and mortality observed in AL cardiomyopathy patients. However, the mechanisms underlying AL-LC related cardiotoxicity remain unknown. Mammalian stanniocalcin1 (STC1) is associated with a number of cellular processes including oxidative stress and cell death. Herein, we find that STC1 expression is elevated in cardiac tissue from AL cardiomyopathy patients, and is induced in isolated cardiomyocytes in response to AL-LC, but not non-amyloidogenic LC. STC1 overexpression in vitro recapitulates the pathophysiology of AL-LC mediated cardiotoxicity, with increased ROS production, contractile dysfunction and cell death. Overexpression of STC1 in vivo results in significant cardiac dysfunction and cell death. Genetic silencing of STC1 prevents AL-LC induced cardiotoxicity in cardiomyocytes and protects against AL-LC induced cell death and early mortality in zebrafish. The cardiotoxic effects of STC1 appears to be mediated via mitochondrial dysfunction as indicated by loss of mitochondrial membrane potential, ROS production and increased mitochondrial calcium levels. Collectively, this work identifies STC1 as a critical determinant of AL-LC cardiotoxicity.

Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway.

Patients with primary (AL) cardiac amyloidosis suffer from progressive cardiomyopathy with a median survival of less than 8 months and a 5-year survival of <10%. Contributing to this poor prognosis is the fact that these patients generally do not tolerate standard heart failure therapies. The molecular mechanisms underlying this deadly form of heart disease remain unclear. Although interstitial amyloid fibril deposition of Ig light chain proteins is a major cause of cardiac dysfunction in AL cardiac amyloidosis, we have previously shown that amyloid precursor proteins directly impair cardiac function at the cellular and isolated organ levels, independent of fibril formation. In this study, we report that amyloidogenic light chain (AL-LC) proteins provoke oxidative stress, cellular dysfunction, and apoptosis in isolated adult cardiomyocytes through activation of p38 mitogen-activated protein kinase (MAPK). AL-LC-induced p38 activation was found to be independent of the upstream MAPK kinase, MKK3/6, and instead depends upon transforming growth factor-beta-activated protein kinase-1 binding protein-1 (TAB1)-mediated p38alpha MAPK autophosphorylation. Treatment of cardiomyocytes with SB203580, a selective p38 MAPK inhibitor, significantly attenuated AL-LC-induced oxidative stress, cellular dysfunction, and apoptosis. Our data provide a unique mechanistic insight into the pathogenesis of AL-LC cardiac toxicity and suggest that TAB1-mediated p38alpha MAPK autophosphorylation may serve as an important event leading to cardiac dysfunction and subsequent heart failure.

Flavoring Agents in E-cigarette Liquids: A Comprehensive Analysis of Multiple Health Risks.

The availability of a wide range of flavored e-cigarettes is one of the primary reasons for vaping initiation and persistent use among adolescents and young people. This plethora of flavors available on the market are crafted using different flavoring agents such as cinnamaldehyde, vanillin, benzaldehyde, ethyl maltol, menthol, and dimethylpyrazine. Recent studies have brought to light the potential risks associated with e-cigarette flavoring agents and their effects on various organ systems, both with and without nicotine. Research has demonstrated that flavoring agents can induce inflammation, endothelial dysfunction, epithelial barrier disruption, oxidative stress, DNA damage, electrophysiological alterations, immunomodulatory effects, and behavioral changes, even independently of nicotine. Notably, these negative outcomes adversely affect cardiovascular system by reducing cell viability, decreasing endothelial nitric oxide synthase, nitric oxide bioavailability, soluble guanylyl cyclase activity and cyclic guanosine monophosphate accumulation, impairing endothelial proliferation and tube formation, and altering vasoreactivity resulting in vascular dysfunction. In the heart, these agents decrease parasympathetic activity, induce depolarization of resting membrane potential, loss of rhythmicity, increase isovolumic relaxation time, and change in ventricular repolarization and ventricular tachyarrhythmias. It is found that the specific response elicited by flavoring agents in different organ systems varies depending on the flavor used, the concentration of the flavoring agent, and the duration of exposure. However, the literature on the effects of flavoring agents is currently limited, emphasizing the need for more preclinical and randomized clinical trials to gain a deeper understanding and provide further evidence of the harmful effects of flavored e-cigarette use. In summary, recent research suggests that flavoring agents themselves can have detrimental effects on the body. To fully comprehend these effects, additional preclinical and clinical studies are needed to explore the risks associated with flavored e-cigarette usage.

Effects of Electronic Cigarette Exposure on Myocardial Infarction and No-Reflow, and Cardiac Function in a Rat Model.

PURPOSE: We investigated the effects of exposure to electronic cigarettes (E-cig) vapor on the sizes of the no-reflow and myocardial infarction regions, and cardiovascular function compared to exposure to purified air and standard cigarette smoke. METHODS AND RESULTS: Sprague Dawley rats (both male and female, 6 weeks old) were successfully exposed to filtered air (n = 32), E-cig with nicotine (E-cig Nic+, n = 26), E-cig without nicotine (E-cig Nic-, n = 26), or standard cigarette smoke (1R6F reference, n = 31). All rats were exposed to inhalation exposure for 8 weeks, prior to being subjected to 30 minutes of left coronary artery occlusion followed by 3 hours of reperfusion. Exposure to E-cig vapor with or without nicotine or exposure to standard cigarettes did not increase myocardial infarct size or worsen the no-reflow phenomenon. Exposure to E-cig Nic+ reduced the body weight gain, and increased the LV weight normalized to body weight and LV wall thickness and enhanced the collagen deposition within the LV wall. E-cig exposure led to cardiovascular dysfunction, such as reductions in cardiac output, LV positive and negative dp/dt, suggesting a reduction in contractility and relaxation, and increased systemic arterial resistance after coronary artery occlusion and reperfusion in rats compared to air or cigarette exposure. CONCLUSIONS: E-cig exposure did not increase myocardial infarct size or worsen the no-reflow phenomenon, but induced deleterious changes in LV structure leading to cardiovascular dysfunction and increased systemic arterial resistance after coronary artery occlusion followed by reperfusion.

One Acute Exposure to E-Cigarette Smoke Using Various Heating Elements and Power Levels Induces Pulmonary Inflammation.

Background: Electronic cigarettes (eC) may not be entirely benign. There is a lack of data on the effect of a single acute exposure of eC vapor using various heating sources and power settings upon lung injury. The purpose of this study was to determine if an acute exposure with eC vapor heated with different heating elements and power levels induced inflammatory changes in the lungs and heart. Methods: Rats were exposed to pure air or received a single, 4-h exposure to eC vapor. The devices used either a stainless steel (SS) or nichrome (NC) heating element randomized to a low or high atomization power (45 versus 70 W). Rats were euthanized within 48 h of exposure. Results: The eC groups showed accumulation of inflammatory cells in bronchial lumen, near the pleura, and within the alveolar spaces. The numbers of inflammatory cells per field in the lung parenchyma were significantly greater in the rats exposed to eC groups vs. the air group. There were significantly higher inflammatory gene expression changes in the lungs of animals assigned to 70 W power. We observed that eC vapor generated using burnt coils were toxic and could cause acute respiratory distress and myocarditis. Conclusion: In conclusion, one 4-h exposure to eC vapor, in the absence of vitamin E oil or nicotine, significantly increased lung inflammation. Effects were seen after exposures to vapor generated using SS and NC heating elements at either high or low power. Vapor from devices with burnt coils can negatively affect the heart and lung.

Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy.

BACKGROUND: Ischemic cardiomyopathy is the major cause of heart failure and a significant cause of morbidity and mortality. The degree of left ventricular dysfunction in this setting is often out of proportion to the amount of overtly infarcted tissue, and how decreased delivery of oxygen and nutrients leads to impaired contractility remains incompletely understood. The Prolyl Hydroxylase Domain-Containing Protein (PHD) prolyl hydroxylases are oxygen-sensitive enzymes that transduce changes in oxygen availability into changes in the stability of the hypoxia-inducible factor transcription factor, a master regulator of genes that promote survival in a low-oxygen environment. METHODS AND RESULTS: We found that cardiac-specific PHD inactivation causes ultrastructural, histological, and functional changes reminiscent of ischemic cardiomyopathy over time. Moreover, long-term expression of a stabilized hypoxia-inducible factor alpha variant in cardiomyocytes also led to dilated cardiomyopathy. CONCLUSIONS: Sustained loss of PHD activity and subsequent hypoxia-inducible factor activation, as would occur in the setting of chronic ischemia, are sufficient to account for many of the changes in the hearts of individuals with chronic coronary artery disease.

Impact of Regional Green Development Strategy on Environmental Total Factor Productivity: Evidence from the Yangtze River Economic Belt, China.

Chinese government policy officially identify the Yangtze River Economic Belt (YREB) as one of regional green development strategies firstly in 2014. This strategy can be regarded as quasi-natural experiment, this paper aims to test its impact on regional environmental total factor productivity (TFP). First, slack-based measure model is used to calculate the environmental TFP from 2005 to 2017 at provincial level. Second, based on Chinese official statistics, differences-in-differences (DID) method is applied to construct an evaluation model of policy effect, combining with the kernel matching in propensity score matching (PSM) method. The results show that environmental TFP of YREB has significant spatial differences, with characteristic of high-east and low-west, its average level is 11.69 percentage points higher than the national average. YREB strategy promotes regional economic growth, but it does no effect on the regional environmental TFP yet. Modelling suggests that YREB strategy may play a role in the short term. From the significance of the control variables, infrastructure construction level is positively correlated with environmental TFP, while per capita GDP, financial development and energy consumption intensity have negative effect on environmental TFP. Based on this, policymakers should focus on green development, promoting industrial transformation, and enhancing environmental protection.

A novel role for tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in the development of cardiac dysfunction and failure.

BACKGROUND: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, is a multifunctional cytokine known to regulate cellular functions in contexts of injury and disease through its receptor, fibroblast growth factor-inducible molecule 14 (Fn14). Although many of the processes and downstream signals regulated by the TWEAK/Fn14 pathway have been implicated in the development of cardiac dysfunction, the role of TWEAK in the cardiovascular system is completely unknown. METHODS AND RESULTS: Herein, we demonstrate that mouse and human cardiomyocytes express the TWEAK receptor Fn14. Furthermore, we determine that elevated circulating levels of TWEAK, induced via transgenic or adenoviral-mediated gene expression in mice, result in dilated cardiomyopathy with subsequent severe cardiac dysfunction. This phenotype was mediated exclusively by the Fn14 receptor, independent of tumor necrosis factor-alpha, and was associated with cardiomyocyte elongation and cardiac fibrosis but not cardiomyocyte apoptosis. Moreover, we find that circulating TWEAK levels were differentially upregulated in patients with idiopathic dilated cardiomyopathy compared with other forms of heart disease and normal control subjects. CONCLUSIONS: Our data suggest that TWEAK/Fn14 may be important in regulating myocardial structural remodeling and function and may play a role in the pathogenesis of dilated cardiomyopathy.

Design considerations for high efficiency liquid crystal decentered microlens arrays for steering light.

We have investigated the causes of low efficiency for optical beam steering devices based on liquid crystal decentered microlens arrays (DLAs). We show that the efficiency is effected by the relative phase of light exiting the individual lenses, the imperfect focusing of small lenses due to diffraction, the aberrations related to off-axis light going through a lens, and the diffraction spreading of light beams going through the DLA structure. A high steering efficiency of over 94.4% is demonstrated by modeling the transmitted light through the DLA with scalar diffraction theory. We also propose modified phase profiles for the lenses that are a function of angle that substantially improve the performance of these types of device over the unmodified profiles.

Environmental Kuznets Curve: Empirical Relationship between Energy Consumption and Economic Growth in Upper-Middle-Income Regions of China.

This paper examines the environmental Kuznets curve (EKC) relationship between energy consumption and economic growth in upper-middle-income regions of China with the panel data of 21 provinces from 2000 to 2017. The influence mechanism of socio-economic factors on the EKC of these regions is also detected. The results show that the energy consumption EKC fitting map in these regions conforms to the classical environmental Kuznets curve, which is an inverted "N" type, and the inflection point is ahead and more accurate after adding spatial effects. The direct effect of energy consumption has delayed the inflection point, indicating that the level of industrialization, urbanization, and population density have a significant impact on EKC. At the same time, it is found that the level of industrialization and population density have a positive relationship with energy consumption, while the level of urbanization has a negative correlation with energy consumption. The spatial spillover effect of the indirect effects of total energy consumption, coal consumption, and crude oil consumption shows that the level of industrialization has a significant and negative link with EKC. The increase in the level of industrialization will affect the total energy consumption of neighboring areas and the consumption of coal and crude oil.

Different Effects of Volatile and Nonvolatile Anesthetic Agents on Long-Term Survival in an Experimental Model of Hemorrhagic Shock.

BACKGROUND: We investigated whether the cardioprotective, volatile gas anesthetic agent, isoflurane, could improve survival and organ function from hemorrhagic shock in an experimental rat model, compared to standard nonvolatile anesthetic agent ketamine/xylazine. METHODS: Sprague Dawley rats (both genders) were randomized to receive either intraperitoneal ketamine/xylazine (K/X, 90 and 10 mg/kg; n = 12) or isoflurane (5% isoflurane induction and 2% maintenance in room air; n = 12) for anesthesia. Blood was withdrawn to maintain mean arterial blood pressure at 30 mm Hg for 1 hour, followed by 30 minutes of resuscitation with shed blood. Rats were allowed to recover and survive for 6 weeks. RESULTS: During the shock phase, the total withdrawn blood volume (expressed as % of estimated total blood volume) to maintain a level of hypotension of 30 mm Hg was significantly higher in the isoflurane group (51.0% ± 1.5%) than in the K/X group (45.3% ± 1.8%; P = .023). Recovery of blood pressure during the resuscitation phase was significantly improved in the isoflurane group compared to the K/X group. The survival rate at 6 weeks was 1 (8.3%) of 12 in rats receiving K/X and 10 (83.3%) of 12 in rats receiving isoflurane (P < .001). Histology performed at 6 weeks demonstrated brain infarction in the 1 surviving rat receiving K/X; no brain infarction occurred in the 10 surviving rats that received isoflurane. No infarction was detected in heart, lung, liver, or kidneys among the surviving rats. CONCLUSIONS: Isoflurane improved blood pressure response to resuscitation and resulted in significantly higher long-term survival rate.

Acute administration of nicotine induces transient elevation of blood pressure and increases myocardial infarct size in rats.

AIMS: We investigated the acute effects of nicotine on myocardial infarct size, no reflow, hemodynamics and cardiac function in an acute myocardial ischemia and reperfusion infarction rat model. MAIN METHODS: Female Sprague-Dawley rats (n = 23/group) received an intravenous loading dose of nicotine at 2.0 µg/kg/min or saline control for 30 min before starting coronary artery occlusion, then followed by a maintenance dose 0.35 µg/kg/min of nicotine to the end of 30 min occlusion and 3 h reperfusion. KEY FINDINGS: At baseline, there was no difference in systolic blood pressure (BP in mmHg) (nicotine, 69.0 ± 2.7; control, 69.3 ± 4.4; p = NS) or diastolic BP (nicotine, 45.7 ± 3.2; control, 48.2 ± 4.2; p = NS) between groups. Nicotine administration initially increased systolic BP (nicotine, 97.0 ± 8.6; control, 69.2 ± 3.3, p < 0.0001) and diastolic BP (nicotine, 65.6 ± 6.4; control, 47.4 ± 3.1, p = 0.0003) at 10 min after starting injection of the loading dose; BP dropped to control levels in both groups at 30 min. During occlusion and reperfusion, the BP and heart rate were not altered by nicotine. Nicotine significantly increased myocardial infarct size as a percentage of the ischemic risk zone compared to the controls (nicotine, 54.9 ± 1.9; control, 48.6 ± 2.7, p < 0.05), but nicotine did not affect the no-reflow size and heart function. SIGNIFICANCE: While acute nicotine only transiently elevated blood pressure, it did not affect hemodynamic parameters during coronary artery occlusion. Nicotine increased myocardial infarct size, suggesting that the increase in infarct size was not simply due to an increase in oxygen demand due to altered afterload, heart rate, or contractility, but may have been due to a more direct effect on the myocardium.

Therapeutic Hypothermia Improves Long-Term Survival and Blunts Inflammation in Rats During Resuscitation of Hemorrhagic Shock.

We tested the hypothesis that therapeutic hypothermia (TH) improves survival and blunts inflammation in rats undergoing experimental hemorrhagic shock. Rats were randomized to TH (n = 16) or normothermia (n = 15). Hemorrhagic shock was induced by withdrawing blood to a fixed mean blood pressure (MBP) of 30 mmHg for 30 minutes followed by reinfusion of shed blood for the next 30 minutes. TH (target 32°C) was started at 5 minutes after MBP reached 30 mmHg and was maintained throughout blood volume resuscitation. In the normothermic control group, body temperature was maintained at 37°C during the procedure. Rats were allowed to recover for 6 weeks. TH significantly improved survival: 4 of 15 (26.7%) rats in the normothermic group and 11 of 16 (68.8%; p = 0.032) rats in the TH group survived 6 weeks. Recovery of MBP during the resuscitation phase was significantly improved and left ventricular fractional shortening was markedly increased in the TH group compared with the normothermic group. Brain infarction was observed in 3 of 4 surviving rats (75%) in normothermic group, and in only 1 of the 11 surviving rats (9%) in TH group. The neutrophil-to-lymphocyte ratio was lower in TH group (0.20 ± 0.02) compared with the normothermic group (0.32 ± 0.03; p = 0.003). TH influenced the levels of blood gases and blood counts, favoring hypothermia over control. TH significantly improved long-term survival and blunted the inflammatory response in experimental hemorrhagic shock.

Remote Ischemic Conditioning in Acute Myocardial Infarction and Shock States.

Remote ischemic conditioning is the phenomenon whereby brief, nonlethal episodes of ischemia in one organ (such as a limb) protect a remote organ from ischemic necrosis induced by a longer duration of severe ischemia followed by reperfusion. This phenomenon has been reproduced by dozens of experimental laboratories and was shown to reduce the size of myocardial infarction in many but not all clinical studies. In one recent large clinical trial, remote ischemic conditioning induced by repetitive blood pressure cuff inflations on the arm did not reduce infarct size or improve clinical outcomes. This negative result may have been related in part to the overall success of early reperfusion and current adjunctive therapies, such as antiplatelet therapy, antiremodeling therapies, and low-risk patients, that may make it difficult to show any advantage of newer adjunctive therapies on top of existing therapies. One relevant area in which current outcomes are not as positive as in the treatment of heart attack is the treatment of shock, where mortality rates remain high. Recent experimental studies show that remote ischemic conditioning may improve survival and organ function in shock states, especially hemorrhagic shock and septic shock. In this study, we review the preclinical studies that have explored the potential benefit of this therapy for shock states and describe an ongoing clinical study.