Dennis Hsu-Tung Chang

Cardiotoxicity with Modern Local Anaesthetics Is There a Safer Choice

The recognition that long-acting local anaesthetics, particularly bupivacaine the de facto standard long-acting local anaesthetic, were disproportionately more cardiotoxic than their shorter-acting counterparts stimulated the development of the bupivacaine congeners, ropivacaine and levobupivacaine. These agents, like all local anaesthetics, can produce cardiotoxic sequelae by direct and indirect mechanisms that derive from their mode of local anaesthetic actions, i.e. inhibition of voltage-gated ion channels. While all local anaesthetics can cause direct negative inotropic effects, ropivacaine and levobupivacaine are less cardiotoxic than bupivacaine judging by the larger doses tolerated in laboratory animal preparations before the onset of serious cardiotoxicity (particularly electro-mechanical dissociation or malignant ventricular arrhythmias). Additionally, they are less toxic to the CNS than bupivacaine judging by the larger doses tolerated before the onset of seizures. This may be clinically important because CNS effects may be involved in the production of serious cardiotoxicity. Preclinical studies in humans are a ‘blunt instrument’ in their ability to distinguish significant differences between these drugs because of the relatively small doses that can be used. Nevertheless, available evidence from human studies corroborates the preclinical laboratory animal studies. Because clinically significant differences between these drugs are more quantitative than qualitative, i.e. toleration of a larger dose before manifestation of toxicity, we have concluded that these newer agents have a lower risk of causing serious cardiotoxicity than bupivacaine. Thus, compared with bupivacaine, the newer agents may be seen as ‘safer’, but they must not be regarded as ‘safe’.

Changes in myocardial protein expression in pacing-induced canine heart failure

Canine rapid ventricular pacing produces a low output cardiomyopathic state which is similar to dilated cardiomyopathy. In this study dogs were paced at 245 beats per minute (bpm) for 3—4 weeks until signs of heart failure were apparent. Unpaced dogs were used as controls. A previous study identified myocardial protein changes in the pH region 4—7 following ventricular pacing by using two‐dimensional electrophoresis (2‐DE) (Heinke et al., Electrophoresis 1998 19, 2021—2030). Many of these proteins were associated with mitochondria, energy metabolism within the cardiomyocyte, the cytoskeleton and calcium cycling. The present study aimed to examine the proteins migrating in the more basic region of the 2‐DE pattern using immobilised pH gradient 3—10 strips to separate myocardial proteins. The expression of 31 proteins was altered in the paced myocardium: 21 were decreased and 10 increased. Following the identification of 23 of these spots by either amino acid compositional analysis or peptide mass fingerprinting or a combination of both, we confirm that many of the proteins whose expression is altered following ventricular pacing are associated with the mitochondria and energy production within the cardiomyocyte, including creatine kinase M, triosephosphate isomerase, phosphoglycerate mutase, cytochrome c oxidase, cytochrome b5, hydroxymethyl glutaryl CoA synthase, myoglobin, and 3,2‐trans‐enoyl‐CoA transferase. Additionally, the cytoskeletal protein actin was increased in the paced hearts. These results strongly support the notion that energy production is impaired and mitochondrial dysfunction is involved in the development of heart failure in the paced dog.

Direct cardiac effects of intracoronary bupivacaine, levobupivacaine and ropivacaine in the sheep

The racemic local anaesthetic agent bupivacaine is widely used clinically for its long duration of action. Levobupivacaine and ropivacaine are bupivacaine enantiopure congeners, developed to improve upon the clinical safety of bupivacaine, especially the risk of fatal arrhythmogenesis. In previous preclinical studies of the safety of these drugs with intravenous administration in conscious ewes over a wide dose range, we found that central nervous system (CNS) excito‐toxicity reversed the cardiac depressant effects when doses approached the convulsant threshold and thus precluded accurate comparison of their cardiovascular system (CVS) effects. To study CVS effects over a wide range of doses with minimal CNS and other influences, brief (3 min) infusions of bupivacaine, levobupivacaine or ropivacaine were administered into the left main coronary arteries of previously instrumented conscious ewes (∼50 Kg body weight). After dose‐ranging studies, the drugs were compared in a randomized, blinded, parallel group design. Equimolar doses were increased from 8 μmol (∼amp;2.5 mg) in 8 μmol increments, to either a fatal outcome or a 40 μmol (∼amp;12.5 mg) maximum. All three drugs produced tachycardia, decreased myocardial contractility and stroke volume and widening of electrocardiographic QRS complexes. Thirteen of 19 animals died of ventricular fibrillation: four of six with bupivacaine (mean±s.e.mean actual fatal dose: 21.8±6.4 μmol), five of seven with levobupivacaine (22.9±3.5 μmol), four of six with ropivacaine (22.9±5.9 μmol). No significant differences in survival or in fatal doses between these drugs were found. The findings suggest that ropivacaine, levobupivacaine and bupivacaine have similar intrinsic ability to cause direct fatal cardiac toxicity when administered by left intracoronary arterial infusion in conscious sheep and do not explain the differences between the drugs found with intravenous dosage.

The use of complementary and alternative medicine by people with cardiovascular disease: a systematic review

BackgroundComplementary and alternative medicine (CAM) may offer benefits as well as risks to people with cardiovascular disease. Understanding the prevalence and the nature of CAM use will encourage beneficial CAM therapies, prevent potential herb-drug interactions and foster communication between patients and physicians.MethodsA systematic search of eight bibliographic databases was conducted for studies that investigated CAM use in patients with cardiovascular diseases. Two independent reviewers selected relevant abstracts and evaluated the quality of included studies.ResultsTwenty-seven studies were included. Prevalence of CAM use in cardiac patients ranged from 4% - 61%. Biologically-based therapies usage ranged from 22% to 68%. Herbal medicines were used by between 2% and 46%. A large proportion of patients did not inform medical practitioners about their CAM use and up to 90% of treating physicians did not discuss CAM use with their patients.ConclusionsCAM use in patients with cardiovascular disease appears common. The findings suggest that the effects of CAM on medical management of cardiovascular disease may be overlooked and that patient-physician communication need to be strengthened.

Berberine alleviates ox-LDL induced inflammatory factors by up-regulation of autophagy via AMPK/mTOR signaling pathway

BackgroundInflammation induced by oxidized low-density lipoprotein (ox-LDL) plays an important role in the pathogenesis of atherosclerosis. Recently, roles of autophagy against inflammation in the process of atherosclerosis have drawn increasing attention. Here, we tested the possible molecular mechanisms by which berberine confers an anti-inflammatory effect in macrophages by upregulation of autophagy.MethodsJ774A.1 macrophages were incubated with various doses of ox-LDL for various times. We evaluated the inflammatory factors and autophagy proteins (LC3II/LC3I, and SQSTM1/p62) to ascertain the optimal dose and time. Ox-LDL–induced inflammatory factors and autophagy in J774A.1 cells were tested by the AimPlex multiplex assay, Western blotting, confocal microscopy, and transmission electron microscopy in the presence of berberine or chloroquine (CQ). Adenosine 5’-monophosphate-activated protein kinase (AMPK) inhibitor compound C was used to evaluate the AMPK/mTOR signaling pathway.ResultsBerberine dose- and time-dependently reduced ox-LDL–induced inflammation and increased the ratio of LC3II/LC3I, and SQSTM1/p62 in J774A.1 cells. CQ significantly attenuated the berberine-induced autophagy and anti-inflammation. In addition, berberine increased the ratio of p-AMPK/AMPK and decreased the ratio of p-mTOR/mTOR. AMPK inhibitor compound C abolished berberine-induced autophagy and promoted p-mTOR/mTOR expression in J774A.1 cells.ConclusionBerberine treatment inhibits inflammation in J774A.1 cells by inducing autophagy, which is mediated through activation of the AMPK/mTOR signaling pathway. Importantly, this study provides new insight into berberine’s molecular mechanism and its therapeutic potential in the treatment of atherosclerosis.

Fifteen Minutes of Chair-Based Yoga Postures or Guided Meditation Performed in the Office Can Elicit a Relaxation Response

This study compared acute (15 min) yoga posture and guided meditation practice, performed seated in a typical office workspace, on physiological and psychological markers of stress. Twenty participants (39.6 ± 9.5 yr) completed three conditions: yoga, meditation, and control (i.e., usual work) separated by ≥24 hrs. Yoga and meditation significantly reduced perceived stress versus control, and this effect was maintained postintervention. Yoga increased heart rate while meditation reduced heart rate versus control (P < 0.05). Respiration rate was reduced during yoga and meditation versus control (P < 0.05). Domains of heart rate variability (e.g., SDNN and Total Power) were significantly reduced during control versus yoga and meditation. Systolic and diastolic blood pressure were reduced secondary to meditation versus control only (P < 0.05). Physiological adaptations generally regressed toward baseline postintervention. In conclusion, yoga postures or meditation performed in the office can acutely improve several physiological and psychological markers of stress. These effects may be at least partially mediated by reduced respiration rate.

Apoptosis of ventricular and atrial myocytes from pacing-induced canine heart failure

OBJECTIVE Rapid ventricular pacing in dogs results in a low output cardiomyopathic state similar to idiopathic dilated cardiomyopathy in man. Cell death by apoptosis may play an important role in the loss of cardiac function. This study investigates the molecular pathways involved in the regulation of apoptosis in dogs with pacing-induced heart failure. METHODS Apoptosis was identified by terminal transferase nick end-labelling (TUNEL) in the ventricles and atria of dog hearts affected by rapid-ventricular pacing. Western blots were used to determine expression of the components involved in the initiation (Fas, Fas-Ligand, FADD), regulation (Bcl-2, Bax) and execution (caspase-2 and caspase-3) of apoptosis. RESULTS Pacing-induced heart failure resulted in a significant increase in the number of ventricular and atrial myocyte nuclei undergoing apoptosis as measured by TUNEL. Compared to the samples from control hearts (n=6) the expression of Bcl-2, an inhibitor of apoptosis, was significantly reduced in ventricles from five dogs with pacing-induced heart failure. No change in the expression of the apoptotic inducer Bax was detected. Fas and FADD were significantly elevated in all paced ventricles, and Fas-L was only detected in the paced hearts. Both caspase-2 and caspase-3 were elevated following ventricular pacing. CONCLUSIONS We have identified components of the signalling pathways along which apoptosis proceeds following the induction of heart failure in dogs. Apoptosis was also detected in the atria raising the possibility that, like human dilated cardiomyopathy, the molecular changes are global.

Interrater Reliability of Chinese Medicine Diagnosis in People with Prediabetes

Background. Achieving reproducibility in research design is challenging when patient cohorts under study are inconsistently defined. Traditional Chinese medicine (TCM) diagnosis is one example where inconsistency between practitioners has been found. We hypothesise that the use of a validated instrument may improve consistency. Biochemical biomarkers may also be used enhance reliability. Methods. Twenty-seven participants with prediabetes were assessed by two TCM practitioners using a validated instrument (TEAMSI-TCM). Inter-rater reliability was summarised using percentage agreement and the kappa coefficient. One-way ANOVA and Tukeys post hoc test were used to test links between TCM diagnosis and biomarkers. Results. The two practitioners agreed on primary diagnosis of 70% of participants. kappa = 0.56 (P < 0.001). The three predominant TCM diagnostic patterns for people with prediabetes were Yin deficiency, Qi and Yin deficiency and Spleen qi deficiency. The Spleen Qi deficiency with Damp cohort had statistically significant higher fasting glucose, higher insulin, higher insulin resistance, higher HbA1c and lower HDL than those with Qi and Yin deficiency. Conclusions. Using the TEAMSI-TCM resulted in moderate interrater reliability between TCM practitioners. This study provides initial evidence of variation in the biomarkers of people with prediabetes according to the different TCM patterns which may suggest a route to further improving interrater reliability.

Effect of an office worksite-based yoga program on heart rate variability: outcomes of a randomized controlled trial

BackgroundChronic work-related stress is an independent risk factor for cardiometabolic diseases and associated mortality, particularly when compounded by a sedentary work environment. The purpose of this study was to determine if an office worksite-based hatha yoga program could improve physiological stress, evaluated via heart rate variability (HRV), and associated health-related outcomes in a cohort of office workers.MethodsThirty-seven adults employed in university-based office positions were randomized upon the completion of baseline testing to an experimental or control group. The experimental group completed a 10-week yoga program prescribed three sessions per week during lunch hour (50 min per session). An experienced instructor led the sessions, which emphasized asanas (postures) and vinyasa (exercises). The primary outcome was the high frequency (HF) power component of HRV. Secondary outcomes included additional HRV parameters, musculoskeletal fitness (i.e. push-up, side-bridge, and sit & reach tests) and psychological indices (i.e. state and trait anxiety, quality of life and job satisfaction).ResultsAll measures of HRV failed to change in the experimental group versus the control group, except that the experimental group significantly increased LF:HF (p = 0.04) and reduced pNN50 (p = 0.04) versus control, contrary to our hypotheses. Flexibility, evaluated via sit & reach test increased in the experimental group versus the control group (p < 0.001). No other adaptations were noted. Post hoc analysis comparing participants who completed ≥70% of yoga sessions (n = 11) to control (n = 19) yielded the same findings, except that the high adherers also reduced state anxiety (p = 0.02) and RMSSD (p = 0.05), and tended to improve the push-up test (p = 0.07) versus control.ConclusionsA 10-week hatha yoga intervention delivered at the office worksite during lunch hour did not improve HF power or other HRV parameters. However, improvements in flexibility, state anxiety and musculoskeletal fitness were noted with high adherence. Future investigations should incorporate strategies to promote adherence, involve more frequent and longer durations of yoga training, and enrol cohorts who suffer from higher levels of work-related stress.Trial registrationACTRN12611000536965

Effects of CNS site-directed carotid arterial infusions of bupivacaine, levobupivacaine, and ropivacaine in sheep.

Background Previous preclinical safety studies in ewes have found intravenous levobupivacaine and ropivacaine to be less potent toward causing central nervous system (CNS) and cardiac toxicity than bupivacaine. Analogous cardiotoxicity has been demonstrated directly in various cardiac preparations ex vivo. Moreover, drug-related arrhythmogenicity has been demonstrated from direct CNS injection of local anesthetic agents in vivo, suggesting CNS-related cardiotoxicity. This study investigated whether CNS site-directed blood-borne drug administration (with minimal systemic recirculation) would demonstrate drug-related cardiotoxicity. Methods Direct CNS effects and indirect cardiotoxic sequelae were determined after bilateral carotid arterial infusions of levobupivacaine, bupivacaine, or ropivacaine in ewes. After pilot studies to validate the procedures, equimolar doses (24–96 &mgr;mol, ≈7.5–30 mg) were infused over 3 min using a crossover design. Behavioral CNS signs, quantitative electroencephalographic (EEG), cardiovascular, and electrocardiographic effects were recorded. Drug blood concentrations in superior sagittal sinus and aorta were measured serially. Results Blood drug concentrations in the superior sagittal sinus were 5–10 times those concurrently in the aorta, confirming highly selective CNS delivery with minimal systemic recirculation. Dose-dependent CNS excitatory behavior and EEG changes, with increased mean arterial blood pressure, heart rate, cardiac output, and myocardial contractility, were found, consistent with sympathetic nervous system stimulation. The overall rank order of potency for these effects was ropivacaine < levobupivacaine < bupivacaine. Nonfatal cardiac arrhythmias were observed, but the type or frequency did not differ between drugs. Conclusions Although CNS site-selective drug delivery produced quantitative differences between bupivacaine, levobupivacaine, and ropivacaine in some CNS effects and cardiac sequelae, no differences were found in their arrhythmogenic potential.