Evaluation of the dopamine ß-hydroxylase (DßH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder.

In the present study, we tested the hypothesis that the potent and selective dopamine-ß-hydroxylase (DßH) inhibitor nepicastat would have minimal effects on cardiovascular and pharmacokinetic parameters associated with cocaine administration and would reduce the positive subjective effects produced by cocaine. We conducted a double-blind, placebo-controlled, inpatient study of oral nepicastat (0, 80 and 160mg) concurrent with intravenous (IV) cocaine (0, 10, 20 and 40mg) in non-treatment seeking participants who metcriteria for cocaine use disorder. Safety analyses revealed that nepicastat was well-tolerated and there were no differences in adverse events observed after nepicastat plus cocaine vs. cocaine alone. In addition, the pharmacokinetic properties of cocaine administration were not altered by nepicastat treatment. Cocaine-induced cardiovascular and subjective effects were evaluated for completers in the cohort randomized to nepicastat (n=13) using a within-subjects statistical analysis strategy. Specifically, the cardiovascular and subjective effects of cocaine were assessed in the presence of placebo (0mg), 80mg of nepicastat or 160mg of nepicastat on study Days 4, 8 and 12, respectively. Analyses revealed a main effect of nepicastat to reduce several cocaine-induced positive subjective effects. Taken together, these data indicate that nepicastat is safe when co-administered with cocaine and may suppress its positive subjective effects, and may be viable as a pharmacotherapy for treatment of cocaine use disorder.

Syncope in adults: systematic review and proposal of a diagnostic and therapeutic algorithm.

This review aims to provide a practical and up-to-date description on the relevance and classification of syncope in adults as well as a guidance on the optimal evaluation, management and treatment of this very common clinical and socioeconomic medical problem. We have summarized recent active research and emphasized the value for physicians to adhere current guidelines. A modern management of syncope should take into account 1) use of risk stratification algorithms and implementation of syncope management units to increase the diagnostic yield and reduce costs; 2) early implantable loop recorders rather than late in the evaluation of unexplained syncope; and 3) isometric physical counter-pressure maneuvers as first-line treatment for patients with neurally-mediated reflex syncope and prodromal symptoms.

Dobutamine stress echocardiography in a patient with Wolff-Parkinson-White syndrome.

We describe the case of a patient with ventricular pre-excitation who underwent dobutamine stress echocardiography to evaluate atypical chest pain. The patient safely underwent the procedure with interesting electrocardiographic findings during pharmacological stress. The risks of dobutamine stress testing, along with possible explanations of this observed event, are discussed. In conclusion, the safety of dobutamine stress testing in patients with ventricular pre-excitation has not been established; further prospective studies are needed to decide whether dobutamine stress testing is safe in certain subsets of this population.

Modeling left ventricular diastolic dysfunction: classification and key indicators.

BACKGROUND: Mathematical modeling can be employed to overcome the practical difficulty of isolating the mechanisms responsible for clinical heart failure in the setting of normal left ventricular ejection fraction (HFNEF). In a human cardiovascular respiratory system (H-CRS) model we introduce three cases of left ventricular diastolic dysfunction (LVDD): (1) impaired left ventricular active relaxation (IR-type); (2) increased passive stiffness (restrictive or R-type); and (3) the combination of both (pseudo-normal or PN-type), to produce HFNEF. The effects of increasing systolic contractility are also considered. Model results showing ensuing heart failure and mechanisms involved are reported. METHODS: We employ our previously described H-CRS model with modified pulmonary compliances to better mimic normal pulmonary blood distribution. IR-type is modeled by changing the activation function of the left ventricle (LV), and R-type by increasing diastolic stiffness of the LV wall and septum. A 5th-order Cash-Karp Runge-Kutta numerical integration method solves the model differential equations. RESULTS: IR-type and R-type decrease LV stroke volume, cardiac output, ejection fraction (EF), and mean systemic arterial pressure. Heart rate, pulmonary pressures, pulmonary volumes, and pulmonary and systemic arterial-venous O2 and CO2 differences increase. IR-type decreases, but R-type increases the mitral E/A ratio. PN-type produces the well-described, pseudo-normal mitral inflow pattern. All three types of LVDD reduce right ventricular (RV) and LV EF, but the latter remains normal or near normal. Simulations show reduced EF is partly restored by an accompanying increase in systolic stiffness, a compensatory mechanism that may lead clinicians to miss the presence of HF if they only consider LVEF and other indices of LV function. Simulations using the H-CRS model indicate that changes in RV function might well be diagnostic. This study also highlights the importance of septal mechanics in LVDD. CONCLUSION: The model demonstrates that abnormal LV diastolic performance alone can result in decreased LV and RV systolic performance, not previously appreciated, and contribute to the clinical syndrome of HF. Furthermore, alterations of RV diastolic performance are present and may be a hallmark of LV diastolic parameter changes that can be used for better clinical recognition of LV diastolic heart disease.

Reducing ischaemia/reperfusion injury through delta-opioid-regulated intrinsic cardiac adrenergic cells: adrenopeptidergic co-signalling.

AIMS: The purpose of this study was to determine whether intrinsic cardiac adrenergic (ICA) cells release calcitonin gene-related peptide (CGRP), exerting synergistic adrenopeptidergic cardioprotection. METHODS AND RESULTS: In situ hybridization coupled with immunostaining demonstrated that ICA cells exclusively expressed CGRP mRNA and co-expressed CGRP and delta-opioid receptor in human and rat left ventricular (LV) myocardium. Radioimmunoassay detected constitutive CGRP release from ICA cells in human and rat hearts. The delta-opioid agonist [D-Pen(25)]-enkephalin (DPDPE) increased CGRP release from ICA cells in denervated rat heart. In an ischaemia/reperfusion rat model, pre-ischaemic treatment with DPDPE reduced infarct size (IS) by 51 +/- 16% (P < 0.01). Co-infusion of beta(2)-adrenergic receptor (beta(2)-AR) and CGRP receptor (CGRP-R) antagonists increased IS by 62 +/- 23% (P < 0.01) compared with saline and abolished DPDPE-initiated IS reduction. Pre-treatment of ICA cell-myocyte co-culture with the beta(2)-AR/CGRP-R antagonists increased myocyte death rate by 24 +/- 4% (P < 0.01) and abolished DPDPE-initiated myocyte protection against hypoxia/reoxygenation (re-O(2)). In the ICA cell-depleted myocyte culture, DPDPE did not confer myocyte protection. Supplementing ICA cell-depleted myocyte culture with beta(2)-AR/CGRP-R agonists reduced hypoxia/re-O(2)-induced myocyte death by 24 +/- 5% (P < 0.01), simulating endogenous neurohormonal effects of ICA cells. Western blot analysis showed that DPDPE markedly increased phosphorylated myocardial Akt levels. This effect was abolished in the presence of beta(2)-AR/CGRP-R blockade. Terminal dUTP nick-end labelling staining analysis of the LV infarct zone demonstrated that DPDPE reduced myocyte apoptosis by 58 +/- 19% (P < 0.05), an effect that was eliminated in the presence of beta(2)-AR/CGRP-R blockade. Finally, echocardiography showed that DPDPE increased LV contractility in a manner dependent on beta-AR/CGRP-R stimulation. CONCLUSION: ICA cells constitute a delta-opioid-regulated adrenopeptidergic paracrine system conferring robust cardioprotection through beta(2)-AR/CGRP-R co-signalling, resulting in the activation of an anti-apoptotic pathway during ischaemia/reperfusion.

Syncope, seizure, or both? An unusual case of complete heart block.

Syncope and epileptic seizures have common presenting features that make it difficult to determine if a patient's collapse is primarily cardiac or neurologic. The distinction is blurred further if epileptic neural activity provokes cardiac arrhythmias known to cause syncope. We present a case of convulsive movements, progressive atrioventricular block, and syncope in a patient known to have epilepsy. The history, serial electrocardiographic tracings, and other diagnostic tests strongly suggest the ictal bradycardia syndrome. The case illustrates interesting aspects of central autonomic function and the diagnostic and therapeutic dilemmas of evaluating and treating patients who present with this problem.

Sudden death prophylaxis in heart failure.

Sudden cardiac death (SCD) is the leading cause of mortality in heart failure (HF). Today the implantable cardioverter-defibrillator (ICD) has become a commonplace therapy around the world for patients with both ischemic and non-ischemic cardiomyopathy and an ejection fraction (EF) < or = 35%. However, EF alone does not discriminate between the modes of death from HF (sudden arrhythmic death vs. non-sudden death). Other risk statifiers, such as electrophysiologic study and microvolt T-wave alternans testing, should therefore be used in the appropriate settings to minimize the number of unnecessary device implants. In addition, left ventricular mechanical dyssynchrony has now become recognized as an additional major marker of cardiac mortality. Its assessment should entail echocardiography rather than measurement of the QRS duration. This will allow us to better integrate the ability of cardiac resynchronization therapy (CRT) in enhancing cardiac function with the ability of an ICD in preventing SCD. This review aims to: 1) give a synthesis of the published evidence regarding the value of implantable ICDs and CRT in the primary prophylaxis of SCD in HF; 2) discuss controversial clinical issues in this area; and 3) recommend practical device-based management strategies.

Role of transesophageal echocardiography guided cardioversion in patients with atrial fibrillation, previous left atrial thrombus and effective anticoagulation.

AIMS: The value of transesophageal echocardiography (TEE) to prevent cardioversion-related thromboembolic events in patients with atrial fibrillation (AF) and left atrial (LA) thrombus is unclear. We compared the embolic risk associated with a strategy of follow-up TEE-guided direct-current cardioversion (DCCV) with that of blind DCCV in patients with AF, pre-existing LA thrombus and effective anticoagulation. METHODS AND RESULTS: We identified 67 subjects with TEE-documented LA appendage thrombi from a total of 520 consecutive patients with symptomatic non-rheumatic AF who were referred to us for elective DCCV. All patients received at least 4 weeks of effective warfarin therapy (target international normalized ratio, 2 to 3) before and after DCCV. At time of DCCV, 20 patients had TEE and 47 did not. There were no clinical and echocardiographic differences between the two groups. Thrombus resolution was documented in 18 (90%) patients. After a median follow-up of 4 weeks, two transient ischemic attacks were observed in patients who were blindly cardioverted and one in patients belonging to the TEE group. Sinus rhythm was documented at the time of each thromboembolic event. By multiple logistic regression analysis the TEE strategy was not associated with lower risk of thromboembolism as compared to blind DCCV (odds ratio 1.37; 95% confidence interval, 0.16% to 15.86%; p=0.20). CONCLUSION: In patients with AF, LA thrombus and effective anticoagulation, there is no difference in the risk of clinical thromboembolism between DCCV with or without follow-up TEE. Benefits of warfarin are related to thrombus resolution and prevention of new thrombus formation.

Medical qualification of a commercial spaceflight participant: not your average astronaut.

BACKGROUND: Candidates for commercial spaceflight may be older than the typical astronaut and more likely to have medical problems that place them at risk during flight. Since the effects of microgravity on many medical conditions are unknown, physicians have little guidance when evaluating and certifying commercial spaceflight participants. This dynamic new era in space exploration may provide important data for evaluating medical conditions, creating appropriate medical standards, and optimizing treatment alternatives for long-duration spaceflight. CASE: A 57-yr-old spaceflight participant for an ISS mission presented with medical conditions that included moderately severe bullous emphysema, previous spontaneous pneumothorax with talc pleurodesis, a lung parenchymal mass, and ventricular and atrial ectopy. The medical evaluation required for certification was extensive and included medical studies and monitoring conducted in analogue spaceflight environments including altitude chambers, high altitude mixed-gas simulation, zero-G aircraft, and high-G centrifuge. To prevent recurrence of pneumothorax, we performed video-assisted thoracoscopic pleurodesis, and to assess lung masses, several percutaneous or direct biopsies. The candidate's 10-d mission was without incident. CONCLUSION: Non-career astronauts applying for commercial suborbital and orbital spaceflight will, at least in the near future, challenge aerospace physicians with unknowns regarding safety during training and flight, and highlight important ethical and risk-assessment problems. The information obtained from this new group of space travelers will provide important data for the evaluation and in-flight treatment of medical problems that space programs have not yet addressed systematically, and may improve the medical preparedness of exploration-class missions.