Pulmonary arterial hypertension is a deadly disease characterized by elevated pulmonary arterial pressures leading to right ventricular hypertrophy and failure. The confirmatory gold standard test is the invasive right heart catheterization. The disease course is monitored by pulmonary artery systolic pressure measurement via transthoracic echocardiography. A simple non-invasive test to frequently monitor the patients is much needed. Search for a novel biomarker that can be detected by a simple test is ongoing and many different options are being studied. Here we review some of the new and unique pre-clinical options for potential pulmonary hypertension biomarkers. These biomarkers can be broadly categorized based on their association with endothelial cell dysfunction, inflammation, epigenetics, cardiac function, oxidative stress, metabolism,extracellular matrix, and volatile compounds in exhaled breath condensate. A biomarker that can be detected in blood, urine or breath condensate and correlates with disease severity, progression and response to therapy may result in significant cost reduction and improved patient outcomes.

OBJECTIVE: The aim of this study was to determine the pertinent anesthetic considerations for patients undergoing surgical sympathectomy for electrical storm (incessant ventricular tachycardia (VT) refractory to traditional therapies). DESIGN: This is a retrospective review of a prospective database. SETTING: This single-center study took place in a university hospital setting. PARTICIPANTS: Twenty-six patients were enrolled. INTERVENTIONS: Fifteen patients underwent left-sided sympathectomy, whereas 11 patients underwent bilateral sympathectomy. MEASUREMENTS AND MAIN RESULTS: Anesthetic management of these patients was quite complex, requiring invasive monitoring, transesophageal echocardiography, one-lung ventilation, programming of cardiac rhythm management devices, and titration of vasoactive medications. Paired t test of hemodynamic data before, during, and after surgery showed no significant difference between preoperative and postoperative blood pressure values, regardless of whether the patient underwent unilateral or bilateral sympathectomy. Eight patients remained free of VT, three patients responded well to titration of oral medications, and one patient required 2 radiofrequency ablations after sympathectomy to control his VT. Three patients continued to have VT episodes, although reduced in frequency compared with before the procedure. Four patients were lost to followup. Overall, five patients within the cohort died within 30 days of the procedure. No patients developed any anesthetic complications or Horners syndrome. The overall perioperative mortality (within the first 7 days of the procedure) was 2 of 26, or 7.7%. CONCLUSIONS: The anesthetic management of patients undergoing surgical sympathectomy for electrical storm can be quite complex, because these patients often present in a moribund and emergent state and cannot be optimized using current ACC/AHA guidelines. Expertise in invasive monitoring, transesophageal echocardiography, one-lung ventilation, cardiac rhythm device management, and pressor management is crucial for optimal anesthetic care.

Modulation of human cardiac mechanical and electrophysiologic function by direct stellate ganglion stimulation has not been performed. Our aim was to assess the effect of low-level left stellate ganglion (LSG) stimulation (SGS) on arrhythmias, hemodynamic, and cardiac electrophysiological indices. Patients undergoing ablation procedures for arrhythmias were recruited for SGS. A stimulating electrode was placed next to the LSG under fluoroscopy and ultrasound imaging; and SGS (5-10 Hz, 10-20 mA) was performed. We measured hemodynamic, intracardiac and ECG parameters, and activation recovery intervals (ARIs) (surrogate for action potential duration) from a duodecapolar catheter in the right ventricular outflow tract. Five patients underwent SGS (3 males, 45 ± 20 years). Stimulating catheter placement was successful, and without complication in all patients. SGS did not change heart rate, but increased mean arterial blood pressure (78 ± 3 mmHg to 98 ± 5 mmHg, P < 0.001) and dP/dt max (1148 ± 244 mmHg/sec to 1645 ± 493 mmHg/sec, P = 0.03). SGS shortened mean ARI from 304 ± 23 msec to 283 ± 17 msec (P < 0.001), although one patient required parasympathetic blockade. Dispersion of repolarization (DOR) increased in four patients and decreased in one, consistent with animal models. QT interval, T-wave duration and amplitude at baseline and with SGS were 415 ± 15 msec versus 399 ± 15 msec (P < 0.001); 201 ± 12 msec versus 230 ± 28 msec; and 0.2 ± 0.09 mV versus 0.22 ± 0.08 mV, respectively. At the level of SGS performed, no increase in arrhythmias was seen. Percutaneous low-level SGS shortens ARI in the RVOT, and increases blood pressure and LV contractility. These observations demonstrate feasibility of percutaneous SGS in humans.

BACKGROUND: Left and bilateral cardiac sympathetic denervation (CSD) have been shown to reduce burden of ventricular arrhythmias acutely in a small number of patients with ventricular tachyarrhythmia (VT) storm. The effects of this procedure beyond the acute setting are unknown. OBJECTIVE: The purpose of this study was to evaluate the intermediate and long-term effects of left and bilateral CSD in patients with cardiomyopathy and refractory VT or VT storm. METHODS: Retrospective analysis of medical records for patients who underwent either left or bilateral CSD for VT storm or refractory VT between April 2009 and December 2012 was performed. RESULTS: Forty-one patients underwent CSD (14 left CSD, 27 bilateral CSD). There was a significant reduction in the burden of implantable cardioverter-defibrillator (ICD) shocks during follow-up compared to the 12 months before the procedure. The number of ICD shocks was reduced from a mean of 19.6 ± 19 preprocedure to 2.3 ± 2.9 postprocedure (P < .001), with 90% of patients experiencing a reduction in ICD shocks. At mean follow-up of 367 ± 251 days postprocedure, survival free of ICD shock was 30% in the left CSD group and 48% in the bilateral CSD group. Shock-free survival was greater in the bilateral group than in the left CSD group (P = .04). CONCLUSION: In patients with VT storm, bilateral CSD is more beneficial than left CSD. The beneficial effects of bilateral CSD extend beyond the acute postsympathectomy period, with continued freedom from ICD shocks in 48% of patients and a significant reduction in ICD shocks in 90% of patients.

Oxidative stress has been implicated in cardiac arrhythmia, although a causal relationship remains undefined. We have recently demonstrated a marked up-regulation of NADPH oxidase isoform 4 (NOX4) in patients with atrial fibrillation, which is accompanied by overproduction of reactive oxygen species (ROS). In this study, we investigated the impact on the cardiac phenotype of NOX4 overexpression in zebrafish. One-cell stage embryos were injected with NOX4 RNA prior to video recording of a GFP-labeled (myl7:GFP zebrafish line) beating heart in real time at 24-31 h post-fertilization. Intriguingly, NOX4 embryos developed cardiac arrhythmia that is characterized by irregular heartbeats. When quantitatively analyzed by an established LQ-1 program, the NOX4 embryos displayed much more variable beat-to-beat intervals (mean S.D. of beat-to-beat intervals was 0.027 s/beat in control embryos versus 0.038 s/beat in NOX4 embryos). Both the phenotype and the increased ROS in NOX4 embryos were attenuated by NOX4 morpholino co-injection, treatments of the embryos with polyethylene glycol-conjugated superoxide dismutase, or NOX4 inhibitors fulvene-5, 6-dimethylamino-fulvene, and proton sponge blue. Injection of NOX4-P437H mutant RNA had no effect on the cardiac phenotype or ROS production. In addition, phosphorylation of calcium/calmodulin-dependent protein kinase II was increased in NOX4 embryos but diminished by polyethylene glycol-conjugated superoxide dismutase, whereas its inhibitor KN93 or AIP abolished the arrhythmic phenotype. Taken together, our data for the first time uncover a novel pathway that underlies the development of cardiac arrhythmia, namely NOX4 activation, subsequent NOX4-specific NADPH-driven ROS production, and redox-sensitive CaMKII activation. These findings may ultimately lead to novel therapeutics targeting cardiac arrhythmia.

For precision medicine to become a reality, we propose three changes. First, healthcare deliverables must be prioritized, enabling translation of knowledge to the clinic. Second, physicians and patients must be convinced to participate, requiring additional infrastructure in health systems. Third, discovery science must evolve to shift the preclinical landscape for innovation. We propose a change in the fundamental relationship between basic and clinical science: rather than two distinct entities between which concepts must be translated, we envision a natural hybrid of these approaches, wherein discovery science and clinical trials coincide in the same health systems and patient populations.

We have previously shown that circulating levels of tetrahydrobiopterin (H₄B) function as a robust biomarker for aortic aneurysms in several independent animal models. In the present study, we examined diagnostic and predictive values of circulating H₄B levels in human patients of thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) for the first time, while clinically applicable biomarkers for aortic aneurysms have never been previously available. Ninety-five patients scheduled for TAA repair surgeries and 53 control subjects were recruited at University of California Los Angeles (UCLA) Ronald Regan Medical Center, while 44 control subjects and 29 AAA patients were recruited through National Institute of Health (NIH) National Disease Research Interchange (NDRI) program. We had intriguing observations that circulating H₄B levels were substantially lower in TAA and AAA patients, linearly correlated with aortic H₄B levels (blood: R = 0.8071, p < 0.0001, n = 75; plasma: R = 0.7983, p < 0.0001, n = 75), and associated with incidence of TAA (blood: adjusted OR 0.495; 95% CI 0.379-0.647; p < 0.001; plasma: adjusted OR 0.501; 95% CI 0.385-0.652; p < 0.001) or AAA (blood: adjusted OR 0.329; 95% CI 0.125-0.868; p = 0.025) after adjustment for other factors. Blood or plasma H₄B levels below 0.2 pmol/μg serve as an important threshold for prediction of aortic aneurysms independent of age and gender (for TAA risk - blood: adjusted OR 419.67; 95% CI 59.191-2975.540; p < 0.001; plasma: adjusted OR 206.11; 95% CI 40.956-1037.279; p < 0.001). This threshold was also significantly associated with incidence of AAA (p < 0.001 by Chi-square analysis). In addition, we observed previously unrecognized inverse association of Statin use with TAA, and an association of AAA with arrhythmia. Taken together, our data strongly demonstrate for the first time that circulating H₄B levels can serve as a first-in-class, sensitive, robust and independent biomarker for clinical diagnosis and prediction of TAA and AAA in human patients, which can be rapidly translated to bedside to fundamentally improve clinical management of the devastating human disease of aortic aneurysms.

Objective

The aim of this study was to determine the pertinent anesthetic considerations for patients undergoing surgical sympathectomy for electrical storm (incessant ventricular tachycardia (VT) refractory to traditional therapies).

Design

This is a retrospective review of a prospective database.

Setting

This single-center study took place in a university hospital setting.

Participants

Twenty-six patients were enrolled.

Interventions

Fifteen patients underwent left-sided sympathectomy, whereas 11 patients underwent bilateral sympathectomy.

Measurements and main results

Anesthetic management of these patients was quite complex, requiring invasive monitoring, transesophageal echocardiography, one-lung ventilation, programming of cardiac rhythm management devices, and titration of vasoactive medications. Paired t test of hemodynamic data before, during, and after surgery showed no significant difference between preoperative and postoperative blood pressure values, regardless of whether the patient underwent unilateral or bilateral sympathectomy. Eight patients remained free of VT, three patients responded well to titration of oral medications, and one patient required 2 radiofrequency ablations after sympathectomy to control his VT. Three patients continued to have VT episodes, although reduced in frequency compared with before the procedure. Four patients were lost to followup. Overall, five patients within the cohort died within 30 days of the procedure. No patients developed any anesthetic complications or Horner's syndrome. The overall perioperative mortality (within the first 7 days of the procedure) was 2 of 26, or 7.7%.

Conclusions

The anesthetic management of patients undergoing surgical sympathectomy for electrical storm can be quite complex, because these patients often present in a moribund and emergent state and cannot be optimized using current ACC/AHA guidelines. Expertise in invasive monitoring, transesophageal echocardiography, one-lung ventilation, cardiac rhythm device management, and pressor management is crucial for optimal anesthetic care.

Background

Left and bilateral cardiac sympathetic denervation (CSD) have been shown to reduce burden of ventricular arrhythmias acutely in a small number of patients with ventricular tachyarrhythmia (VT) storm. The effects of this procedure beyond the acute setting are unknown.

Objective

The purpose of this study was to evaluate the intermediate and long-term effects of left and bilateral CSD in patients with cardiomyopathy and refractory VT or VT storm.

Methods

Retrospective analysis of medical records for patients who underwent either left or bilateral CSD for VT storm or refractory VT between April 2009 and December 2012 was performed.

Results

Forty-one patients underwent CSD (14 left CSD, 27 bilateral CSD). There was a significant reduction in the burden of implantable cardioverter-defibrillator (ICD) shocks during follow-up compared to the 12 months before the procedure. The number of ICD shocks was reduced from a mean of 19.6 ± 19 preprocedure to 2.3 ± 2.9 postprocedure (P < .001), with 90% of patients experiencing a reduction in ICD shocks. At mean follow-up of 367 ± 251 days postprocedure, survival free of ICD shock was 30% in the left CSD group and 48% in the bilateral CSD group. Shock-free survival was greater in the bilateral group than in the left CSD group (P = .04).

Conclusion

In patients with VT storm, bilateral CSD is more beneficial than left CSD. The beneficial effects of bilateral CSD extend beyond the acute postsympathectomy period, with continued freedom from ICD shocks in 48% of patients and a significant reduction in ICD shocks in 90% of patients.