Left ventricular remodeling in premature ventricular contraction-induced cardiomyopathy: Effect of coupling intervals and atrioventricular dissociation.

Background: Left ventricular dyssynchrony (LVD) and postextrasystolic potentiation (PESP) associated with premature ventricular contractions (PVCs) may play a role in the development of premature ventricular contraction-induced cardiomyopathy (PVC-CM). Long-coupled (LC) PVCs have a greater LVD than short-coupled (SC) PVCs, whereas SC-PVCs have a stronger PESP than LC-PVCs. Objective: The purpose of this study was to compare SC-PVCs and LC-PVCs to evaluate the roles of LVD, PESP, and atrioventricular dissociation (AVD) in the development of PVC-CM. Methods: Thirty-six canines underwent pacemaker implantation to induce bigeminal right ventricular apical epicardial PVCs (50% burden) for 12 weeks. Telemetry assessed PVC burden and AVD. Animals were grouped as SC-PVC (coupling interval [CI] 200-220ms), LC-PVC (CI 330 ms), or sham (control). Echocardiographic changes, AVD, and hemodynamics were monitored for 12 weeks. Results: PVC burden was similar between SC-PVC and LC-PVC groups but was statistically higher in the SC-PVC group (50% vs 47.5%; P = .028). After 12 weeks, left ventricular ejection fraction (LVEF) significantly decreased in both SC-PVC and LC-PVC groups (47.1% ± 1.4% and 45.5% ± 2%, respectively) compared to sham group (61% ± 1.6%; P <.001). Overall AVD was similar between SC-PVC and LC-PVC groups, and there was no significant correlation between AVD and reduction in LVEF at 12 weeks (r = 0.09, P = .5; and r = 0.06, P = .8, respectively). Additionally, both SC-PVC and LC-PVC groups experienced substantial declines in max and min dP/dt after 12 weeks compared to baseline. Conclusion: Neither PVC CI nor AVD played an independent role in the development or severity of PVC-CM. LVD and PESP make equal relative contributions to the development of PVC-CM.

Mechanisms of adaptive hypertrophic cardiac remodeling in a large animal model of premature ventricular contraction-induced cardiomyopathy.

Frequent premature ventricular contractions (PVCs) promoted eccentric cardiac hypertrophy and reduced ejection fraction (EF) in a large animal model of PVC-induced cardiomyopathy (PVC-CM), but the molecular mechanisms and markers of this hypertrophic remodeling remain unexplored. Healthy mongrel canines were implanted with pacemakers to deliver bigeminal PVCs (50% burden with 200-220 ms coupling interval). After 12 weeks, left ventricular (LV) free wall samples were studied from PVC-CM and Sham groups. In addition to reduced LV ejection fraction (LVEF), the PVC-CM group showed larger cardiac myocytes without evident ultrastructural alterations compared to the Sham group. Biochemical markers of pathological hypertrophy, such as store-operated Ca2+ entry, calcineurin/NFAT pathway, ß-myosin heavy chain, and skeletal type α-actin were unaltered in the PVC-CM group. In contrast, pro-hypertrophic and antiapoptotic pathways including ERK1/2 and AKT/mTOR were activated and/or overexpressed in the PVC-CM group, which appeared counterbalanced by an overexpression of protein phosphatase 1 and a borderline elevation of the anti-hypertrophic factor atrial natriuretic peptide. Moreover, the potent angiogenic and pro-hypertrophic factor VEGF-A and its receptor VEGFR2 were significantly elevated in the PVC-CM group. In conclusion, a molecular program is in place to keep this structural remodeling associated with frequent PVCs as an adaptive pathological hypertrophy.

Alterations of sarcoplasmic reticulum-mediated Ca2+ uptake in a model of premature ventricular contraction (PVC)-induced cardiomyopathy.

Premature ventricular contractions (PVCs) are the most frequent ventricular arrhythmias in the overall population. PVCs are known to acutely enhance contractility by the post-extrasystolic potentiation phenomenon, but over time persistent PVCs promote PVC-induced cardiomyopathy (PVC-CM), characterized by a reduction of the left ventricular (LV) ejection fraction. Ca2+ cycling in myocytes commands muscle contraction and in this process, SERCA2 leads the Ca2+ reuptake into the sarcoplasmic reticulum (SR) shaping cytosolic Ca2+ signal decay and muscle relaxation. Altered Ca2+ reuptake can contribute to the contractile dysfunction observed in PVC-CM. To better understand Ca2+ handling using our PVC-CM model (canines with 50% PVC burden for 12 weeks), SR-Ca2+ reuptake was investigated by measuring Ca2+ dynamics and analyzing protein expression. Kinetic analysis of Ca2+ reuptake in electrically paced myocytes showed a ~ 21 ms delay in PVC-CM compared to Sham in intact isolated myocytes, along with a ~ 13% reduction in SERCA2 activity assessed in permeabilized myocytes. Although these trends were not statistically significant between groups using hierarchical statistics, relaxation of myocytes following contraction was significantly slower in PVC-CM vs Sham myocytes. Western blot analyses indicate a 22% reduction in SERCA2 expression, a 23% increase in phospholamban (PLN) expression, and a 50% reduction in PLN phosphorylation in PVC-CM samples vs Sham. Computational analysis simulating a 20% decrease in SR-Ca2+ reuptake resulted in a ~ 22 ms delay in Ca2+ signal decay, consistent with the experimental result described above. In conclusion, SERCA2 and PLB alterations described above have a modest contribution to functional adaptations observed in PVC-CM.

Safety and feasibility of left bundle branch area pacing following valvular interventions: Multicenter study.

OBJECTIVES: To evaluate the safety and feasibility of left bundle branch area pacing (LBBAP) in patients with valvular interventions. METHODS: Eighty-four patients were included in this study. All patients underwent recent surgical or percutaneous valvular interventions. LBBAP was attempted in all patients. Implant success rates, peri- and postprocedure electrocardiogram, pacing parameters, and complications were assessed at implant, and during follow-up. RESULTS: LBBAP implantation was successful in 80/84 (95%) patients. Mean age was 74.1 ± 13.8 years and 56% patients were male. Prior valvular replacements included: percutaneous aortic (26), surgical aortic (36), combined surgical aortic plus mitral (6), MVR (10), tricuspid (1), and pulmonic (1). Average LVEF was 52.6 ± 11%. Majority of patients underwent LBBAP due to atrioventricular block (76%) and sinus node disease (13%). Total procedure duration was 74.1 ± 12.5 min and fluoroscopic duration was 9.7 ± 6.8 min. Pacing parameters were stable during follow-up period of 10.0 ± 6.3 months. Pacing QRS duration was significantly narrower than baseline QRS duration (131.5 ± 31.4 ms vs. 114.3 ± 13.7 ms, p < .001, respectively). No acute complications were observed. Mean follow-up was 10.0 ± 6.3 months (median: 8.4 months, min: 1 and max: 24 months). During follow-up, there were three device infections and two patients had loss of LBBA capture within 1 month of implant. CONCLUSIONS: LBBAP is a feasible and safe pacing modality in patients with prior interventions for valvular heart disease.

Rapid, Fatal Acute Right Ventricular Failure After Locoregional Cytokine Therapy for Uveal Melanoma Liver Metastases.

Locoregional cytokine treatment, or immunoembolization, is an experimental targeted therapy for uveal melanoma metastatic to the liver. Unlike systemic cytokine treatments that have been associated with substantial toxicity, this method of drug delivery appears to be better tolerated. Because this newer therapy is being prescribed more widely, oncologists, interventional radiologists, cardiologists, pulmonologists, critical care specialists, and other providers should become familiar with potential adverse reactions. We describe the case of a 67-year-old man who had metastatic uveal melanoma. Before he underwent liver-directed immunoembolization, he had elevated markers of endothelial dysfunction. He died after the rapid onset of acute right ventricular failure from severe pulmonary hypertension with possible superimposed isolated right ventricular takotsubo cardiomyopathy. In discussing this rare case, we focus on the differential diagnosis.

Lack of relationship between epidermal denervation by capsaicin and incisional pain behaviours: A laser scanning confocal microscopy study in rats.

BACKGROUND: Spontaneous pain after surgical incision is a significant problem for most post-operative patients. Pain management that relies on opioids is hindered by numerous side effects, fuelling interest in non-opioid alternatives and multimodal approaches. Subcutaneous capsaicin infiltration has shown potential for reducing post-operative pain, but there are unanswered questions about safety and possible side effects. In adult rats, we characterized the analgesic effects of pre-operative capsaicin infiltration into the skin prior to plantar incision and assessed wound healing and epidermal innervation. METHODS: The surgical site on the plantar surface of the rat hind paw was infiltrated with 1% capsaicin or vehicle 30 min or 1 week prior to surgical incision. Spontaneous and evoked pain behaviours were assessed. Digital images of incised hind paws were used to quantify the surface area of the wound after suture removal. Epidermal nerve fibre quantification was performed on peri-incisional tissue biopsies. RESULTS: Intraplantar administration of capsaicin 30 min before surgical incision attenuated spontaneous pain behaviours, heat hyperalgesia, epidermal innervation, but it did not alter the rate of wound healing. Incisional pain hypersensitivity returned to baseline 2 weeks post-incision, at a time when no recovery of epidermal innervation is observed. CONCLUSIONS: Subcutaneous infiltration of capsaicin prior to surgical incision attenuated incision-induced pain behaviours and reduced epidermal innervation around the incision site. The long-lasting epidermal denervation by capsaicin had no impact in the rate of wound healing and recovery from pain behaviours. SIGNIFICANCE: Pre-operative capsaicin infiltration attenuated spontaneous pain-like behaviour and prevented the development of heat hyperalgesia following plantar skin incision. While capsaicin caused long-lasting and widespread loss of epidermal and dermal nerve fibres, there was no measurable impact on the rate of wound healing. Pre- or intra-operative infiltration of capsaicin into surgical sites could act as a safe prophylactic for post-operative pain and reduce the need for opioids during recovery.

Use of Cangrelor as a Bridge to Left Ventricular Assist Device Implantation in a Patient with a Recent Drug-Eluting Stent Who Developed Acute Tirofiban-Related Thrombocytopenia.

Current guidelines emphasize the need for at least 6-12 months of oral dual antiplatelet therapy consisting of aspirin and a P2Y12 inhibitor following drug-eluting coronary artery stent implantation. In patients with recently implanted coronary artery stents who require urgent cardiac or noncardiac surgery, the benefits of maintaining oral dual antiplatelet therapy must be carefully weighed against the risks of excessive bleeding, and current practice is largely guided by individual surgeon preferences. When the effects of a second oral antiplatelet agent are undesirable during the perioperative period, the use of a short-acting intravenous antiplatelet agent as "bridge" therapy that can be discontinued shortly before surgery is associated with a reduced occurrence of adverse clinical events in patients with recently implanted coronary stents requiring urgent coronary artery bypass graft surgery. Cangrelor is an intravenous adenosine triphosphate analog P2Y12 receptor antagonist with a short plasma half-life that has been used off label in patients with recent coronary stents as a bridge to invasive procedures with excessive bleeding risk. To our knowledge, this is the first case report to demonstrate the safe and effective use of cangrelor as a bridge to left ventricular assist device implantation in a patient with a recently implanted drug-eluting coronary artery stent who developed acute thrombocytopenia following reexposure to tirofiban, a glycoprotein IIb/IIIa inhibitor.

Spontaneous pain-like behaviors are more sensitive to morphine and buprenorphine than mechanically evoked behaviors in a rat model of acute postoperative pain.

BACKGROUND: Nonevoked spontaneous pain is most problematic for postoperative patients. Physicians assess this form of pain using the human visual analog scale or verbal numeric rating scale. Recent studies have proposed that spontaneous foot-lifting (SFL) behaviors are an expression of spontaneous pain in animals after spinal nerve injury or adjuvant-induced inflammation. In the current study, we characterize SFL behaviors in a rat model of acute postoperative pain, which includes comparisons with evoked behaviors to analgesic treatments. METHODS: SFL was manually recorded over four 5-minute periods with 10-minute intervals between each testing session. Paw-withdrawal thresholds were subsequently measured with an electronic von Frey esthesiometer. To evaluate the effects of age, rats were tested in different age groups: 2, 7, and >26 months. The effects of buprenorphine and morphine were tested in a separate group of animals, which received intraperitoneal injections of saline, morphine (0.01, 0.1, 1, or 2 mg/kg), or buprenorphine (0.001, 0.01, or 0.1 mg/kg) before testing. RESULTS: SFL behaviors peaked at 3 hours after incision and significantly recovered by the 3rd or 4th postoperative day (P < 0.0001). The presentation of these behaviors did not significantly vary with animal age (2, 7, and >26 months old; P = 0.30). SFL behaviors, with the exception of rapid SFL at 3 hours after incision, did not show significant correlation with paw-withdrawal threshold behaviors. The median effective dose of buprenorphine for reversal of mechanical hyperalgesia (0.0452 mg/kg; 95% CI, 0.0259-0.0787) was significantly larger than for reversing rapid (0.0027 mg/kg; 95% CI, 0.0009-0.0083; P < 0.0001) and prolonged (0.0004 mg/kg, 95% CI, 0.0000, 0.0035; P = 0.001) SFL at 3 hours after incision. Similarly, the median effective dose of morphine for reversal of mechanical hypersensitivity behaviors (2.901 mg/kg; 95% CI, 1.132-7.436) was larger than for SFL count (0.4044 mg/kg; 95% CI, 0.1048-1.561; P = 0.0103) and SFL duration (0.0309 mg/kg; 95% CI, 0.0095-0.0998; P < 0.0001) at 3 hours after incision. CONCLUSIONS: The present study demonstrates that a hindpaw plantar incision induces SFL behaviors in rats and that these behaviors have higher bioassay sensitivity to analgesic interventions with morphine and buprenorphine compared with mechanically evoked behaviors.

Effect of focal lamina cribrosa defect on glaucomatous visual field progression.

OBJECTIVE: To evaluate the association between focal, structural defects of the lamina cribrosa (LC) and glaucomatous visual field (VF) progression. DESIGN: Retrospective, observational study. PARTICIPANTS: A total of 169 patients with glaucoma (169 eyes) with a range of glaucomatous damage. METHODS: Serial horizontal and vertical enhanced-depth imaging optical coherence tomography (EDI OCT) B-scans of the optic nerve head were obtained from patients with glaucoma with 5 or more prior Humphrey 24-2 VFs (Carl Zeiss Meditec, Inc, Dublin, CA). The EDI OCT scans were reviewed for the presence of focal LC defects (laminar holes or disinsertions with a diameter >100 µm). The VF progression was defined as having ≥ 2 significantly progressing test points (with a slope calculated using pointwise linear regression [PLR], worse than -1.0 dB/year at P<0.01). Age, intraocular pressure (IOP), baseline VF mean deviation (MD), disc hemorrhage, and central corneal thickness (CCT) were recorded. MAIN OUTCOME MEASURES: The relationship between focal LC defects and the rate and risk of VF progression. RESULTS: Mean age and VF MD at the time of EDI OCT were 69 ± 12 years and -11.49 ± 6.87 dB, respectively. Sixty eyes (36%) progressed according to PLR criteria. Progression was more common in eyes with, rather than without, focal LC defects (38/81 eyes [47%] vs. 22/88 eyes [25%], P = 0.003). Among the evaluated parameters, the presence of focal LC defects, disc hemorrhage, higher mean follow-up IOP, greater number of VFs, and longer follow-up period were significantly associated with VF progression in the multivariable analyses (odds ratios, 2.90, 4.66, 1.22, 1.25, and 1.27, respectively; P = 0.010, P = 0.002, P = 0.002, P<0.001, and P<0.001, respectively). The mean global progression rate was significantly faster in the group with focal LC defect than in the group with no focal LC defect (-0.54 ± 0.99 dB/year vs. -0.28 ± 0.52 dB/year; P = 0.031). Among the 60 progressing eyes, despite no significant difference in the mean number of progressing VF points per eye (6.7 ± 7.0 vs. 6.5 ± 4.4; P = 0.899), the mean localized progression rate was significantly faster in the eyes with focal LC defects than in the eyes with no focal LC defects (-2.85 ± 1.85 dB/year vs. -1.75 ± 0.56 dB/year; P = 0.009). CONCLUSIONS: Focal LC defects are strongly associated with glaucomatous VF progression, and eyes with focal LC defects tend to progress faster than those without.

A modified Hargreaves' method for assessing threshold temperatures for heat nociception.

This study describes a modified Hargreaves' method for assessing paw withdrawal threshold temperatures for heat (PWT-H) nociception in the hind paws of rats. This method utilises radiant heat to maintain controlled lamp temperatures (CLTs) on a glass floor beneath the rat hind paw. An ascending series of CLTs were applied for 10s, with 5-10min intervals between applications, until characteristic withdrawal behaviour was observed or a cutoff CLT was reached. The average plantar epicutaneous temperatures measured from anaesthetised rats corresponding to CLTs and withdrawal latencies were used for determining PWT-H. The mean PWT-H in 2-month-old (mo) naïve Sprague-Dawley rats (n=38) was 47.6±0.2°C, which is comparable to the noxious threshold temperature for human glabrous skin (46.5±0.5°C). The PWT-H was consistent between trials and daily assessments over four consecutive days. No significant differences were observed between the PWT-H in 2-, 6- to 8-, and >24-mo F344 rats, but the PWT-H in 1-mo rats was significantly reduced. Three hours following plantar incision, the PWT-H decreased to 37.5±0.2°C, consistent with previous observations of C-fibre afferents from incised glabrous skin firing at 36.7±3.6°C. Parallel testing, using the current method and an electronic von Frey device, illustrated similar degrees of incision-induced hyperalgesia, gradual improvements in hyperalgesia, and reversals induced through morphine and gabapentin. In conclusion, the present method facilitates a comparison of PWT-H using electrophysiological and human psychophysical studies involving thermosensation, and as a behavioural assay identical to von Frey testing, this method also measures the threshold for nociception.