Kim H. Chan

Immediate balloon deflation for prevention of persistent phrenic nerve palsy during pulmonary vein isolation by balloon cryoablation

BACKGROUND Persistent phrenic nerve palsy is the most frequent complication of cryoballoon ablation for atrial fibrillation and can be disabling. OBJECTIVES To describe a technique-immediate balloon deflation (IBD)-for the prevention of persistent phrenic nerve palsy, provide data for its use, and describe in vitro simulations performed to investigate the effect of IBD on the atrium and pulmonary vein. METHODS Cryoballoon procedures for atrial fibrillation were analyzed retrospectively (n = 130). IBD was performed in patients developing phrenic nerve dysfunction (n = 22). In vitro simulations were performed by using phantoms. RESULTS No adverse events occurred, and all patients recovered normal phrenic nerve function before leaving the procedure room. No patient developed persistent phrenic nerve palsy. The mean cryoablation time to onset of phrenic nerve dysfunction was 144 ± 64 seconds. Transient phrenic nerve dysfunction was seen more frequently with the 23-mm balloon than with the 28-mm balloon (11 of 39 cases vs 11 of 81 cases; P = .036). Balloon rewarming was faster following IBD. The time to return to 0 and 20° C was shorter in the IBD group (6.7 vs 8.9 seconds; P = .007 and 16.7 vs 37.6 seconds; P<.0001). In vitro simulations confirmed that IBD caused more rapid tissue warming (time to 0°C, 14.0 ± 3.4 seconds vs 46.0 ± 8.1; P = .0001) and is unlikely to damage the atrium or pulmonary vein. CONCLUSIONS IBD results in more rapid tissue rewarming, causes no adverse events, and appears to prevent persistent phrenic nerve palsy. Simulations suggest that IBD is unlikely to damage the atrium or pulmonary vein.

Haem oxygenase-1 and cardiovascular disease: mechanisms and therapeutic potential.

Cardiovascular disease remains the leading cause of death worldwide. Despite progress in management, there remain a significant number of patients who are not eligible for current treatment options. Traditionally, HO-1 (haem oxygenase-1), one of two isoenzymes that initiate haem catabolism, was thought to only play a metabolic role. However, HO-1 is now recognized to have additional protective activities in states of heightened noxious stimuli or stress such as acute coronary syndromes. The present review article provides an overview of the mode of action of HO-1 in vascular protection, with particular emphasis on its atheroprotective, anti-inflammatory and antioxidative properties, as well as its role in vascular repair. Furthermore, we present evidence for the protective effects of HO-1 in CVD (cardiovascular disease) in both animal and human studies. Given its potential in vascular protection and repair, strategies aimed at inducing HO-1 emerge as a novel and alternative therapeutic target in the management of CVD.

The effect of inhaling a dry powder of sodium chloride on the airways of asthmatic subjects

Wet aerosols of 4.5% sodium chloride (NaCl) are often used to assess the bronchial responsiveness associated with asthma. We questioned whether dry NaCl could be used as an alternative. Dry powder NaCl was inhaled from capsules containing either 5, 10, 20 or 40 mg to a cumulative dose of 635 mg. The powder was delivered via an Inhalator or Halermatic. The airway sensitivity to the dry and wet NaCl was compared in 24 patients with asthma aged 19-39 yrs. All subjects responded to both preparations and the geometric mean (95% confidence intervals) for the provocative dose of NaCl causing forced expiratory volume in one second (FEV1) to fall 20% from baseline (PD[20,NaCl]) for dry NaCl was 103 mg (68-157) versus 172 mg (102-292), p<0.03 for the wet NaCl. The response to dry NaCl was reproducible and on repeat challenge the PD20 was 108 mg (75-153). The mean maximum fall in FEV1 was approximately 25% on each of the two test days. Spontaneous recovery occurred within 60 min after challenge with dry NaCl and within 5 min after bronchodilator. There were no serious side-effects requiring medical attention, however some patients coughed on inhalation of the 40 mg dose and three gagged. Arterial oxygen saturation remained within normal limits. We conclude that a suitably prepared dry powder of sodium chloride could potentially replace wet sodium chloride to assess bronchial responsiveness in patients with asthma, but further studies are required to establish the long-term stability of the dry powder preparation.

Obstructive sleep apnea: novel trigger and potential therapeutic target for cardiac arrhythmias

Obstructive sleep apnea (OSA), the most common form of sleep-disordered breathing, is prevalent and frequently underdiagnosed in our community. Although presenting with predominantly respiratory symptoms, the most serious complications from OSA are cardiovascular, including arrhythmias, disease of the sinus node and conducting system, and sudden cardiac death. The acute and chronic effects of OSA on the cardiovascular system, which include major effects on autonomic function during sleep and wakefulness, are potent contributors to the development and persistence of cardiac arrhythmias. Although large randomized studies are currently lacking, treatment of OSA may be an important primary or additional therapy to supplement the use of drugs or devices in the treatment of cardiac arrhythmias.

Balloon warming time is the strongest predictor of late pulmonary vein electrical reconnection following cryoballoon ablation for atrial fibrillation

BACKGROUND Pulmonary vein isolation by cryoballoon ablation is an accepted method of treating atrial fibrillation. Little data exist regarding factors affecting late electrical reconnection of pulmonary veins following cryoballoon ablation. OBJECTIVE To investigate factors determining pulmonary vein reconnection in patients undergoing repeat catheter ablation for recurrent atrial fibrillation following cryoballoon ablation. METHODS Fifty-one consecutive patients undergoing repeat catheter ablation for recurrent atrial fibrillation following initial cryoballoon ablation underwent retrospective assessment of initial cryoablation characteristics, including balloon and vein sizes, venogram occlusion score, balloon freezing time from 0 to -30 °C, nadir temperature, and balloon warming time from -30 to +15 °C, recorded during the initial cryoballoon procedure. RESULTS Of 199 veins assessed, 91 had reconnected (1.8 per patient). Balloon warming time (odds ratio [OR] 3.21; 95% confidence interval [CI] 2.00-5.13; P < .0001), nadir temperature (OR 1.94; 95% CI 1.42-2.66; P < .0001), vein occlusion score (OR 1.74; 95% CI 1.29-2.34; P = .0003), and balloon freezing time (OR 1.58; 95% CI 1.03-2.42; P = .037) predicted pulmonary vein reconnection. On multivariate analysis, balloon warming time (OR 3.71; 95% CI 2.2-6.24; P ≤ .0001), pulmonary vein size (OR 1.63; 95% CI 1.08-2.43; P = .020), and vein occlusion score (OR 1.48; 95% CI 1.06-2.08; P = .021) remained statistically significant independent predictors of pulmonary vein reconnection. The receiver operating characteristic for the multivariate model yielded an area under the curve of 0.82. CONCLUSIONS Balloon warming time, vein occlusion score, and pulmonary vein size predict pulmonary vein reconnection. Balloon warming time was the most important predictive factor, and the manipulation of balloon warming may be a novel therapeutic strategy for improving outcomes of cryoballoon ablation for atrial fibrillation.

The relationship between coronary stenosis severity and compression type coronary artery movement in acute myocardial infarction.

BACKGROUND Acute myocardial infarction is thought to occur at sites of minor coronary stenosis. Recent data challenge this and also propose a role for coronary artery movement (CAM) in plaque instability. We examined the relationship between coronary stenosis severity, CAM pattern, and infarct-related lesions (IRLs) in acute myocardial infarction. METHODS We investigated 203 consecutive patients with ST-segment elevation myocardial infarction after successful fibrinolysis. Quantitative coronary angiography, CAM pattern, and extent score (atheroma burden) analysis was performed for each coronary artery segment. RESULTS The IRL stenosis was at least moderate (>50%) and severe (>70%) in 78% and 31% of patients, respectively. Culprit arteries were associated with higher atheroma extent scores (25.2 vs 21.6, P < .001). Analysis of 2,228 coronary segments showed that stenosis severity and IRLs were highly correlated, such that the likelihood of being a culprit segment progressively increased with worsening stenosis (odds ratio [OR] 30.0, 95% confidence interval [CI] 19.0-47.6, P < .001, for >70% vs <30% stenosis). Compression CAM was also strongly associated with culprit segments (OR 3.4, 95% CI 2.6-4.5, P < .001). In addition, compression CAM and stenosis severity were strongly correlated, with the likelihood of a coronary segment having compression CAM progressively increasing with worsening stenosis (OR 56.4, 95% CI 37.9-83.8, P < .001, for >70% vs <30% stenosis). CONCLUSIONS In patients with ST-segment elevation myocardial infarction, there is a strong relationship between stenosis severity and IRLs. Our study also raises the hypothesis that compression CAM may accelerate atherosclerosis and predispose to plaque vulnerability.

Hypoxia and inflammation.

To the Editor: In their review article on hypoxia and inflammation, Eltzschig and Carmeliet (Feb. 17 issue)1 were thorough in promoting the role of hypoxia-inducible transcription factor (HIF) and related mechanisms to regain homeostasis in hypoxic tissue environments. Although very exacting in its discussion, the review unfortunately failed to include other, equally important mechanisms that lead to inflammation from hypoxic–ischemic reperfusion injury. I am referring in part to the importance of the inflammasome, and in particular to the NLRP3 inflammasome that responds to danger-associated molecular patterns (e.g., urates, free ATP) resulting from nucleoprotein catabolism induced by such injury. Such stimulation leads to secretion of proinflammatory cytokines, in particular interleukin-1β,2 resulting in neutrophilic inflammation. The NLRP3 inflammasome mechanism was first discovered in autosomal autoinflammatory syndromes, namely cryopyrin-associated periodic syndromes, and these disorders have responded beautifully to interleukin-1–targeted therapies. Now there is current interest among several pharmaceutical companies to test similar therapies in inflammatory disorders caused by hypoxic–ischemic reperfusion injury.2-4To the Editor: In their review article on hypoxia and inflammation, Eltzschig and Carmeliet (Feb. 17 issue)1 were thorough in promoting the role of hypoxia-inducible transcription factor (HIF) and related mechanisms to regain homeostasis in hypoxic tissue environments. Although very exacting in its discussion, the review unfortunately failed to include other, equally important mechanisms that lead to inflammation from hypoxic–ischemic reperfusion injury. I am referring in part to the importance of the inflammasome, and in particular to the NLRP3 inflammasome that responds to danger-associated molecular patterns (e.g., urates, free ATP) resulting from nucleoprotein catabolism induced by such injury. Such stimulation leads to secretion of proinflammatory cytokines, in particular interleukin-1β,2 resulting in neutrophilic inflammation. The NLRP3 inflammasome mechanism was first discovered in autosomal autoinflammatory syndromes, namely cryopyrin-associated periodic syndromes, and these disorders have responded beautifully to interleukin-1–targeted therapies. Now there is current interest among several pharmaceutical companies to test similar therapies in inflammatory disorders caused by hypoxic–ischemic reperfusion injury.2-4

Measurement of pulmonary flow reserve and pulmonary index of microcirculatory resistance for detection of pulmonary microvascular obstruction

Background The pulmonary microcirculation is the chief regulatory site for resistance in the pulmonary circuit. Despite pulmonary microvascular dysfunction being implicated in the pathogenesis of several pulmonary vascular conditions, there are currently no techniques for the specific assessment of pulmonary microvascular integrity in humans. Peak hyperemic flow assessment using thermodilution-derived mean transit-time (Tmn) facilitate accurate coronary microcirculatory evaluation, but remain unvalidated in the lung circulation. Using a high primate model, we aimed to explore the use of Tmn as a surrogate of pulmonary blood flow for the purpose of measuring the novel indices Pulmonary Flow Reserve [PFR = (maximum hyperemic)/(basal flow)] and Pulmonary Index of Microcirculatory Resistance [PIMR = (maximum hyperemic distal pulmonary artery pressure)×(maximum hyperemic Tmn)]. Ultimately, we aimed to investigate the effect of progressive pulmonary microvascular obstruction on PFR and PIMR. Methods and Results Temperature- and pressure-sensor guidewires (TPSG) were placed in segmental pulmonary arteries (SPA) of 13 baboons and intravascular temperature measured. Tmn and hemodynamics were recorded at rest and following intra-SPA administration of the vasodilator agents adenosine (10–400 µg/kg/min) and papaverine (3–24 mg). Temperature did not vary with intra-SPA sensor position (0.010±0.009 v 0.010±0.009°C; distal v proximal; p = 0.1), supporting Tmn use in lung for the purpose of hemodynamic indices derivation. Adenosine (to 200 µg/kg/min) & papaverine (to 24 mg) induced dose-dependent flow augmentations (40±7% & 35±13% Tmn reductions v baseline, respectively; p<0.0001). PFR and PIMR were then calculated before and after progressive administration of ceramic microspheres into the SPA. Cumulative microsphere doses progressively reduced PFR (1.41±0.06, 1.26±0.19, 1.17±0.07 & 1.01±0.03; for 0, 104, 105 & 106 microspheres; p = 0.009) and increased PIMR (5.7±0.6, 6.3±1.0, 6.8±0.6 & 7.6±0.6 mmHg.sec; p = 0.0048). Conclusions Thermodilution-derived mean transit time can be accurately and reproducibly measured in the pulmonary circulation using TPSG. Mean transit time-derived PFR and PIMR can be assessed using a TPSG and adenosine or papaverine as hyperemic agents. These novel indices detect progressive pulmonary microvascular obstruction and thus have with a potential role for pulmonary microcirculatory assessment in humans.

The relationship between endothelial progenitor cell populations and epicardial and microvascular coronary disease-a cellular, angiographic and physiologic study.

Background Endothelial progenitor cells (EPCs) are implicated in protection against vascular disease. However, studies using angiography alone have reported conflicting results when relating EPCs to epicardial coronary artery disease (CAD) severity. Moreover, the relationship between different EPC types and the coronary microcirculation is unknown. We therefore investigated the relationship between EPC populations and coronary epicardial and microvascular disease. Methods Thirty-three patients with a spectrum of isolated left anterior descending artery disease were studied. The coronary epicardial and microcirculation were physiologically interrogated by measurement of fractional flow reserve (FFR), index of microvascular resistance (IMR) and coronary flow reserve (CFR). Two distinct EPC populations (early EPC and late outgrowth endothelial cells [OECs]) were isolated from these patients and studied ex vivo. Results There was a significant inverse relationship between circulating OEC levels and epicardial CAD severity, as assessed by FFR and angiography (r = 0.371, p = 0.04; r = -0.358, p = 0.04; respectively). More severe epicardial CAD was associated with impaired OEC migration and tubulogenesis (r = 0.59, p = 0.005; r = 0.589, p = 0.004; respectively). Patients with significant epicardial CAD (FFR<0.75) had lower OEC levels and function compared to those without hemodynamically significant stenoses (p<0.05). In contrast, no such relationship was seen for early EPC number and function, nor was there a relationship between IMR and EPCs. There was a significant relationship between CFR and OEC function. Conclusions EPC populations differ in regards to their associations with CAD severity. The number and function of OECs, but not early EPCs, correlated significantly with epicardial CAD severity. There was no relationship between EPCs and severity of coronary microvascular disease.

Characterization of Endothelial Progenitor Cell Interactions with Human Tropoelastin

The deployment of endovascular implants such as stents in the treatment of cardiovascular disease damages the vascular endothelium, increasing the risk of thrombosis and promoting neointimal hyperplasia. The rapid restoration of a functional endothelium is known to reduce these complications. Circulating endothelial progenitor cells (EPCs) are increasingly recognized as important contributors to device re-endothelialization. Extracellular matrix proteins prominent in the vessel wall may enhance EPC-directed re-endothelialization. We examined attachment, spreading and proliferation on recombinant human tropoelastin (rhTE) and investigated the mechanism and site of interaction. EPCs attached and spread on rhTE in a dose dependent manner, reaching a maximal level of 56±3% and 54±3%, respectively. EPC proliferation on rhTE was comparable to vitronectin, fibronectin and collagen. EDTA, but not heparan sulfate or lactose, reduced EPC attachment by 81±3%, while full attachment was recovered after add-back of manganese, inferring a classical integrin-mediated interaction. Integrin αVβ3 blocking antibodies decreased EPC adhesion and spreading on rhTE by 39±3% and 56±10% respectively, demonstrating a large contribution from this specific integrin. Attachment of EPCs on N-terminal rhTE constructs N25 and N18 accounted for most of this interaction, accompanied by comparable spreading. In contrast, attachment and spreading on N10 was negligible. αVβ3 blocking antibodies reduced EPC spreading on both N25 and N18 by 45±4% and 42±14%, respectively. In conclusion, rhTE supports EPC binding via an integrin mechanism involving αVβ3. N25 and N18, but not N10 constructs of rhTE contribute to EPC binding. The regulation of EPC activity by rhTE may have implications for modulation of the vascular biocompatibility of endovascular implants.