Seasonal Variation in Occurrence of Pulmonary Embolism: Analysis of the Database of the Emilia‐Romagna Region,Italy

Seasonal variation in the occurrence of cardiovascular and cerebrovascular events, including pulmonary embolism (PE), has been reported; however, recent large‐scale, population‐based studies conducted in the United States did not confirm such seasonality. The aim of this large‐scale population study was to determine whether a temporal pattern in the occurrence of PE exists. The analysis considered all consecutive cases of PE in the database of all hospital admissions of the Emilia Romagna region in Italy at the Center for Health Statistics between January 1998 and December 2005. PE cases were first grouped according to season of occurrence, and the data were analyzed by the χ² test for goodness of fit. Then, inferential chronobiologic (cosinor and partial Fourier) analysis was applied to monthly data, and the best‐fitting curve for the annual variation was derived. The total sample consisted of 19,245 patients (8,143 male, mean age 71.6±14.1 yrs; 11,102 female, mean age 76.1±13.7 yrs). Of these, 2,484 were <65 yrs, 5,443 were between 65 and 74, and 11,318 were ≥75 yrs. There were 4,486 (23.3%) fatal‐case outcomes. PE occurred least frequently in spring (n=4,442 or 23.1%) and most frequent in winter (n=5,236 or 27.2%, goodness of fit χ²=75.75, p<0.001). Similar results were obtained for subgroups formed by gender, age, fatal/non‐fatal outcome, presence/absence of major underlying co‐morbid conditions, and specific risk factors. Inferential chronobiological analysis identified a significant annual pattern in PE, with the peak between November and December for the total sample of cases (p<0.001), males (p<0.001), females (p=0.002), fatal and non‐fatal cases (p<0.001 for both), and subgroups formed by age (<65 yrs, p=0.012; 65–74 yrs, p<0.001; ≥75 yrs, p=0.012). This pattern was independent of the presence/absence of hypertension (p=0.003 and p<0.001, respectively), pulmonary disease (p<0.001 and p<0.001, respectively), stroke (p<0.001 and p=0.004, respectively), neoplasms (p=0.005 and p=0.001, respectively), heart failure (p=0.022 and p<0.001, respectively), and deep vein thrombosis (p=0.002 and p<0.001, respectively). However, only a non‐statistically significant trend was found for subgroups formed by cases of diabetes mellitus, infections, renal failure, and trauma.     

Pulmonary arterial hypertension: a disease of tethers, SNAREs and SNAPs?

Histological and electron microscopic studies over the past four decades have highlighted "plump," "enlarged" endothelial, smooth muscle, and fibroblastic cellular elements with increased endoplasmic reticulum, Golgi stacks, and vacuolation in pulmonary arterial lesions in human and in experimental (hypoxia and monocrotaline) pulmonary arterial hypertension. However, the contribution of disrupted intracellular membrane trafficking in the pathobiology of this disease has received insufficient attention. Recent studies suggest a pathogenetic role of the disruption of intracellular trafficking of vasorelevant proteins and cell-surface receptors in the development of this disease. The purpose of this essay is to highlight the molecular regulation of vesicular trafficking by membrane tethers, SNAREs and SNAPs, and to suggest how their dysfunction, directly and/or indirectly, might contribute to development of pulmonary arterial hypertension in experimental models and in humans, including that due to mutations in bone morphogenetic receptor type 2.     

Comparison of Isoflurane and α-Chloralose in an Anesthetized Swine Model of Acute Pulmonary Embolism Producing Right Ventricular Dysfunction

Pulmonary embolism (PE) is a leading cause of sudden cardiac death, and a model is needed for testing potential treatments. In developing a model, we compared the hemodynamic effects of isoflurane and α-chloralose in an acute swine model of PE because the choice of anesthesia will likely affect the cardiovascular responses of an animal to PE. At baseline, swine that received α-chloralose (n = 6) had a lower heart rate and cardiac output and higher SpO_2, end-tidal CO_2, and mean arterial pressure than did those given isoflurane (n = 9). After PE induction, swine given α-chloralose compared with isoflurane exhibited a lower heart rate (63 ± 10 compared with 116 ± 15 bpm) and peripheral arterial pressure (52 ± 12 compared with 61 ± 12 mm Hg); higher SpO₂ (98% ± 3% compared with 95% ± 1%), end-tidal CO₂ (35 ± 4 compared with 32 ± 5), and systolic blood pressure (121 ± 8 compared with 104 ± 20 mm Hg); and equivalent right ventricular:left ventricular ratios (1.32 ± 0.50 compared with 1.23 ± 0.19) and troponin I mean values (0.09 ± 0.07 ng/mL compared with 0.09 ± 0.06 ng/mL). Isoflurane was associated with widely variable fibrinogen and activated partial thromboplastin time. Intraexperiment mortality was 0 of 6 animals for α-chloralose and 2 of 9 swine for isoflurane. All swine anesthetized with α-chloralose survived with sustained pulmonary hypertension, RV-dilation-associated cardiac injury without the confounding vasodilatory or coagulatory effects of isoflurane. These data demonstrate the physiologic advantages of α-chloralose over isoflurane for anesthesia in a swine model of severe submassive PE.Abbreviations: LV, left ventricle; PAP, pulmonary arterial pressure; PE, pulmonary embolism; RV, right ventriclePulmonary embolism (PE) is one of the leading causes of noncardiac sudden death in Western nations and is the third most common cause of cardiovascular morbidity.^4,6,7,18 In survivors, severe PE damages the right heart, leading to a clinical course complicated by hypotension and circulatory shock, suggesting acute right heart failure in about 10% of patients and followed by persistent pulmonary hypertension or right ventricular dysfunction and dyspnea in at least 15% of patients.^{9,15,16,23,29} To test treatments to reduce right heart failure, a standardized model that is repeatable, accurate, and precise and that mimics the gross pathologic, cardiovascular, pulmonary, autonomic, hematologic, biochemical, and cellular characteristics of PE in humans with disease is needed.⁸Three lines of rationale favor domestic pigs as a model for PE. Several publications, using different methods of anesthesia, have found that swine manifest hemodynamic responses similar to those of humans in the presence of autologous PE, including elevated heart rate, decreased cardiac output, and reduced oxygen saturation.^2,12,30 Swine have similar platelet concentrations, and their coagulation profile on thromboelastography has been shown to be similar to humans, with the exception of higher fibrin crosslinking but less fibrin, leading to resistance to plasmin.^5,11,19,34 Market swine, which would otherwise be destined for slaughter, are relatively cost effective compared with other large animals and are of sufficient size for placement of an adult pulmonary arterial catheter for measurement of pulmonary vascular resistance in a closed-chest preparation.In view of the differences in the hemodynamic effects of different anesthetic agents, the choice of anesthesia will likely affect the cardiovascular responses of an animal to PE. However, current literature lacks a methodologic publication that compares the cardiovascular, right ventricular, pulmonary, and hematologic responses to PE in closed-chest swine models incorporating different anesthetic regimens.Figure 1 presents features of an ideal animal model for the purpose of testing treatments for PE. To develop a swine model of PE that closely resembles this physiologic ideal model, we induced PE in swine maintained in a surgical plane of anesthesia with either isoflurane or α-chloralose. Each of these agents has potential advantages and disadvantages. Isoflurane can be titrated minute by minute but causes undesirable vasodilation, whereas α-chloralose is believed to preserve cardiovascular reflexes but requires heating to dissolve and continuous infusion or repeated boluses.^26,35 We hypothesized that, compared with isoflurane, α-chloralose would meet more of the features described in Figure 1.Open in a separate windowFigure 1.Desirable features of large animal model of severe submassive PE designed for translational research.     

The Role of Zinc in Thrombosis and Pulmonary Embolism in the Course of Antiphospholipid Syndrome (APS)—Short Review

Antiphospholipid antibodies may occur in the course of various diseases, but its presence is not necessarily associated with clinical symptoms. Zinc has multiple biological roles. For example, it stabilizes the cell’s membrane and regulates its functions by influencing the synthesis of phospholipids and its distribution. The present review focuses on the possible associations between zinc and antiphospholipid antibodies and with the symptoms of antiphospholipid syndrome.     

Pulmonary and renal pressure-flow relationships: what should be taught?

This article is from a symposium presented at the annual meeting of the Human Anatomy and Physiology Society (HAPS) on June 11, 2000. The presentation was funded under the auspices of a National Science Foundation Course, Curriculum, and Laboratory Improvement Program entitled "Development of Active Learning Materials for Physiology and Functional Anatomy: A Cooperative HAPS-APS Initiative." This symposium was part of the first module to be developed on "gradients and conductances: what flows where and why?" This presentation was designed to model the usefulness of the general model of gradients and conductances in the physiology and pathophysiology of the respiratory and renal systems. Thirteen different examples of pressure-flow-resistance and concentration-flux relationships are introduced; several ideas for active-learning activities and simple figures appropriate for undergraduate physiology classes are included. The symposium assumes that undergraduate students have already learned about diffusion, osmosis, and the basic principles of cardiovascular physiology. The presentation was designed to follow a symposium entitled: "Cardiovascular pressure-flow relationships: what should be taught?"     

Pulmonary vein isolation: do all roads lead to Rome?

Pulmonary vein isolation (PVI) for the treatment of atrial fibrillation (AF) appears to be here to stay. In just a few years since the landmark publications by Haissaguerre and Pappone, countless variations on the theme of ostial or antral PVI, with or without additional lines or point lesions, have been published. The procedure has found its way into daily practice and international guidelines, and is currently the most performed ablation in the Netherlands.     

Elevated Plasma CXCL12α Is Associated with a Poorer Prognosis in Pulmonary Arterial Hypertension

Rationale

Recent work in preclinical models suggests that signalling via the pro-angiogenic and pro-inflammatory cytokine, CXCL12 (SDF-1), plays an important pathogenic role in pulmonary hypertension (PH). The objective of this study was to establish whether circulating concentrations of CXCL12α were elevated in patients with PAH and related to mortality.

Methods

Plasma samples were collected from patients with idiopathic pulmonary arterial hypertension (IPAH) and PAH associated with connective tissue diseases (CTD-PAH) attending two pulmonary hypertension referral centres (n = 95) and from age and gender matched healthy controls (n = 44). Patients were subsequently monitored throughout a period of five years.

Results

CXCL12α concentrations were elevated in PAH groups compared to controls (P<0.05) and receiver-operating-characteristic analysis showed that plasma CXCL12α concentrations discriminated patients from healthy controls (AUC 0.80, 95% confidence interval 0.73-0.88). Kaplan Meier analysis indicated that elevated plasma CXCL12α concentration was associated with reduced survival (P<0.01). Multivariate Cox proportional hazards model showed that elevated CXCL12α independently predicted (P<0.05) earlier death in PAH with a hazard ratio (95% confidence interval) of 2.25 (1.01-5.00). In the largest subset by WHO functional class (Class 3, 65% of patients) elevated CXCL12α independently predicted (P<0.05) earlier death, hazard ratio 2.27 (1.05-4.89).

Conclusions

Our data show that elevated concentrations of circulating CXCL12α in PAH predicted poorer survival. Furthermore, elevated circulating CXCL12α was an independent risk factor for death that could potentially be included in a prognostic model and guide therapy.     

Pulmonary intravascular macrophages and lung health: what are we missing?

Pulmonary intravascular macrophages (PIMs) are constitutively found in species such as cattle, horse, pig, sheep, goat, cats, and whales and can be induced in species such as rats, which normally lack them. It is believed that human lung lacks PIMs, but there are previous suggestions of their induction in patients suffering from liver dysfunction. Recent data show induction of PIMs in bile-duct ligated rats and humans suffering from hepato-pulmonary syndrome. Because constitutive and induced PIMs are pro-inflammatory in response to endotoxins and bacteria, there is a need to study their biology in inflammatory lung diseases such as sepsis, asthma, chronic obstructive pulmonary diseases, or hepato-pulmonary syndrome. We provide a review of PIM biology to make an argument for increased emphasis and better focus on the study of human PIMs to better understand their potential role in the pathophysiology and mechanisms of pulmonary diseases.     

Pulmonary hypertension in infants with congenital heart defects: are leukotrienes involved?

The circulating levels of leukotriene E4 in infants with congenital heart defects, increased pulmonary blood flow and pulmonary arterial hypertension, were determined and compared with infants with decreased pulmonary blood flow (Tetralogy of Fallot). There was no correlation (r=0.38) between the pulmonary arterial pressure (56+/-4 mmHg) and the leukotriene E4 levels (1.37+/-0.67 ng/ml blood) measured in peripheral blood samples from the hypertensive group prior to surgery. There was considerable variation in the detectable leukotriene E4 levels in blood samples from different patients. The levels detected in the blood samples between the two groups of patients was similar. These data suggest that neither the surgical repair during cardiopulmonary bypass nor the pulmonary hypertension appeared to modify the leukotriene E4 blood levels in the small number of patients studied.     

PPAR-γ Regulates Carnitine Homeostasis and Mitochondrial Function in a Lamb Model of Increased Pulmonary Blood Flow

Objective

Carnitine homeostasis is disrupted in lambs with endothelial dysfunction secondary to increased pulmonary blood flow (Shunt). Our recent studies have also indicated that the disruption in carnitine homeostasis correlates with a decrease in PPAR-γ expression in Shunt lambs. Thus, this study was carried out to determine if there is a causal link between loss of PPAR-γ signaling and carnitine dysfunction, and whether the PPAR-γ agonist, rosiglitazone preserves carnitine homeostasis in Shunt lambs.

Methods and Results

siRNA-mediated PPAR-γ knockdown significantly reduced carnitine palmitoyltransferases 1 and 2 (CPT1 and 2) and carnitine acetyltransferase (CrAT) protein levels. This decrease in carnitine regulatory proteins resulted in a disruption in carnitine homeostasis and induced mitochondrial dysfunction, as determined by a reduction in cellular ATP levels. In turn, the decrease in cellular ATP attenuated NO signaling through a reduction in eNOS/Hsp90 interactions and enhanced eNOS uncoupling. In vivo, rosiglitazone treatment preserved carnitine homeostasis and attenuated the development of mitochondrial dysfunction in Shunt lambs maintaining ATP levels. This in turn preserved eNOS/Hsp90 interactions and NO signaling.

Conclusion

Our study indicates that PPAR-γ signaling plays an important role in maintaining mitochondrial function through the regulation of carnitine homeostasis both in vitro and in vivo. Further, it identifies a new mechanism by which PPAR-γ regulates NO signaling through Hsp90. Thus, PPAR-γ agonists may have therapeutic potential in preventing the endothelial dysfunction in children with increased pulmonary blood flow.     

Pulmonary Nodule Detection in Patients with a Primary Malignancy Using Hybrid PET/MRI: Is There Value in Adding Contrast-Enhanced MR Imaging?

Purpose

To investigate the added value of post-contrast VIBE (volumetric-interpolated breath-hold examination) to PET/MR imaging for pulmonary nodule detection in patients with primary malignancies.

Materials and Methods

This retrospective institutional review board–approved study, with waiver of informed consent, included 51 consecutive patients who underwent ¹⁸F-fluorodeoxyglucose (FDG) PET/MR followed by PET/CT for cancer staging. In all patients, the thorax was examined with pre-and post-contrast VIBE MR with simultaneous PET acquisition. Two readers blinded to the patients’ data independently recorded their level of suspicion for pulmonary nodules based on PET, pre-contrast VIBE, and fused PET/MR images (first session), and reassessed them 4-weeks later after addition of post-contrast VIBE (second session). Jackknife alternative free-response receiver-operating-characteristic (JAFROC) analysis was performed, with PET/CT as the reference standard.

Results

A total of 151 pulmonary nodules (44 FDG-avid, 107 non-FDG-avid nodules) were detected on PET/CT, including 62 nodules≥5mm in diameter and 89 nodules<5mm. In the first session, the average nodule detection rate was 53.3% for all nodules, 97.7% for FDG-avid, 35.0% for non-FDG-avid nodules, 87.9% for nodules≥5mm and 29.2% for nodules<5mm. In the second session, the average detection rate was 53.3% for all nodules, 97.7% for FDG-avid, 35.0% for non-FDG-avid nodules, 85.5% for nodules≥5mm and 30.9% for nodules<5mm. The average JAFROC figure-of-merit was 0.837 in the first session and 0.848 in the second session. There were no significant differences in detection performance between sessions (P=0.48).

Conclusion

The addition of post-contrast VIBE to hybrid PET/MR imaging provided no additional value in the detection of pulmonary nodules.