Metalloproteinase inhibition protects against cardiomyocyte injury during experimental acute pulmonary thromboembolism

Objectives: Up-regulated matrix metalloproteinases may be involved in the development of cardiomyocyte injury and the degradation of troponin associated with acute pulmonary thromboembolism. We examined whether pretreatment with doxycycline (a nonspecific matrix metalloproteinase inhibitor) protects against cardiomyocyte injury associated with acute pulmonary thromboembolism. Design: Controlled animal study. Setting: University research laboratory. Subjects: Mongrel dogs. Interventions: Anesthetized animals received doxycycline (10 mg/kg intravenously) or saline and acute pulmonary thromboembolism was induced with autologous blood clots injected into the right atrium. Control animals received doxycycline (or saline). Measurements and Main Results: Hemodynamic measurements were performed, and acute pulmonary thromboembolism increased baseline mean pulmonary arterial pressure and pulmonary vascular resistance by approximately 160% and 362%, respectively (both p<.05), 120 mins after acute pulmonary thromboembolism. Pretreatment with doxycycline attenuated these increases (to 125% and 232%, respectively; both p<.05). Although acute pulmonary thromboembolism tended to increase the right ventricle maximum rate of isovolumic pressure development and the maximum rate of isovolumic pressure decay, doxycycline produced no effects on these parameters. Gelatin zymograms of right ventricle showed that acute pulmonary thromboembolism marginally increased matrix metalloproteinase-9 (but not matrix metalloproteinase-2) levels in the right ventricle. A fluorometric assay to assess net matrix metalloproteinase activities showed that acute pulmonary thromboembolism increased matrix metalloproteinase activities in the right ventricle by >100% (p<.05), and this finding was confirmed by in situ zymography of the right ventricle. Doxycycline attenuated acute pulmonary thromboembolism-induced increases in right ventricle matrix metalloproteinase activities. Acute pulmonary thromboembolism induced neutrophil accumulation in the right ventricle, as estimated by myeloperoxidase activity, and doxycycline blunted this effect (p<.05). Serum cardiac troponin I concentrations, which reflect cardiomyocyte injury, increased after acute pulmonary thromboembolism, and this increase was attenuated by pretreatment with doxycycline (p<.05). Conclusions: We found evidence supporting the idea that acute pulmonary thromboembolism is associated with increased matrix metalloproteinase activities in the right ventricle, which may lead to degradation of sarcomeric proteins, including cardiac troponin I. Inhibition of matrix metalloproteinases may be an effective therapeutic intervention in the management of acute pulmonary thromboembolism. (Crit Care Med 2011; 39: 349-356)

Circulating cell-free DNA levels in plasma increase with severity in experimental acute pulmonary thromboembolism

Background: The diagnosis of acute pulmonary thromboembolism (APT) and its severity is challenging. No previous study has examined whether there is a linear relation between plasma DNA concentrations and the severity of APT. We examined this hypothesis in anesthetized dogs. We also examined the changes in plasma DNA concentrations in microspheres lung embolization and whether the therapy of APT with nitrite could modify APT-induced changes in plasma DNA concentrations. In vitro DNA release from blood clots was also studied. Methods: APT was induced with autologous blood clots (saline, 1, 3, or 5 ml/kg) injected into the right atrium. A group of dogs received 300 pm microspheres into the inferior vena cava to produce similar pulmonary hypertension. Another group of dogs received 6.75 mu mol/kg nitrite after APT with blood clots of 5 ml/kg. Hemodynamic evaluations were carried out for 120 min. DNA was extracted from plasma samples using QIAamp DNA Blood Mini Kit and quantified using Quant-iT (TM) PicoGreen (R) dsDNA detection kit at baseline and 120 min after APT. Results: APT produced dose-dependent increases in plasma DNA concentrations. which correlated positively with pulmonary vascular resistance (P=0.002, r=0.897) and with mean pulmonary arterial pressure (P=0.006, r=0.856). Conversely, lung embolization with microspheres produced no significant changes in plasma DNA concentrations. While nitrite attenuated APT-induced pulmonary hypertension, it produced no changes in plasma DNA concentrations. Blood clots released dose-dependent amounts of DNA in vitro. Conclusions: Cell-free DNA concentrations increase in proportion to the severity of APT, probably as a result of increasing amounts of thrombi obstructing the pulmonary vessels. (C) 2009 Elsevier B.V. All rights reserved.

Three-Dimensional Contrast-Enhanced Magnetic Resonance Pulmonary Angiography in the Study of Pulmonary Vascular Pathology

OBJECTIVES: To assess the feasibility of performing pulmonary angiography using MRI with contrast enhancement in patients with pulmonary vascular disease. METHODS: We present our experience in ten individuals, two controls and eight patients who underwent the exam after injection of a gadolinium-based contrast agent on a 1 Tesla MR scanner using a time-of-flight sequence and breath-holding during injection of contrast. RESULTS: Pathology in the main pulmonary artery and its major branches was detected easily while resolution at the segmental and subsegmental levels was inadequate. CONCLUSION: Contrast-enhanced magnetic resonance pulmonary angiography is feasible on a 1 Tesla MR scanner for the study of pathology of the main pulmonary artery and its major branches, like massive pulmonary embolism. However its ability to detect and define distal vessel pathology as found in chronic thromboembolic pulmonary hypertension and small pulmonary emboli is limited.

Fatal pulmonary thromboembolism in gastrectomy intraoperative procedures by gastric adenocarcinoma: case report

The case of a patient with gastric adenocarcinoma with indication for gastrectomy is reported. The surgery took place without complications. A palliative, subtotal gastrectomy was performed after para-aortic lymph nodes compromised by neoplasm were found, which was confirmed by pathological exam of frozen sections carried out during the intervention. At the end of the gastroenteroanastomosis procedure, the patient began to show intense bradycardia: 38 beats per minute (bpm), arterial hypotension, changes in the electrocardiogram's waveform (upper unlevelling of segment ST), and cardiac arrest. Resuscitation maneuvers were performed with temporary success. Subsequently, the patient had another circulatory breakdown and again was recovered. Finally, the third cardiac arrest proved to be irreversible, and the intra-operative death occurred. Necropsy showed massive pulmonary embolism. The medical literature has recommended heparinization of patients, in an attempt to avoid pulmonary thromboembolism following major surgical interventions. However, in the present case, heparinization would have been insufficient to prevent death. This case indicates that it is necessary to develop preoperative propedeutics for diagnosing the presence of venous thrombi with potential to migrate, causing pulmonary thromboembolism (PTE). If such thrombi could be detected, preventative measures, such as filter installation in the Cava vein could be undertaken.

Occult lung infarction may induce false interpretation of 18F-FDG PET in primary staging of pulmonary malignancies.

PURPOSE: The aim of the present report is to describe abnormal (18)F-fluorodeoxyglucose (FDG) accumulation patterns in the pleura and lung parenchyma in a group of lung cancer patients in whom lung infarction was present at the time of positron emission tomography (PET). METHODS: Between November 2002 and December 2003, a total of 145 patients (102 males, 43 females; age range 38-85 years) were subjected to whole-body FDG PET for initial staging (n=117) or restaging (n=11) of lung cancer or for evaluation of solitary pulmonary nodules (n=17). Of these patients, 24 displayed abnormal FDG accumulation in the lung parenchyma that was not consistent with the primary lesion under investigation (ipsilateral n=12, contralateral n=9 or bilateral n=3). Without correlative imaging, this additional FDG uptake would have been considered indeterminate in differential diagnosis. RESULTS: Of the 24 patients who were identified as having such lesions, six harboured secondary tumour nodules diagnosed as metastases, while in three the diagnosis of a synchronous second primary lung tumour was established. Additionally, nine patients were identified as having post-stenotic pneumonia and/or atelectasis (n=6) or granulomatous lung disease (n=3). In the remaining six (4% of all patients), a diagnosis of recent pulmonary embolism that topographically matched the additional FDG accumulation (SUV(max) range 1.4-8.6, mean 3.9) was made. Four of these six patients were known to have pulmonary embolism, and hence false positive interpretation was avoided by correlating the PET findings with those of the pre-existing diagnostic work-up. The remaining two patients were harbouring small occult infarctions that mimicked satellite nodules in the lung periphery. Based on histopathological results, the abnormal FDG accumulation in these two patients was attributed to the inflammatory reaction and tissue repair associated with the pathological cascade of pulmonary embolism. CONCLUSION: In patients with pulmonary malignancies, synchronous lung infarction may induce pathological FDG accumulation that can mimic active tumour manifestations. Identifying this potential pitfall may allow avoidance of false positive FDG PET interpretation.

Rapid fatal outcome from pulmonary arteries compression in transitional cell carcinoma.

Transitional cell carcinoma of the urinary bladder is a malignancy that metastasizes frequently to lymph nodes including the mediastinal lymph nodes. This occurrence may produce symptoms due to compression of adjacent structures such as the superior vena cava syndrome or dysphagia from esophageal compression. We report the case of a 59-year-old man with metastatic transitional cell carcinoma for whom mediastinal lymphadenopathy led to pulmonary artery compression and a rapidly fatal outcome. This rare occurrence has to be distinguished from pulmonary embolism, a much more frequent event in cancer patients, in order that proper and prompt treatment be initiated.

Acute pulmonary embolectomy.

Acute pulmonary embolism (PE) is a common condition frequently associated with a high mortality worldwide. It can be classified into non-massive, sub-massive and massive, based on the degree of haemodynamic compromise. Surgical pulmonary embolectomy, despite having been in existence for over 100 years, is generally regarded as an option of last resort, with expectedly high mortality rates. Recent advances in diagnosis and recognition of key qualitative predictors of mortality, such as right ventricular stress on echocardiography, have enabled the re-exploration of surgical pulmonary embolectomy for use in patients prior to the development of significant circulatory collapse, with promising results. We aim to review the literature and discuss the indications, perioperative workup and outcomes of surgical pulmonary embolectomy in the management of acute PE.

Pulmonary 64-MDCT angiography with 50 mL of iodinated contrast material in an unselected patient population: a feasible protocol

Abstract Objective: To propose a protocol for pulmonary angiography using 64-slice multidetector computed tomography (64-MDCT) with 50 mL of iodinated contrast material, in an unselected patient population, as well as to evaluate vascular enhancement and image quality. Materials and Methods: We evaluated 29 patients (22-86 years of age). The body mass index ranged from 19.0 kg/m2 to 41.8 kg/m2. Patients underwent pulmonary CT angiography in a 64-MDCT scanner, receiving 50 mL of iodinated contrast material via venous access at a rate of 4.5 mL/s. Bolus tracking was applied in the superior vena cava. Two experienced radiologists assessed image quality and vascular enhancement. Results: The mean density was 382 Hounsfield units (HU) for the pulmonary trunk; 379 and 377 HU for the right and left main pulmonary arteries, respectively; and 346 and 364 HU for the right and left inferior pulmonary arteries, respectively. In all patients, subsegmental arteries were analyzed. There were streak artifacts from contrast material in the superior vena cava in all patients. However, those artifacts did not impair the image analysis. Conclusion: Our findings suggest that pulmonary angiography using 64-MDCT with 50 mL of iodinated contrast can produce high quality images in unselected patient populations.

Elevated Plasma Hemoglobin Levels Increase Nitric Oxide Consumption in Experimental and Clinical Acute Pulmonary Thromboembolism

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Low-dose pulmonary CT angiography: reduced radiation exposure and iodine load at low tube kilovoltage

CT pulmonary angiography is the currently accepted standard in ruling out acute pulmonary embolism. Issues of radiation dose received by patients via CT have been extensively disputed by radiologists and reported by the media. In recent years there has been considerable research performed to find ways for reducing radiation exposure from CT. Herein, we will discuss specific measures that have been shown to be valuable for CT pulmonary angiography. The limitations and the potential benefits of reduced CT peak tube kilovoltage will be detailed as this method is capable of reducing both radiation exposure and iodine load to the patient simultaneously. We discuss some of the emerging tools, which will hopefully play a significant role in wider acceptance of low-dose CT pulmonary angiography protocols.

Acute pulmonary embolectomy three days following a coronary artery bypass graft procedure

Pulmonary embolism is very rarely reported early after cardiac surgery, most probably due to full heparinisation during cardiopulmonary bypass. We report a 66-year-old man without thromboembolic history who presented three days after a coronary artery bypass grafting procedure with acute dyspnoea and haemodynamic instability. A CT scan confirmed paracentral bilateral pulmonary embolism requiring an urgent and successful embolectomy. Review of the literature confirms that pulmonary embolism may occur in up to 3% of post-cardiopulmonary bypass patients. The possibility of pulmonary embolism must be taken into consideration in post-cardiopulmonary bypass patients with acute onset of chest pain and respiratory insufficiency.

Effect of X-ray tube parameters, iodine concentration, and patient size on image quality in pulmonary computed tomography angiography: a chest-phantom-study

OBJECTIVES: The aim of this phantom study was to evaluate the contrast-to-noise ratio (CNR) in pulmonary computed tomography (CT)-angiography for 300 and 400 mg iodine/mL contrast media using variable x-ray tube parameters and patient sizes. We also analyzed the possible strategies of dose reduction in patients with different sizes. MATERIALS AND METHODS: The segmental pulmonary arteries were simulated by plastic tubes filled with 1:30 diluted solutions of 300 and 400 mg iodine/mL contrast media in a chest phantom mimicking thick, intermediate, and thin patients. Volume scanning was done with a CT scanner at 80, 100, 120, and 140 kVp. Tube current-time products (mAs) varied between 50 and 120% of the optimal value given by the built-in automatic dose optimization protocol. Attenuation values and CNR for both contrast media were evaluated and compared with the volume CT dose index (CTDI(vol)). Figure of merit, calculated as CNR/CTDIvol, was used to quantify image quality improvement per exposure risk to the patient. RESULTS: Attenuation of iodinated contrast media increased both with decreasing tube voltage and patient size. A CTDIvol reduction by 44% was achieved in the thin phantom with the use of 80 instead of 140 kVp without deterioration of CNR. Figure of merit correlated with kVp in the thin phantom (r = -0.897 to -0.999; P < 0.05) but not in the intermediate and thick phantoms (P = 0.09-0.71), reflecting a decreasing benefit of tube voltage reduction on image quality as the thickness of the phantom increased. Compared with the 300 mg iodine/mL concentration, the same CNR for 400 mg iodine/mL contrast medium was achieved at a lower CTDIvol by 18 to 40%, depending on phantom size and applied tube voltage. CONCLUSIONS: Low kVp protocols for pulmonary embolism are potentially advantageous especially in thin and, to a lesser extent, in intermediate patients. Thin patients profit from low voltage protocols preserving a good CNR at a lower exposure. The use of 80 kVp in obese patients may be problematic because of the limitation of the tube current available, reduced CNR, and high skin dose. The high CNR of the 400 mg iodine/mL contrast medium together with lower tube energy and/or current can be used for exposure reduction.

Venous thromboembolism and occult malignancy: simultaneous detection during pulmonary CT angiography with CT venography

OBJECTIVE: We explored the potential for patients with proven venous thromboembolism or pulmonary embolism (PE) to have occult malignancies detected during the same CT examination. To verify this, we compared the presence of occult malignancies identified on pulmonary artery CT angiography (CTA) and CT venography (CTV) when venous thromboembolism (VTE) was present. SUBJECTS AND METHODS: Pulmonary artery CTA combined with CTV was performed on a 16-MDCT scanner on 186 adult patients suspected of having pulmonary embolism without any known malignancies. CTV was performed from the diaphragm to the knee 180 seconds after CTA. Two radiologists evaluated the presence of VTE, that is PE or deep venous thrombosis (DVT), and tumor lesions on both examinations in consensus. The malignant nature of the possibly identified tumors was confirmed by pathologic examination. RESULTS: VTE was found in 49 patients (26%). Malignant tumors were detected in 24 patients (13%). Eleven patients with malignant tumors had VTE (46% of patients with malignant tumors; 22% with VTE and 6% of all patients). There was correlation with presence of malignancies between both and DVT and DVT associated with PE but not between presence of malignancies and PE only. Patients with DVT and those with DVT associated with PE had a risk ratio of 3.2 and 3.3, respectively, for having a malignant tumor discovered simultaneously. CONCLUSION: A high number of malignant tumors can be incidentally discovered on pulmonary artery CTA, even more so with additional CTV. Radiologists should scrutinize scans to pick up unknown malignancies, especially in patients with identified VTE.