Morphofunctional changes in the myocardium after extensive bilateral resection of the lungs

In the experiment, performed on 89 dogs, after 67-75% resection of the lungs, functional morphology of the myocardium has been studied by means of histological, electron microscopical and morphometrical methods. Bilateral extensive resections of the lungs are accompanied with hypertrophy of the cardiac muscle, that is revealed at all the levels of its structural organization. Simultaneously, the hypertrophy develops against the background of dystrophic and destructive changes of the myocardium, their depth and extensiveness correlate with duration of the postoperative observations. If an extrapulmonary anastomosis is formed between the inferior lobular pulmonary artery and the corresponding vein before the resection of 67-75% of the lungs, it eliminates the acute overloading of the right ventricle, makes better conditions for development of compensatory-adaptive processes in the myocardium, prevents advancement of the cardio-pulmonary deficiency during the postoperative period.     

Pulmonary arterial hypertension in a patient treated with dasatinib: a case report

Background

There have been several reports on dasatinib-induced reversible pulmonary hypertension. This is the first reported case in Latvia; the patient did not discontinue the drug after the first adverse effects in the form of pleural effusions, which we speculate led only to partial reversion of the disease.

Case presentation

A 67-year-old white man with chronic myelogenous leukemia was treated with the dual Src and BCR-ABL tyrosine kinase inhibitor dasatinib. After treatment with dasatinib he had multiple pleural effusions which were suspected to be caused by congestive heart failure. Later a transthoracic Doppler echocardiography and right-sided heart catheterization revealed severe pulmonary hypertension with pulmonary vascular resistance of 12 Wood units and mean pulmonary artery pressure of 53 mmHg. Computed tomography ruled out a possible pulmonary embolism; laboratory specific tests for human immunodeficiency virus, rheumatoid factor, and anti-nuclear antibodies were negative, and dasatinib-induced pulmonary arterial hypertension was diagnosed.A follow-up right-sided heart catheterization and 6-minute walk test done a month after the discontinuation of dasatinib showed significant improvement: mean pulmonary artery pressure of 34 mmHg and pulmonary vascular resistance of 4 Wood units.

Conclusions

Patients should always be closely monitored when using dasatinib for a prolonged time. Dasatinib-induced pulmonary hypertension may be fully reversible after the therapy is suspended, but the key factors involved are still unclear and need to be further studied.

     

Selective right, but not left, coronary endothelial dysfunction precedes development of pulmonary hypertension and right heart hypertrophy in rats

We investigated a causal role for coronary endothelial dysfunction in development of monocrotaline (MCT)-induced pulmonary hypertension and right heart hypertrophy in rats. Significant increases in pulmonary pressure and right ventricular weight did not occur until 3 wk after 60 mg/kg MCT injection (34 +/- 4 vs. 19 +/- 2 mmHg and 37 +/- 2 vs. 25 +/- 1% septum + left ventricular weight in controls, respectively). Isolated right coronary arteries (RCA) showed significant decreases in acetylcholine-induced NO dilation in both 1-wk (33 +/- 3% with 0.3 microM; n = 5) and 3-wk (18 +/- 3%; n = 11) MCT rats compared with control rats (71 +/- 8%, n = 10). Septal coronary arteries (SCA) showed a smaller decrease in acetylcholine dilation (55 +/- 8% and 33 +/- 7%, respectively, vs. 73 +/- 8% in controls). No significant change was found in the left coronary arteries (LCA; 88 +/- 6% and 81 +/- 6%, respectively, vs. 87 +/- 3% in controls). Nitro-L-arginine methyl ester-induced vasoconstriction, an estimate of spontaneous endothelial NO-mediated dilation, was not significantly altered in MCT-treated SCA or LCA but was increased in RCA after 1 wk of MCT (-41 +/- 6%) and decreased after 3 wk (-18 +/- 3% vs. -27 +/- 3% in controls). A marked enhancement to 30 nM U-46619-induced constriction was also noted in RCA of 3-wk (-28 +/- 6% vs. -9 +/- 2% in controls) but not 1-wk (-12 +/- 7%) MCT rats. Sodium nitroprusside-induced vasodilation was not different between control and MCT rats. Together, our findings show that a selective impairment of right, but not left, coronary endothelial function is associated with and precedes development of MCT-induced pulmonary hypertension and right heart hypertrophy in rats.     

Effect of 5-lipoxygenase on the development of pulmonary hypertension in rats

5-Lipoxygenase (5-LO) and its downstream leukotriene products have been implicated in the development of pulmonary hypertension. In this study, we examined the effects of 5-LO overexpression in rat lungs on pulmonary hypertension using a recombinant adenovirus expressing 5-LO (Ad5-LO). Transthoracic echocardiography and right heart catheterization data showed that 5-LO overexpression in the lung did not cause pulmonary hypertension in normal rats; however, it markedly accelerated the progression of pulmonary hypertension in rats treated with monocrotaline (MCT). An increase in pulmonary artery pressure occurred earlier in the rats treated with MCT + Ad5-LO (7-10 days) compared with those treated with control vector, MCT + adenovirus expressing green fluorescent protein (AdGFP), or MCT alone (15-18 days). The weight ratio of the right ventricle to left ventricle plus septum was higher in the MCT + Ad5-LO group than that of the MCT + AdGFP or MCT group (0.45 +/- 0.08 vs. 0.35 +/- 0.03 or 0.33 +/- 0.06). Lung tissue histological sections from MCT + Ad5-LO rats exhibited more severe inflammatory cell infiltration and pulmonary vascular muscularization than those from MCT + AdGFP- or MCT-treated rats. Administration of 5-LO inhibitors, zileuton or MK-886, to either MCT- or MCT + Ad5-LO-treated rats prevented the development of pulmonary hypertension. These data suggest that 5-LO plays a critical role in the progression of pulmonary hypertension in rats and that the detrimental effect of 5-LO is manifest only in the setting of pulmonary vascular endothelial cell dysfunction.     

Functional, morphologic and histochemical changes in the myocardium and their role in the development of cor pulmonale following pulmonary resection]

Functional, morphological and histochemical alterations were studied in 32 dogs within the period of 5 days--18 months after resection of 32-80% of the pulmonary tissue. According to the presence of hypertrophy of the heart right ventricle wall, morphological changes of the myocardium and disorders in the functional features of the cardiovascular activity all the animals were divided into 4 groups: 1--control animals; 2--experimental animals without hypertrophy of the right ventricle wall; 3--experimental animals with hypertrophy of the right ventricle wall in the stage of compensation; 4--experimental animals with hypertrophy of the right ventricle wall in the stage of decompensation. In the myocardium of the second group animals a decrease of aerobic processes and an increase of anaerobic ones were found to take place. The aerobic processes increased and the anaerobic processes decreased in the myocardium of dogs having hypertrophy of the right ventricle wall in the stage compensation. In the muscle of the decompensated pulmonary heart there occurred a pronounced decrease of aerobic and anaerobic processes, a disturbance of the protein and fat metabolism. All this resulted in a decreased contractive function of the myocardium with distrubed hemodynamics. The investigations have shown the interrelationships of morphological, histochemical and ECG alterations in the dynamics of the pulmonary heart development after resection of lungs.     

Decreased surfactant proteins in lambs with pulmonary hypertension secondary to increased blood flow

Infants with increased pulmonary blood flow secondary to congenital heart disease suffer from tachypnea, dyspnea, and recurrent pulmonary infections. We have recently established a model of pulmonary hypertension secondary to increased pulmonary blood flow in lambs after in utero placement of an aortopulmonary vascular graft. The purpose of the present study was to utilize our animal model to determine the effects on the expression of surfactant proteins A (SP-A), B (SP-B), and C (SP-C). At age 4 wk, SP-A mRNA content in lambs decreased to 61.4 +/- 8% of age-matched control value (n = 5; P < 0.05). In addition, SP-A protein content was decreased to 50 +/- 12% of control value (n = 6; P < 0.0001). Although we did not observe statistically significant changes in SP-B mRNA content, SP-B protein was decreased to 74 +/- 25% of control value (n = 4; P < 0.02). There was no difference in SP-C mRNA. These data show that in a model of congenital heart disease with pulmonary hypertension secondary to increased pulmonary blood flow, there is a decrease in SP-A gene expression as well as a decrease in SP-A and SP-B protein contents.     

An unusual case of cardiomyopathy in a 75-year-old woman

In this report we describe a 75-year-old woman who presented with an acute coronary syndrome and transient catecholamine-induced cardiomyopathy with severe pulmonary oedema necessitating mechanical ventilation. During mechanical ventilation several episodes of hypertension occurred despite severe left ventricular systolic dysfunction. A pheochromocytoma was diagnosed and after successful surgical resection the patient''s condition improved. Three months after surgery myocardial scintigraphic examination demonstrated a normal ejection fraction and no signs of adenosine-induced ischaemia.     

Structural and functional characteristics of myocardial capillaries after resection of the lungs

In the experiment performed on 107 dogs, after resection of 33-75% of the pulmonary volume, it has been stated that considerable disturbances take place in the myocardial microcirculatory bed. At early stage after the operation the amount of capillaries per 1 mm2 of the section increases, their lumens become wide. With elapse of time after the operation, as a result of myocardial hypertrophy, density in arrangement of the capillaries decreases, and the transversal section area of the cardiomyocyte per one capillary increases. In the capillary walls destructive changes are also noted; they result in myocardiodistrophy and in development of cardiac failure.     

Inflammatory cytokines in pulmonary hypertension

Pulmonary hypertension is an “umbrella term” used for a spectrum of entities resulting in an elevation of the pulmonary arterial pressure. Clinical symptoms include dyspnea and fatigue which in the absence of adequate therapeutic intervention may lead to progressive right heart failure and death. The pathogenesis of pulmonary hypertension is characterized by three major processes including vasoconstriction, vascular remodeling and microthrombotic events. In addition accumulating evidence point to a cytokine driven inflammatory process as a major contributor to the development of pulmonary hypertension.This review summarizes the latest clinical and experimental developments in inflammation associated with pulmonary hypertension with special focus on Interleukin-6, and its role in vascular remodeling in pulmonary hypertension.     

Selected Contribution: Pulmonary hypertension in mice following intermittent hypoxia.

Sleep apnea (intermittent periods of hypoxia with or without hypercapnia) is associated with systemic hypertension and increased mortality from cardiovascular disease, but the relationship to pulmonary hypertension is uncertain. Previous studies on intermittent hypoxia (IH) in rats that demonstrated pulmonary hypertension utilized relatively long periods of hypoxia. Recent studies that utilized brief periods of hypoxia have conflicting reports of right ventricular (RV) hypertrophy. In addition, many studies have not measured pulmonary hemodynamics to asses the severity of pulmonary hypertension in vivo. Given the increasing availability of genetically engineered mice and the need to establish a rodent model of IH-induced pulmonary hypertension, we studied the effect of IH (2-min cycles of 10% and 21% O2, 8 h/day, 4 wk) on wild-type mice, correlating in vivo measurements of pulmonary hypertension with RV mass and pulmonary vascular remodeling. RV systolic pressure was increased after IH (36 +/- 0.9 mmHg) compared with normoxia (29.5 +/- 0.6) but was lower than continuous hypoxia (44.2 +/- 3.4). RV mass [RV-to-(left ventricle plus septum) ratio] correlated with pressure measurements (IH = 0.27 +/- 0.02, normoxia = 0.22 +/- 0.01, and continuous hypoxia = 0.34 +/- 0.01). Hematocrits were also elevated after IH and continuous hypoxia (56 +/- 1.6 and 54 +/- 1.1 vs. 44.3 +/- 0.5%). Evidence of neomuscularization of the distal pulmonary circulation was found after IH and continuous hypoxia. We conclude that mice develop pulmonary hypertension following IH, representing a possible animal model of pulmonary hypertension in response to the repetitive hypoxia-reoxygenation of sleep apnea.     

PDE5A inhibition attenuates bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition of ROS generation and RhoA/Rho kinase activation

Pulmonary hypertension frequently complicates interstitial lung disease, where it is associated with a high mortality. Patients with this dual diagnosis often fare worse than those with pulmonary arterial hypertension (PAH) alone and respond poorly to standard PAH therapy, often dying of right ventricular (RV) failure. We hypothesize that nitric oxide synthase (NOS) uncoupling is important in the pathogenesis of interstitial lung disease-associated pulmonary hypertension, and this process can be abrogated by phosphodiesterase type 5 (PDE5) inhibition to improve pulmonary vascular remodeling and right ventricular function. Intratracheal bleomycin (4 U/kg) or saline control was administered to C57/BL6 mice after anesthesia. After recovery, animals were fed a diet of sildenafil (100 mg.kg(-1).day(-1)) or vehicle for 2 wk when they underwent hemodynamic measurements, and tissues were harvested. Survival was reduced in animals treated with bleomycin compared with controls and was improved with sildenafil (100.0 vs. 73.7 vs. 84.2%, P < 0.05). RV/LV+S ratio was higher in bleomycin-alone mice with improvement in ratio when sildenafil was administered (33.00 +/- 0.01% vs. 20.98 +/- 0.01% P < 0.05). Histology showed less pulmonary vascular and RV fibrosis in the group cotreated with sildenafil. Bleomycin was associated with a marked increase in superoxide generation by DHE histological staining and luminol activity in both heart and lung. Treatment with sildenafil resulted in a concomitant reduction in superoxide levels in both heart and lung. These data demonstrate that PDE5 inhibition ameliorates RV hypertrophy and pulmonary fibrosis associated with intratracheal bleomycin in a manner that is associated with improved NOS coupling and a reduction in reactive oxygen species signaling.     

Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice

Heterozygous bone morphogenetic protein receptor-II-knockout (BMPR2(+/-)) mice have a similar genetic trait like that in some idiopathic pulmonary arterial hypertension patients. To examine the effect of pulmonary endothelial injury in BMPR2(+/-) mice, we challenged the mice with two injections of monocrotaline combined with intratracheal instillation of replication-deficient adenovirus expressing 5-lipoxygenase (MCT+Ad5LO). After the challenge (1 wk), BMPR2(+/-) mice exhibited a doubling of right ventricular systolic pressure that was greater than that of wild-type mice and remained elevated for 3 wk before heart failure developed. Muscularization and thickening of small pulmonary arterioles was evident in the BMPR2(+/-) lungs at 2 wk after the challenge and became severe at 3 wk. Marked perivascular infiltration of T cells, B cells, and macrophages was associated with the remodeled vessels. Real-time PCR analysis showed that the expression of six endothelial cell markers in lung tissue was decreased to 20-40% of original levels at 1 wk after the challenge in both BMPR2(+/-) and wild-type mice and largely recovered in wild-type (50-80%) but not BMPR2(+/-) lungs (30-50%) at 3 wk after the challenge. Macrophage inflammatory protein-1alpha and fractalkine receptor expression doubled in BMPR2(+/-) compared with wild-type lungs. Expression of type I and type II BMP receptors, but not transforming growth factor-beta receptors, in the challenged BMPR2(+/-) and wild-type lungs showed a similar pattern of expression as that of endothelial markers. Apoptotic responses at 1 wk after MCT and Ad5LO challenge were also significantly greater in the BMPR2(+/-) lungs than the wild-type lungs. These data show that BMPR2(+/-) mice are more sensitive to MCT+Ad5LO-induced pulmonary hypertension than wild-type mice. Greater endothelial injury and an enhanced inflammatory response could be the underlying causes of the sensitivity and may work in concert with BMPR2 heterozygosity to promote the development of persistent pulmonary hypertension.     

可逆性肺动脉高压的治疗在心脏移植围术期的应用

目的：通过早期判断并治疗心脏移植围术期可逆性肺动脉高压,降低移植手术后右心功能衰竭的发生率。方法：20例接受心脏移植手术的病人,术前放置肺动脉导管,测定肺动脉压、肺循环阻力。对肺动脉高压的病人在肺动脉端泵入硝酸甘油、前列腺素E1以确定可逆性。并在术后早期抗排异治疗的基础上应用增强心肌收缩力、降低肺动脉压力、强化氧疗和呼吸管理等综合措施。结果：20例病人中6例出现急性右心功能衰竭,其中4例经治疗后症状改善、出院,2例死亡。结论：术前早期判断并治疗可逆性肺动脉高压,可以有效预防并减少心脏移植术后右心功能衰竭的发生,提高手术成功率。     

Unilateral radiation pneumonitis in sheep: physiological changes and bronchoalveolar lavage

Radiation pneumonitis is a life-threatening result of therapeutic thoracic irradiation, yet its mechanisms are poorly understood. We studied the effects of unilateral lung irradiation (3,000 rad) in sheep from the immediate response to the later development of radiation pneumonitis. We defined radiation pneumonitis by its diagnostic clinical feature, radiographic infiltration of the irradiated zone with a straight margin corresponding to the radiation port. The immediate response in the few hours after irradiation was characterized by cough, labored respiration, hypoxemia (arterial PO2 decreased 19 Torr), mild pulmonary hypertension (pulmonary arterial pressure increased 20%), and lymphopenia. Hemodynamics and gas exchange returned to normal by day 2 but became abnormal again before or during radiation pneumonitis at 32 +/- 2 days. Respiratory distress, hypoxemia, and pulmonary hypertension recurred during radiation pneumonitis. Bronchoalveolar lavage during radiation pneumonitis contained increased neutrophils (19 +/- 4%, control = 7%), increased protein (0.27 +/- 0.1 g/dl, control = 0.12 +/- 0.03), and severely impaired ability to lower surface tension. Alveolar macrophages from both lungs during unilateral radiation pneumonitis exhibited impaired generation of superoxide after phorbol myristate (only a 30% increase). Normal control alveolar macrophages increased superoxide production after stimulation greater than 400%. We conclude that unilateral lung irradiation in sheep causes a mild immediate response followed by radiation pneumonitis at 1 mo. Unilateral radiation pneumonitis in this model is associated with ipsilateral neutrophilic alveolitis, increased bronchoalveolar lavage protein, and impaired surfactant function, as well as bilateral functional abnormalities of alveolar macrophages.     

Acute Hemodynamic Effects of Angiotensin II: Preliminary Report

Angiotensin II was given to over 200 patients during heart catheterization studies. Left to right shunts through atrial and ventricular septal defects were increased. Shunts not detected under control conditions could then be recognized. In normal subjects left atrial pressure increased about 5-10 mm. Hg, producing a secondary rise in pulmonary artery pressure. The response of the pulmonary vessels to angiotensin was usually passive. Cardiac output declined in the normal subject after angiotensin administration. Right to left shunts decreased after angiotensin administration in some patients with cyanotic congenital heart disease, thus decreasing cyanosis. This finding has possible therapeutic applications. The pulmonary arterioles of patients with pulmonary hypertension may respond to angiotensin in a different manner from those with normal pulmonary arterioles.     

Lack of additional action of oxygen on pulmonary artery pressure at the peak of verapamil or captopril action in pulmonary hypertension secondary to mitral stenosis]

The aim of the study was to investigate whether oxygen causes a further decrease in pulmonary artery pressure after administration of calcium channel blocker-verapamil-or angiotensin converting enzyme inhibitor-captopril-in the secondary pulmonary hypertension. We studied 37 patients with the secondary pulmonary hypertension (mean pulmonary artery systolic pressure = 56.1 mm Hg) due to mitral stenosis. After having completed hemodynamic diagnostic procedures, basal oxygen test was performed and pulmonary artery pressure was recorded at 10 min of oxygen breathing. Then, 10 mg of verapamil was injected into the pulmonary artery of 16 patients and 21 patients received 75 mg of oral captopril. At the peak of vasodilation, 30 min after verapamil and 90 min after captopril administration, pulmonary artery pressure was recorded and oxygen test was repeated. Baseline oxygen test produced a statistically significant decrease in pulmonary artery pressure. Verapamil and captopril also lowered pulmonary artery systolic and diastolic pressures. The second oxygen test did not cause a further decrease in the pulmonary artery pressure; mean pulmonary artery systolic pressure was 52.3 +/- 23.7 mm Hg, pulmonary artery diastolic pressure 22.7 +/- 10.6 mm Hg before and 49.1 +/- 23.8 mm Hg and 23.0 +/- 13.5 mm Hg, respectively after the test in verapamil group, and 47.0 +/- 15.5 mm Hg and 21.7 +/- 8.4 mm Hg before and 46.6 +/- 15.4 mm Hg, respectively in captopril subset. The results may support the thesis that vasodilating effect depends rather on the degree of pulmonary vascular changes than on the vasodilatory mechanism of particular drugs.     

Evaluation of endothelin-1-induced pulmonary vasoconstriction following myocardial infarction

Endothelin (ET) levels are elevated in congestive heart failure secondary to myocardial infarction (MI) and correlate well with the severity of pulmonary hypertension (PH), suggesting that the ET peptide could contribute to the pathophysiology of venous PH. Alterations of pulmonary vasoreactivity to ET after MI and the respective roles of the ET(A) and ET(B) receptors (ET(A)-R and ET(B)-R) have never been evaluated, to our knowledge. MI was induced in rats. Three weeks later, small pulmonary resistance arteries were mounted on a microvascular myograph. Cumulative concentration-response curves to ET-1 and sarafotoxin 6c (S6c) were performed. Response to ET was also assessed in the presence of ET-R antagonists. Heterodimerization of receptors was evaluated by immunoprecipitation of the ET(B)-R, followed by western blotting for the expression of the ET(A)-R. Maximal vasoconstriction and sensitivity to ET-1 were similar in sham and MI with values of 88 +/- 3.9% and 80 +/- 3.8%, respectively. The response to S6c was similarly less in both sham (67 +/- 5.7%) and MI groups (60 +/- 6.6%). When administered alone, the ET(A)-R antagonist (10 nM A-147627.1) and the ET(B)-R antagonist (1 microM A-192621.1) had no significant effect. However, their combination markedly reduced vaso-constriction (52 +/- 5.3%; P < 0.001). The endothelial and medial distribution of ET-Rs was similar in sham and MI groups. In vitro studies demonstrated co-immunoprecipitation of the ET(A)-R and ET(B)-R. Vasoconstriction of isolated resistance pulmonary arteries to ET agonists is not altered after MI. Dual antagonism results in optimal blockade of vasoconstriction, possibly because the ET(A)-R and ET(B)-R can form functional heterodimers.     

Intrauterine hypertension decreases lung VEGF expression and VEGF inhibition causes pulmonary hypertension in the ovine fetus

Although vascular endothelial growth factor (VEGF) plays a vital role in lung vascular growth in the embryo, its role in maintaining endothelial function and modulating vascular structure during late fetal life has not been studied. We hypothesized that impaired lung VEGF signaling causes pulmonary hypertension, endothelial dysfunction, and structural remodeling before birth. To determine whether lung VEGF expression is decreased in an experimental model of persistent pulmonary hypertension of the newborn (PPHN), we measured lung VEGF and VEGF receptor protein content from fetal lambs 7-10 days after ductus arteriosus ligation (132-140 days gestation; term = 147 days). In contrast with the surge in lung VEGF expression during late gestation in controls, chronic intrauterine pulmonary hypertension reduced lung VEGF expression by 78%. To determine whether VEGF inhibition during late gestation causes pulmonary hypertension, we treated fetal lambs with EYE001, an aptamer that specifically inhibits VEGF(165). Compared with vehicle controls, EYE001 treatment elevated pulmonary artery pressure and pulmonary vascular resistance by 22 and 50%, respectively, caused right ventricular hypertrophy, and increased wall thickness of small pulmonary arteries. EYE001 treatment reduced lung endothelial nitric oxide synthase protein content by 50% and preferentially impaired the pulmonary vasodilator response to ACh, an endothelium-dependent agent. We conclude that chronic intrauterine pulmonary hypertension markedly decreases lung VEGF expression and that selective inhibition of VEGF(165) mimics the structural and physiological changes of experimental PPHN. We speculate that hypertension downregulates VEGF expression in the developing lung and that impaired VEGF signaling may contribute to the pathogenesis of PPHN.     

Pulmonary hypertension: the role of the electrocardiogram

A 54-year-old female was referred to our centre for further evaluation of recently established severe pulmonary hypertension. Six months prior to presentation to the cardiologist of the referring centre, the patient had first experienced exertional dyspnoea. At the time of presentation to the referring cardiologist, the patient’s ECG showed signs of an increased right heart load. Interestingly, this patient had undergone a thorough cardiac evaluation in the referring centre seven years before when she presented with severe hyperthyroidism. At that time there were no symptoms or signs of pulmonary hypertension on ECG, echocardiography, or at heart catheterisation. Thorough evaluation in cooperation with the referring centre demonstrated that this patient was suffering from idiopathic pulmonary arterial hypertension, a rare form of pulmonary hypertension. We conclude this report with a discussion on the potential use of the ECG for the diagnosis of increased right heart load. (Neth Heart J 2008;16:250-4.)     

Serial noninvasive assessment of progressive pulmonary hypertension in a rat model

Current methods used to investigate pulmonary hypertension in rat models of the disease allow for only one to two measurements of pulmonary artery (PA) pressure in the life of a rat. We investigated whether transthoracic echocardiography can be used to assess the progression of pulmonary hypertension in rats at multiple time points. Serial echocardiographic measurements were performed over a 6-wk period on rats injected with monocrotaline (MCT) or placebo. Development of a midsystolic notch in the PA waveform, a decrease in the PA flow acceleration time (PAAT), an increase in right ventricular (RV) free-wall thickness, and the development of tricuspid regurgitation (TR) were observed as pulmonary hypertension developed. Changes in the PA waveform and PAAT began in week 3 of disease development as the PA systolic pressure (PASP) reached 25-30 mmHg according to right heart catheterization. The RV free-wall thickness increased significantly by week 5 (PASPs 40-50 mmHg). Development of quantifiable TR occurred in week 6 or at PASPs > 65 mmHg. A linear correlation was found between the PAAT and PASP in the range of 30-65 mmHg and between the RV-right atrial pressure gradient (derived from TR velocity) and PASP at pressures >65 mmHg, which enabled a noninvasive estimate of the PASP over a wide range of pressures based on these parameters. These data indicate that transthoracic echocardiography can be used for monitoring the progress of pulmonary hypertension in a rat model.