Isolated chronic mitral regurgitation with preserved systolic left ventricular function and severe pulmonary hypertension

Pulmonary hypertension in chronic mitral valve disease has been related most commonly to left ventricular dysfunction or mitral stenosis; its association with chronic, isolated mitral regurgitation and preserved left ventricular systolic function is unclear. In 41 catheterized patients with chronic mitral regurgitation (known history of mitral regurgitation for greater than 18 months) and preserved left ventricular systolic function (ejection fraction greater than 0.55), historic, electrocardiographic, echocardiographic and hemodynamic variables were analyzed. Ten patients (Group I) had normal pulmonary artery systolic pressure (less than 30 mm Hg), whereas 31 patients had pulmonary hypertension. Pulmonary artery systolic pressure was mildly increased (30 to 49 mm Hg) in 13 patients (Group II) and was greater than or equal to 50 mm Hg in 18 patients (Group III). Univariate analysis showed the more frequent occurrence of male gender and ruptured chordae tendineae in the groups with pulmonary hypertension. Mean pulmonary capillary wedge pressure, size of the V wave in pulmonary capillary wedge pressure and pulmonary arteriole resistance were higher, whereas cardiac index was lower in the hypertension groups. Multivariate stepwise analysis revealed higher mean pulmonary capillary wedge pressure and pulmonary arteriole resistance as the only variables independently differing among groups. In conclusion, pulmonary hypertension occurs frequently (76% of cases) in patients with chronic, isolated mitral regurgitation with preserved left ventricular systolic function. In these patients, a severe increase in pulmonary capillary wedge pressure is associated with elevation in pulmonary artery resistance, a finding similar to that in mitral stenosis.     

Pulmonary edema during acute infusion of epoprostenol in a patient with pulmonary hypertension and limited scleroderma.

Epoprostenol (prostacyclin) is currently approved for treatment of primary pulmonary hypertension; however, it is being evaluated in other forms of pulmonary hypertension, particularly scleroderma. Side effects associated with this medication are usually minor; serious complications are most often due to the delivery system required for continuous infusion. We describe a life threatening side effect of acute epoprostenol infusion (pulmonary edema) in a patient with pulmonary hypertension associated with limited scleroderma and discuss its management and potential etiology. This is the first case where epoprostenol has been successfully reinstituted.     

Effects of intravenous nesiritide on pulmonary vascular hemodynamics in pulmonary hypertension

BACKGROUND: Nesiritide is effective in the treatment of decompensated heart failure (HF). We evaluated the acute hemodynamic effects of nesiritide, a recombinant B-type natriuretic peptide, in patients with HF and pulmonary hypertension (PH). METHODS AND RESULTS: Twenty patients with HF and PH (mean pulmonary arterial [PA] pressure >25 mm Hg) were enrolled: 10 with postpulmonary capillary wedge (PCW) >15 mm Hg and 10 with precapillary PH (PCW) < or =15. The pulmonary and systemic hemodynamics were determined by right heart catheterization at baseline and at 15 and 30 minutes after an intravenous nesiritide infusion (2 mcg/kg bolus and 0.01 mcg.kg.min). For the patients with postcapillary PH, the mean left ventricular ejection fraction was 28 +/- 15%. After the 30-minute nesiritide infusion, right atrial (RA) pressure decreased 48% (P < .0001), mean PA pressure decreased 29% (P < .0001), PCW pressure decreased 40% (P < .0001), cardiac index (CI) increased 35% (P = .009), pulmonary vascular resistance index (PVRI) decreased 35% (P = .01), and arteriovenous oxygen difference (AVDO(2)) decreased 27% (P = .0003). For precapillary PH patients, there was no change in RA, PA, or PCW pressure, nor any change in CI, PVRI, or AVDO(2). CONCLUSIONS: Nesiritide acutely and significantly reduced PA pressure, PVRI, and biventricular filling pressures in patients with postcapillary PH. However, for patients with precapillary PH, nesiritide had no significant acute hemodynamic effect on the pulmonary hemodynamics. The lack of acute beneficial effects of nesiritide in patients with advanced precapillary PH may be related to their relatively fixed remodeling of the pulmonary vasculature.     

Acute cardiomyopathy with recurrent pulmonary edema and hypotension following heroin overdosage.

An 18-year-old man developed acute pulmonary edema following heroin overdose. Two days after initial improvement, there was recurrence of hypotension and pulmonary edema with severe hypoxemia refractory to mechanical ventilatory support utilizing positive and end-expiratory pressure. Cardiac catheterization revealed elevated pulmonary capillary wedge pressure suggestive of left ventricular failure. The use of digitalis and diuretics resulted in prompt clinical improvement and ultimate recovery. Evidence is presented indicating that this patient represents an uncommon but important syndrome of acute cardiomyopathy with left ventricular failure which complicates the clinical course of certain cases of heroin overdose. Its physiologic diagnosis is of obvious importance in the choice of proper therapy, thereby increasing the patient's chances of recovery.     

A case of severe pulmonary hypertension associated with COPD treated with epoprostenol

A rare case of chronic obstructive pulmonary disease (COPD) with severe pulmonary hypertension (PH) was found in a 68-year-old man. COPD was diagnosed in his 50s, from which time he received home oxygen therapy. In January 2007, he was admitted due to progression of dyspnea. On admission to our hospital, arterial blood gas analysis showed severe hypoxemia. Moreover, echocardiographic findings demonstrated severe deviation of the interventricular septum toward the left ventricle, with right ventricular dilatation. Cardiac catheterization data demonstrated pulmonary arterial hypertension with a low cardiac output. Because severe PH is uncommon in patients with COPD and there was no apparent etiology of PH other than COPD, we thought this case was predominantly a pulmonary vascular disease such as idiopathic pulmonary arterial hypertension. Though we first treated this patient with bosentan, it was not effective. Therefore, he was treated with continuous infusion of epoprostenol. Epoprostenol administration along with bosentan resulted in decrease of BNP and right ventricular function improvement. We report a case of severe PH due to severe COPD treated with continuous administration of epoprostenol.     

Hemodynamic effects of epoprostenol in patients with systemic sclerosis and pulmonary hypertension

STUDY OBJECTIVES: To determine the cause of pulmonary hypertension (PH) in systemic sclerosis (SSc) patients since PH can occur because of pulmonary arteriopathy, pulmonary parenchymal destruction, and left ventricular cardiac dysfunction. DESIGN AND SETTING: Consecutive case series in a university hospital. PATIENTS: Nine SSc patients with PH (mean pulmonary artery pressure, 41 mm Hg), with (n = 6) or without (n = 3) concomitant interstitial lung disease (ILD). METHODS: Acute infusion of epoprostenol was begun at 2 ng/kg/min and was titrated upward at a rate of 2 ng/kg/min every 30 min until symptomatic complications developed or pulmonary artery vascular resistance (PVR) was reduced by 50%. RESULTS: Eight of nine patients demonstrated a reduction of > or = 20% in PVR, suggesting that vasoreactivity is common despite the presence of significant ILD. A single patient had no response to infusion with unchanged hemodynamics and oxygenation. One patient developed hypoxemia as cardiac output increased, suggesting a worsening of ventilation/perfusion matching or the presence of an anatomic shunt. Acute pulmonary edema developed in one patient at an infusion rate of 6 ng/kg/min. The results of cardiac catheterization suggested that pulmonary edema was caused by SSc heart disease. CONCLUSION: SSc patients with ILD have diverse and sometimes multiple causes of PH that can be determined by short-term epoprostenol infusion. Beneficial effects can be obtained from epoprostenol despite extensive ILD.     

Natural history of primary pulmonary hypertension elucidated by pulmonary hemodynamics

The present study was undertaken to clarify the natural history of primary pulmonary hypertension (PPH) from a hemodynamic point of view. The subjects consisted of 83 patients (18 men and 65 women), whose ages ranged from 14 to 69 years and averaged 33 years. They were contacted through a nationwide survey. All patients underwent right-sided cardiac catheterization; cardiac output was measured in 52 patients and pulmonary capillary wedge pressure, in 40 patients. The following results were obtained. 1. The patients who died within three months of their cardiac catheterization were in severe right ventricular failure as shown by their elevated right atrial pressures and decreased cardiac indices. 2. The patients who died suddenly within two years of their cardiac catheterization had the same degree of right ventricular failure. The only difference was severe hypoxia in the patients with cardiac failure (54 +/- 21 vs 66 +/- 4 mmHg, p less than 0.05). 3. The patients who survived more than two years had normal right ventricular function. 4. Among the hemodynamic variables used to estimate prognosis; namely, pulmonary artery diastolic pressure, pulmonary capillary wedge pressure, cardiac index, pulmonary vascular resistance and pulmonary to systemic vascular resistance ratio, the cardiac index was the best predictor of prognosis.     

Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial

BACKGROUND: Pulmonary hypertension is a progressive and often fatal complication of the scleroderma spectrum of disease for which no treatment has been proven effective in a randomized trial. OBJECTIVE: To determine the effect of epoprostenol on pulmonary hypertension secondary to the scleroderma spectrum of disease. DESIGN: Randomized, open-label, controlled trial. SETTING: 17 pulmonary hypertension referral centers. PATIENTS: 111 patients with moderate to severe pulmonary hypertension. INTERVENTION: Epoprostenol plus conventional therapy or conventional therapy alone. MEASUREMENTS: The primary outcome measure was exercise capacity. Other measures were cardiopulmonary hemodynamics, signs and symptoms of pulmonary hypertension and scleroderma, and survival. RESULTS: Exercise capacity improved with epoprostenol (median distance walked in 6 minutes, 316 m at 12 weeks compared with 270 m at baseline) but decreased with conventional therapy (192 m at 12 weeks compared with 240 m at baseline). The difference between treatment groups in the median distance walked at week 12 was 108 m (95% CI, 55.2 m to 180.0 m) (P < 0.001). Hemodynamics improved at 12 weeks with epoprostenol. The changes in mean pulmonary artery pressure for the epoprostenol and conventional therapy groups were -5.0 and 0.9 mm Hg, respectively (difference, -6.0 mm Hg [CI, -9.0 to -3.0 mm Hg), and the mean changes in pulmonary vascular resistance were -4.6 and 0.9 mm Hg/L per minute, respectively (difference, -5.5 mm Hg/L per minute [CI, -7.3 to -3.7 mm Hg/L per minute). Twenty-one patients treated with epoprostenol and no patients receiving conventional therapy showed improved New York Heart Association functional class. Borg Dyspnea Scores and Dyspnea-Fatigue Ratings improved in the epoprostenol group. Trends toward greater improvement in severity of the Raynaud phenomenon and fewer new digital ulcers were seen in the epoprostenol group. Four patients in the epoprostenol group and five in the conventional therapy group died (P value not significant). Side effects of epoprostenol therapy included jaw pain, nausea, and anorexia. Adverse events related to the epoprostenol delivery system included sepsis, cellulitis, hemorrhage, and pneumothorax (4% incidence for each condition). CONCLUSIONS: Continuous epoprostenol therapy improves exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary hypertension due to the scleroderma spectrum of disease.     

Recurrent noncardiac pulmonary edema accompanying pregnancy-induced hypertension

Severe pulmonary edema occurred in a patient during the third trimester of two consecutive pregnancies, 17 months apart. Noncardiac origin of the pulmonary edema was demonstrated by normal pulmonary capillary wedge pressures, normal roentgenographic cardiac dimensions with absence of effusions, normal echocardiographic ejection fraction, and elevated thermodilution cardiac outputs; moderate reduction in serum albumin levels may have contributed. In the setting of pregnancy-induced hypertension, the development of ARDS on each occasion suggests a pathophysiologic link.     

Nesiritide: past, present, and future

B-type natriuretic peptide (BNP) is an endogenous cardiac neurohormone, produced in the ventricles in response to pressure and volume elevation. Nesiritide is identical to endogenous BNP and is synthesized using recombinant DNA technology. It is currently used in the treatment of acute decompensated heart failure. In clinical trials, nesiritide has been shown to decrease pulmonary capillary wedge pressure, pulmonary artery pressure, right atrial pressure, and systemic vascular resistance, as well as increase cardiac index and stroke volume index. Infusions of nesiritide have led to increased diuresis and natriuresis. Patients treated with nesiritide have reported improvements in global clinical status, dyspnea, and fatigue. Therapy with nesiritide has resulted in decreased plasma renin, aldosterone, norepinephrine, and endothelin-1 levels, as well as reduced ventricular ectopy and ventricular tachycardia. Heart rate variability also improved with nesiritide. Patients with acute coronary syndromes, serious arrhythmia, renal disease, diastolic dysfunction, or vasopressor dependence have been safely managed with nesiritide. Early treatment with nesiritide in the emergency department may lead to decreased length of hospital stay and reduced readmission rates compared to standard care. Outpatient serial infusions of nesiritide in severe heart failure patients on optimal medical therapy may result in improved clinical status, increased ejection fraction, reduced aldosterone and endothelin-1 levels, and decreased hospitalizations. Potential future uses of nesiritide include treatment of acute coronary syndromes, pulmonary hypertension, bronchospasm in chronic lung disease, and as antifibrotic/anti-remodeling therapy or bridge to cardiac transplant. The possibility of subcutaneous injections of nesiritide has been studied in both animals and humans.     

Acute circulatory failure caused by primary pulmonary hypertension or pulmonary embolism

Patients with acute massive pulmonary embolism or primary pulmonary hypertension may develop acute circulatory failure and are therefore admitted in the intensive care. The mortality rate of patients with pulmonary embolism and shock varies between 25 and 35% whereas the corresponding figure in patients with submassive embolism is less than 10%. Spiral computed tomography may be the most convenient test for diagnosing pulmonary embolism in the setting of acute circulatory failure. In the few patients who remain unstable despite adequate symptomatic treatment, transthoracic echocardiography combined with clinical judgement is appropriate. Inotropic support and thrombolytic therapy are clearly indicated for patients with massive embolism and shock. The role of the latter is more controversial in patients with right ventricular distension and normal blood pressure. The optimal duration of anticoagulant therapy for pulmonary embolism remains to be defined. Most patients are adequately treated with a six-month course of oral anticoagulants. A shorter duration may be sufficient when a transient risk factor is the cause of the initial event whereas patients with cancer or antithrombin deficiency may require a life long treatment. Primary pulmonary hypertension is a much more uncommon disease which can also lead to right ventricular failure. Symptomatic treatment combines oxygen, inotropic drugs, as well as the optimisation of right ventricular filling pressure. Specific treatment includes inhaled nitric oxide or intravenous epoprostenol followed by anticoagulants with either calcium channel blockers in patients responding acutely to vasodilators or a continuous infusion of epoprostenol in those who do not respond to acute challenge or who are not improving with calcium channel blockers. Although the long term survival has markedly improved as a result of epoprostenol treatment, some patients with refractory primary pulmonary hypertension remain candidates for lung transplantation.     

The effect of chronic pulmonary hypertension on left ventricular size, function, and interventricular septal motion

The effect of right ventricular pressure overload secondary to chronic pulmonary arterial hypertension on left ventricular size and function and on interventricular septal motion was studied in 13 patients in whom coronary artery disease, hypertension, and hypoxemia were excluded. Regional and global left ventricular function were assessed by computer-assisted analysis of two-dimensional directed M-mode echocardiograms obtained within 24 hours of a hemodynamic study. Septal position and motion were further analyzed by delineating seven points along the right and left sides of the septum during a single cardiac cycle. All echocardiographic data were compared to those of 10 normal subjects. Mean values for right ventricular systolic, mean pulmonary artery and pulmonary capillary wedge pressures were: 71 +/- 26 mm Hg, 46 +/- 16 mm Hg, and 7 +/- 1 mm Hg, respectively. Septal motion was interpreted from the M-mode echocardiograms as normal in seven patients (group I) and abnormal in the remaining six patients (group II). The only hemodynamic parameter which distinguished these two patterns was delta P, the transseptal systolic pressure gradient across the interventricular septum, which was significantly different (p less than 0.02) in group I (delta P = 65 +/- 16 mm Hg) from that of group II (delta P = 21 +/- 24 mm Hg). As a result of abnormal septal position, the septal-free wall dimensions of the left ventricle were reduced, but there was no evidence of depressed left ventricular performance in these patients. We conclude that resting left ventricular function is well preserved in patients with pulmonary hypertension, despite significant alterations in septal position and left ventricular size.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disproportionate pulmonary hypertension in a patient with early-onset pulmonary emphysema treated with specific drugs for pulmonary arterial hypertension

Severe pulmonary hypertension in chronic obstructive pulmonary disease (COPD) is referred to as 'disproportionate' because the elevated pulmonary artery pressure does not match the degree of air flow limitation. We report a 41-year-old man presenting with early-onset pulmonary emphysema and pulmonary hypertension with a mean pressure of 74 mmHg. Continuous intravenous epoprostenol led to marked hemodynamic improvement, and epoprostenol was successfully replaced with bosentan. The patient has been followed for 3 years without exacerbation. This is the first report demonstrating the long-term efficacy of specific drugs for pulmonary arterial hypertension in disproportionate pulmonary hypertension in COPD.     

Epoprostenol in chronic thromboembolic pulmonary hypertension with distal lesions.

BACKGROUND: Although patients with primary pulmonary hypertension and patients with chronic thromboembolic pulmonary hypertension with distal lesions may share similar pathophysiological characteristics, scarce information is available on the usefulness of epoprostenol in this form of secondary pulmonary hypertension. The aim of this study was to evaluate the feasibility, safety and efficacy of epoprostenol therapy in surgically untreatable patients with chronic thromboembolic pulmonary hypertension. METHODS: Continuous infusive therapy with epoprostenol was undertaken in 16 patients with primary pulmonary hypertension and in 11 surgically untreatable thromboembolic pulmonary hypertension patients. The median follow-up was 12.4 months (range 6-23 months). Patients underwent clinical, echocardiographic and hemodynamic evaluation at baseline and a 6-min walk test every 3 months after beginning epoprostenol; ultrasound evaluations were repeated in a subgroup of patients. RESULTS: Epoprostenol therapy improved the clinical status, exercise tolerance and NYHA functional class. A greater left ventricular end-diastolic volume was recorded at echocardiography in both groups. CONCLUSIONS: Epoprostenol therapy may be feasible, safe and clinically effective in patients with surgically untreatable chronic thromboembolic pulmonary hypertension.     

Effect of nesiritide in isolated right ventricular failure secondary to pulmonary hypertension

Treatment of right ventricular failure (RVF) can be challenging due to the correlation between RVF and worsening renal function with diuretic therapy. Nesiritide has been studied in patients with left ventricular failure but has not been evaluated in isolated RVF. The authors retrospectively analyzed 140 patients admitted with RVF, pulmonary hypertension (PH), and preserved left ventricular systolic function. Seventy patients were treated with nesiritide while the remaining patients received only furosemide (no nesiritide group). Serum creatinine and GFR at baseline, 72?hours, discharge, and 1?month post-treatment, as well as hemodynamic data were compared between the groups. In the nesiritide group, there was a significant decrease in mean GFR (42.77±25.33, P<.001) at day of discharge and 1?month post-nesiritide infusion (41.17±24.94, P<.001) but not in the no nesiritide group. There was a significant difference in >25% decrease in GFR anytime through day 30 (47.14% vs. 25.71%, P=.036) between the two groups. On multivariate analysis, nesiritide remained an important predictor of renal function at discharge and at 1?month (P<.01) as well as a predictor of >25% decrease in GFR anytime through day 30 (P=.007). Thus, nesiritide is associated with worsening kidney function in patients with RVF in the setting of PH.     

Nesiritide acutely increases pulmonary and systemic levels of nitric oxide in patients with pulmonary hypertension

BackgroundPulmonary hypertension (PH) is characterized by decreased pulmonary vascular expression of nitric oxide (NOx), a vasodilator that increases levels of smooth muscle cyclic guanosine monophosphate (cGMP). This study investigated mechanisms by which the vasodilator B-type natriuretic peptide (BNP) affects the systemic and pulmonary vasculature in PH patients.Methods and ResultsTwenty PH patients with mean pulmonary artery (PA) pressure >25 mm Hg were enrolled. Ten had precapillary (pulmonary capillary wedge pressure [PCWP] ≤15 mm Hg) and 10 had postcapillary (PCWP >15 mm Hg) PH. Right heart catheterization was performed before and 30 minutes after intravenous nesiritide infusion. NOx and cGMP levels from the PA and systemic (AO) arteries were obtained before and after nesiritide infusion. The postcapillary PH patients demonstrated significantly reduced pulmonary vascular resistance after nesiritide; there was no change in the precapillary PH cohort. NOx levels increased significantly in both AO (P < .0001) and PA (P = .0093), as did cGMP levels (P < .0001). There was a higher increase in NOx levels from the pulmonary arteries in precapillary PH patients compared to postcapillary PH patients (P = .020).ConclusionIn PH patients, nesiritide infusion significantly increases NOx levels, suggesting a novel mechanism for its vasodilatory effects. These responses may differ between pre- and postcapillary PH patients.     

Cyclic changes in pulmonary wedge v waves in dilated cardiomyopathy

Right and left cardiac catheterization was performed in a 29-year-oldmale with dilated cardiomyopathy. During the procedure, prominentv waves appeared spontaneously in the pulmonary capillary wedgepressure recording with a simultaneous decrease in left ventricularsystolic pressure. Left ventricular angiography showed moderateto severe mitral regurgitation and an ejection fraction of 22%.The right ventricular endomyocardial biopsy revealed histologicalfindings consistent with dilated cardiomyopathy. Cardiac catheterization was repeated 9 months later, after aperiod of clinical improvement and a reduction in the rightand left ventricular filling pressures was documented. The cyclicswings in the pulmonary capillary wedge pressure and in theleft ventricular systolic pressure were not observed. Left ventriculographyshowed mild mitral regurgitation with an ejection fraction of37%. Right ventricular endomyocardial biopsy documented a reductionin myofibrillar and nuclear hypertrophy. Thus, cyclic changesin pulmonary wedge v waves may be observed in dilated cardiomyopathy.This finding is consistent with cyclic variations in the degreeof mitral regurgitation. Disappearance of this factor seemsto be related to improvement in left ventricular contractility.     

Sildenafil decreased pulmonary arterial pressure but may have exacerbated portal hypertension in a patient with cirrhosis and portopulmonary hypertension

Portopulmonary hypertension is a recognized but uncommon complication of cirrhosis. Liver transplantation may be contraindicated in patients with severe portopulmonary hypertension. In order to decrease the pulmonary arterial pressure, intravenous administration of epoprostenol has been shown to provide substantial beneficial results in these patients. Additionally, a recent case report demonstrated that long-term oral administration of sildenafil decreased pulmonary arterial pressure, but its effects on splanchnic hemodynamics were not measured. We report on a patient with cirrhosis and portopulmonary hypertension and the changes in the hemodynamic status after an oral administration of sildenafil. This case report clearly delineates that sildenafil decreases pulmonary arterial pressure but may exacerbate portal hypertension and hyperdynamic circulation in patients with cirrhosis and portopulmonary hypertension.     

Epoprostenol for treatment of pulmonary hypertension in patients with systemic lupus erythematosus

OBJECTIVE: Pulmonary hypertension with pathological changes similar to those observed in primary pulmonary hypertension occurs in patients with systemic lupus erythematosus (SLE). The efficacy of chronic epoprostenol therapy in SLE has not been well described. The objective of this paper is to describe our experience with long-term epoprostenol therapy in patients with pulmonary hypertension associated with SLE. DESIGN: Case series of six patients with SLE and associated pulmonary hypertension receiving chronic treatment with epoprostenol. RESULTS: All 6 patients had severe pulmonary hypertension. Mean pulmonary artery pressure (mPAP) was 57 +/- 9 mm Hg (mean +/- SD), and pulmonary vascular resistance was 14 +/- 7 units before beginning therapy with epoprostenol. In 4 patients who underwent repeat hemodynamic evaluation (9 to 16 months after starting epoprostenol), mean pulmonary artery pressure decreased by 38 +/- 21% and pulmonary vascular resistance by 58 +/- 12%. Clinically, all patients improved from New York Heart Association class III or IV to class I or II. Doses of epoprostenol ranged from 4 to 46 ng/kg/min, and the longest duration of therapy has been 2.5 years. Side effects from epoprostenol have not differed from those seen in patients with primary pulmonary hypertension, and except for one patient, there has been no exacerbation of SLE. CONCLUSION: Epoprostenol was effective for the treatment of pulmonary hypertension in this small group of patients with SLE. Further evaluation of epoprostenol therapy for patients with SLE and other diseases associated with pulmonary hypertension is warranted.     

Left ventricular failure produces profound lung remodeling and pulmonary hypertension in mice: heart failure causes severe lung disease

Chronic left ventricular failure causes pulmonary congestion with increased lung weight and type 2 pulmonary hypertension. Understanding the molecular mechanisms for type 2 pulmonary hypertension and the development of novel treatments for this condition requires a robust experimental animal model and a good understanding of the nature of the resultant pulmonary remodeling. Here we demonstrate that chronic transverse aortic constriction causes massive pulmonary fibrosis and remodeling, as well as type 2 pulmonary hypertension, in mice. Thus, aortic constriction-induced left ventricular dysfunction and increased left ventricular end-diastolic pressure are associated with a ≤5.3-fold increase in lung wet weight and dry weight, pulmonary hypertension, and right ventricular hypertrophy. Interestingly, the aortic constriction-induced increase in lung weight was not associated with pulmonary edema but resulted from profound pulmonary remodeling with a dramatic increase in the percentage of fully muscularized lung vessels, marked vascular and lung fibrosis, myofibroblast proliferation, and leukocyte infiltration. The aortic constriction-induced left ventricular dysfunction was also associated with right ventricular hypertrophy, increased right ventricular end-diastolic pressure, and right atrial hypertrophy. The massive lung fibrosis, leukocyte infiltration, and pulmonary hypertension in mice after transverse aortic constriction clearly indicate that congestive heart failure also causes severe lung disease. The lung fibrosis and leukocyte infiltration may be important mechanisms in the poor clinical outcome in patients with end-stage heart failure. Thus, the effective treatment of left ventricular failure may require additional efforts to reduce lung fibrosis and the inflammatory response.