Hypertension In Connective Tissue Disease Research Articles

Pulmonary hypertension in connective tissue diseases: epidemiology, pathogenesis, and treatment.

Pulmonary hypertension (PH) is a clinical condition characterized by increased pulmonary arterial pressure arising from a heterogeneous range of diseases that has a deteriorating effect on the quality of life and may cause early mortality if left untreated. Connective tissue disorders (CTD)-associated PH is the second most common cause of pulmonary arterial hypertension (PAH), after the idiopathic form, categorized as group I. Systemic scleroderma (SSc) accounts for 75% of CTD-associated PH cases. Although SSc ranks first place for CTD-associated PH, SSc is followed by systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD), having a lesser frequency of PH occurrence, while it occurs as a rare complication in cases with rheumatoid arthritis (RA) and inflammatory myositis. PH may also occur during non-SSc CTDs and even other rheumatic diseases, including Behcet's disease and adult-onset Still's disease, albeit to a lesser extent. The prognosis of CTD-associated PH is worse than the other forms of PH. Although, as in idiopathic pulmonary arterial hypertension (IPAH), the mechanism of CTD-related PH is associated with an increase in vasoconstrictors like endothelin-1 and a decrease in vasodilators like prostacyclin and nitric oxide production, inflammation, and autoimmune mechanisms also play a role in the development and progression of PH. This may lead to the involvement of more than one mechanism in CTD-associated PH. Knowing which mechanism is dominant is very important in determining the treatment option. This review will primarily focus on the epidemiology, risk factors, and prognosis of PH that develops during rheumatic diseases; the pathogenesis and treatment will be briefly mentioned in light of the newly published guidelines. Key Points • Pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) in Western countries is the second most common type of PAH after idiopathic PAH (IPAH). • CTD-PH can be seen most often in systemic scleroderma (SSc), less in systemic lupus erythematosus (SLE), mixed CTD (MCTD), and rarely in other CTDs. • While current guidelines recommend annual transthoracic echocardiography as a screening test for asymptomatic SSc patients, screening for PH is not advised in the absence of symptoms suggestive of PH in other CTDs. • CTD-PH treatment can be divided into specific vasodilator PH treatments and immunosuppressive therapy. Current treatment guidelines recommend the same treatment algorithm for patients with CTD-associated PH as for patients with IPAH. Several case series have shown the beneficial effect of immunosuppressive agents in patients with SLE-PH and MCTD-PH.

Hypertension in connective tissue disease.

It is well documented that connective tissue disease (CTD) is a type of autoimmune disease characterized by chronic inflammation, which can occur across various organ systems throughout the whole body. Although the clinical manifestations of CTD are different, studies have shown that different CTD diseases have similar pathogenesis, implying that different CTD diseases may have similar clinical outcomes. Recent population-based studies have demonstrated an increased risk of cardiovascular disease (CVD) in patients with CTD compared with the control group, which is partially attributed to traditional cardiovascular risk factors, such as hypertension (HT), and that controlling the patients' blood pressure (BP) still constitutes one of the most effective means to prevent CVD. Although many studies have shown that the prevalence of HT in patients with CTD is higher than that in the general population, there is a lack of adequate data on the possible pathogenesis of HT. Also, the factors that promote the rise of BP, especially the relationship between connective tissue disease- hypertension (CTD-HT) and traditional cardiovascular risk factors (aging, sex, race, dyslipidemia, diabetes mellitus, smoking, obesity, etc.), have not been fully confirmed. In this review, we explore the mechanisms that might lead to elevated BP in patients with CTD and the factors that contribute to elevated BP and the management of CTD-HT, and we focus on whether traditional cardiovascular risk factors, the disease, and the presence of related therapeutic drugs are associated with an increased risk of HT in patients with CTD.

Quality of life in ambulatory pulmonary arterial hypertension in connective tissue diseases and its relationship with risk stratification.

The Pulmonary Arterial Hypertension Symptoms and Impact Questionnaire (PAH-SYMPACT) is a PAH-specific patient-reported outcome scale assessing patients’ quality of life from four aspects: cardiopulmonary symptoms, cardiovascular symptoms, physical impacts and cognitive/emotional impacts. This study aimed to validate the Chinese version of PAH-SYMPACT and explore its relationship with risk stratification in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH). In addition, 75 patients with CTD-PAH confirmed by right heart catheterization were invited to complete questionnaires including PAH-SYMPACT, the 36-item Medical Outcomes Study Short Form Survey (SF-36) and EuroQol five dimensions questionnaire (EQ-5D). The demographic, clinical, laboratory and treatment data were collected. The endpoint was treatment goal achievement status in 6–12 months after completing the questionnaires, defined as an integrated outcome. Participants’ mean age was 36.4 ± 11.9 years and the mean pulmonary arterial pressure was 38.9 ± 13.67 mmHg. The reliability of the PAH-SYMPACT domains ranged from 0.83 to 0.88. Results of factor analysis basically conformed the original PAH-SYMPACT. The treatment goal achievement (TGA) status in 6–12 months was significantly associated with physical impacts scores (odds ratio: 0.180, 95% confidence interval: 0.036–0.908, P=0.038). The Chinese version of PAH-SYMPACT is a reliable measurement to evaluate quality of life in CTD-PAH patients and is also a potential predictor of patient’s condition change in routine clinical practice.

Pulmonary hypertension in connective tissue diseases, new evidence and challenges.

Pulmonary arterial hypertension is a lethal complication of different connective tissue diseases such as systemic sclerosis, mixed connective tissue disease and systemic lupus erythematosus. Although the treatment possibilities for patients with pulmonary arterial hypertension have increased in the last two decades and survival of patients with idiopathic pulmonary arterial hypertension has improved, the latter is not the case for patients with pulmonary arterial hypertension associated with connective tissue disease. In this narrative review, we review recent literature and describe the improvement of early diagnostic possibilities, screening modalities and treatment options. We also point out the pitfalls in diagnosis in this patient category and describe the unmet needs and what the focus of future research should be.

Genetic Background of Hypertension in Connective Tissue Diseases.

Peroxisome proliferator-activated receptors (PPAR gamma-2) and beta-3-adrenergic receptors (ADRB3) are involved in the risk of hypertension. But their exact role in blood pressure modulation in patients with connective tissue diseases (CTD) is still not well defined. In this study, 104 patients with CTD and 103 gender- and age-matched controls were genotyped for Pro12Ala and C1431T polymorphisms of the PPAR gamma-2 gene and Trp64Arg polymorphism of the ADRB gene. Anthropometric and biochemical measurements were evaluated, followed by genotyping using TaqMan® SNP genotyping assays and polymerase chain reaction-restriction fragment length polymorphism. The prevalence of analyzed genotypes and alleles was comparable between patients with CTD and the control group, as well as hypertensive and normotensive subjects. Patients with CTD have lower body fat and higher body water amount, serum glucose, and triglyceride (TG) levels. Hypertensive subjects are older and have higher body mass, BMI, waist circumference (WC), body water content, glucose, and TG concentration. The multivariate analysis revealed that hypertensive subjects with Ala12/X or Trp64Trp have higher body mass and WC when compared to normotensive subjects. Trp64Trp polymorphism was also characterized by a higher TG level, while T1431/X subjects had higher WC. The presence of CTD, visceral fat distribution, and increased age are the predictors of hypertension development. Hypertensive patients with CTD and Trp64Trp polymorphism have an increased risk of visceral obesity development and metabolic complications, which in turn affects the value of blood pressure. In addition, either Ala12/X or T1431/X predicts the visceral body fat distribution in hypertensive subjects.

Early Detection of Pulmonary Hypertension in Connective Tissue Disease

Early Detection of Pulmonary Hypertension in Connective Tissue Disease

Pulmonary Hypertension in Connective Tissue Disease is Associated with the New York Heart Association Functional Class and Forced Vital Capacity, But Not with Interstitial Lung Disease

Pulmonary Hypertension in Connective Tissue Disease is Associated with the New York Heart Association Functional Class and Forced Vital Capacity, But Not with Interstitial Lung Disease

Pulmonary hypertension in connective tissue diseases: an update.

Pulmonary hypertension (PH) is a relatively commoner complication of systemic sclerosis (SSc) with estimated prevalence ranging between 8% and 12% as compared to much lower figures in other connective tissue diseases (CTD). It is a major cause of morbidity and mortality in CTDs. PH is classified into five major groups. CTD-associated PH belongs to group 1 PH, also known as pulmonary arterial hypertension (PAH). Around 30% of scleroderma-related deaths are due to PAH. Underlying pathogenesis is related to pulmonary vasculopathy involving small vessels. The Evidence-based Detection of Pulmonary Arterial Hypertension in Systemic sclerosis (DETECT) algorithm outperforms the current European Society of Cardiology/European Respiratory Society guidelines as a screening tool in SSc-PAH; it can, therefore, suggest when to refer a patient for right heart catheterization. CTD-PAH patients constitute at least 20% of patients included in all major trials of PH-specific therapy and the results are comparable to those of idiopathic PAH. The role of anticoagulation in CTD-PAH is associated with a high risk-benefit ratio with the caveat of its potential role in those with severe disease. There appears to be no role of immunosuppression in scleroderma-PAH; however, immunosuppressive agents, namely the combination of glucocorticoids and pulse cyclophosphamide / possibly mycophenolate, may result in clinical improvement in a subset of patients with systemic lupus erythematosus and mixed connective tissue disease-related PAH.

Review of the diagnosis and pharmacological management of pulmonary arterial hypertension in connective tissue disease

AbstractConnective-tissue-disease-associated pulmonary arterial hypertension (CTD-PAH) is a well-recognised pulmonary complication most commonly seen in patients with systemic sclerosis, followed by systemic lupus erythematosus and mixed connective tissue disease. In systemic-sclerosis-associated-pulmonary arterial hypertension (SSc-PAH), patients usually present late and the progression can be rapid with poor prognosis and survival. Early detection and prompt intervention of SSc-PAH is an important cornerstone to halt the disease progression. Various pulmonary vasodilatory agents were developed over the past two decades. They were shown to improve patients’ symptoms, functional status, exercise capacity, haemodynamics and long-term survival. Other immunosuppressive therapies also demonstrated to improve symptoms and functional status in certain group of patients. This article is to review the diagnosis and pharmacological management of patient with CTD-PAH.

Screening and Early Detection of Pulmonary Arterial Hypertension in Connective Tissue Diseases. It Is Time to Institute It!

Screening and Early Detection of Pulmonary Arterial Hypertension in Connective Tissue Diseases. It Is Time to Institute It!

Isolated pulmonary hypertension in connective tissue disease

Isolated pulmonary hypertension in connective tissue disease

GW25-e0152 Effect of Th17 and Treg Axis Disorder on Outcomes of Pulmonary Arterial Hypertension in Connective Tissue Diseases

This prospective cohort study is to verify the hypothesis that the balance of Th17 and Treg cells frequencies in the peripheral circulation is disturbed in patients with varying degrees of connective tissue diseases-associated pulmonary arterial hypertension (CTD-aPAH), and to prove the influence of

Effect of Th17 and Treg axis disorder on outcomes of pulmonary arterial hypertension in connective tissue diseases.

This prospective cohort study is to verify the hypothesis that the balance of Th17 and Treg cells frequencies in the peripheral circulation is disturbed in patients with varying degrees of connective tissue diseases-associated pulmonary arterial hypertension (CTD-aPAH) and to prove the influence of Th17/Treg imbalance on prognosis. We detected the frequencies and absolute counts of Th17 and Treg cells and related serum cytokines secretion and expressions of key transcription factors in 117 patients with connective tissue diseases (CTD), 53 patients with CTD-aPAH, and 48 healthy volunteers. Moreover, the median value according to levels of Th17/Treg ratios in patients with CTD-aPAH was chosen as basis of group division for survival analysis. CTD-aPAH patients revealed significant increase in peripheral Th17 cells, Th17-related cytokines, and ROR γt mRNA levels. They also presented a significant decrease in Treg cells, Treg-related cytokines, and Foxp3 mRNA levels as compared with CTD patients and healthy controls. More importantly, the Th17/Treg ratio was significantly related to the severity and prognosis of CTD-aPAH. This study indicated that the Th17/Treg axis disorder plays a critical role in CTD-aPAH. Furthermore, the dynamic balance between Th17 and Treg cells was likely to influence prognosis of patients with CTD-aPAH.

SAT0192 High Frequency of Left-Sided Heart Diseases as an Important Cause of Pulmonary Hypertension in Connective Tissue Diseases

BackgroundPulmonary hypertension (PH) is one of the fatal complications in the connective tissue disease (CTD).(1) CTD-associated pulmonary hypertension (CTD-PH) is sometimes associated with left heart disease and interstitial lung disease...

THU0056 A Small Chemical Compound Identified as an ACE2 Activator Prevented Pulmonary Arterial Hypertension Induced by Monocrotaline

BackgroundPulmonary arterial hypertension (PAH) is a lethal clinical symptom characterized by progressive increase in pulmonary arterial pressure and causes right ventricular hypertrophy (RVH) with RV failure. Complications of PAH are...

Pulmonary Arterial Hypertension in Connective Tissue Diseases

Pulmonary arterial hypertension (PAH) may complicate diverse connective tissue diseases (CTDs). Approximately 10% of patients with systemic sclerosis develop PAH, the prevalence being much lower in other CTDs. However, PAH is an important contributor to morbidity and mortality in all forms of CTD. Despite similarities in presentation, hemodynamic perturbations, and pathogenesis, patients with CTD-associated PAH (CTD-PAH) usually have a poorer response to PAH-specific medications and poorer prognosis than patients with idiopathic PAH (IPAH). Select patients with CTD-PAH may be candidates for lung transplantation, but results are less favorable than for IPAH because of comorbidities and complications specifically associated with CTD.

Treatment of Pulmonary Arterial Hypertension in Connective Tissue Disease

Pulmonary arterial hypertension (PAH) is a group of distinct disorders that includes idiopathic PAH (IPAH), familial PAH and PAH associated with other conditions (APAH) such as connective tissue disease (CTD-APAH) or congenital heart disease. PAH is characterized by increased pulmonary arterial pressure and pulmonary vascular resistance. If left untreated, PAH can lead to right heart failure and premature death. CTD-APAH represents an important clinical subgroup of APAH that has a higher risk of death than IPAH. The European treatment guidelines advocate the use of PAH-targeted therapies including bosentan, ambrisentan, sildenafil, inhaled iloprost, intravenous epoprostenol (I-A recommendations), tadalafil or treprostinil (I-B recommendations) for patients in WHO functional class II-III. Not all randomized clinical studies of the approved PAH-targeted therapies have included patients with CTD-APAH. The purpose of this review is to describe the clinical characteristics of CTD-APAH and discuss the approved pharmacological treatments, with a focus on data specific to this subgroup where possible.

Pulmonary Arterial Hypertension in Connective Tissue Diseases

Pulmonary hypertension (PH) was found to be the primary cause of death in mixed connective tissue disease (MCTD). This led to investigation of the prevalence of PH in other connective tissue diseases (CTD). In 1998, the Ministry of Health and Welfare's MCTD Research Committee revealed complication of PH diagnosed by physicians in 5.02% MCTD patients, 0.90% systemic lupus erythematosus patients, 2.64% systemic sclerosis patients, and 0.56% polymyositis/dermatomyositis patients. These results have been supported by a similar survey performed in North America. As quite a few rheumatologists find right heart catheterization difficult to perform, doppler echocardiography is frequently used for screening and diagnosing PH. The MCTD Research Committee set the revised criteria for MCTD-PH, in which the threshold of estimated pulmonary arterial systolic pressure value for diagnosis of pulmonary arterial hypertension (PAH) is set at 36 mmHg, as proposed by the European Society of Cardiology. Right heart catheterization is strongly recommended for commencing the treatment. Since PH due to thromboembolism can potentially be cured surgically, lung perfusion scintigraphy should be performed for all patients diagnosed with PH. Most CTD-PH are PAH, and since idiopathic PAH (IPAH) patients sometimes have immune disorders, treatment for IPAH may be applicable to CTD-PH. The greatest difference between the treatment strategy for CTD-PH and IPAH is the usage of corticosteroids and other immunosuppressants. The MCTD Research Committee updated its therapeutic guidelines for MCTD-PH in 2011. Validation of these guidelines is also needed.

A Histopathological Study of Pulmonary Hypertension in Connective Tissue Disease

Connective tissue diseases (CTD), such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCTD), develop pulmonary hypertension (PH). Generally all PH cases associated with any CTD are classified into the same PH group. However, histological examination shows both common and specific lesions for each disease. In patients with SLE, fibrosis is generally rare and mild. The findings of PH in SLE are similar to those in primary pulmonary hypertension. Many cases of SSc are accompanied by fibrosis. MCTD is rather close to SSc. Arterial and arteriolar lesions of MCTD are characterized by fibrous intimal thickening. In this review, we describe the pathological features of PH associated with each CTD.

2009 ESC/ERS Pulmonary Hypertension Guidelines and Connective Tissue Disease

Pulmonary hypertension was defined as mean pulmonary artery pressure ≥ 25 mmHg at the 4th World Symposium on Pulmonary Hypertension. In 2009, the European Society of Cardiology and European Respiratory Society jointly created guidelines for practical pulmonary hypertension classifications and treatments based on the discussions at the 4th World Symposium. This classification is characterized by division into five groups: Pulmonary arterial hypertension (PAH); Pulmonary hypertension due to left heart disease; Pulmonary hypertension due to lung disease and/or hypoxia; Chronic thromboembolic pulmonary hypertension; and Pulmonary hypertension with unclear and/or multifactorial mechanisms. PAH is a common and fatal complication of connective tissue disease (CTD), but pulmonary hypertension in CTD consists of PAH, pulmonary hypertension caused by myocardial involvement, pulmonary veno-occlusive disorder, pulmonary hypertension due to interstitial lung disease. PAH has been studied widely in SSc and the estimated prevalence of 7-12%. Treatment of CTD associated PAH (CTD-PAH) consists of general therapeutic options and specific treatment. Specific treatment of CTD-PAH patients is targeted to produce vasodilatation. Calcium channel blockers (CCBs) are indicated in cases where a sufficient decrease in pulmonary arterial pressure is seen in vasoreactivity testing. If vasoreactivity is absent in CTD-PAH patients, the treatment consists of the endothelin receptor antagonists, the prostacyclin analogues and phosphodiesterase-type 5 inhibitors. Few data are available to support the use of immunosuppression in CTD-PAH. However, some case reports suggested that a minority of CTD-PAH patients could benefit from immunosuppressive therapy. The treatment of CTD-PAH patients may differ from the treatment of idiopathic PAH.