The association between obesity and pulmonary hypertension: a tale of two diseases

PVRI Member Authors: Mamotabo Rossy Matshela

 Introduction

Obesity is a complex metabolic disorder often associated with multiple systemic and cardiovascular diseases which contribute to increased morbidity and mortality. Although the relationship between obesity and systemic hypertension has been well reported, its relationship with pulmonary hypertension (PH) is only emerging. However, as there are still some conflicting reports regarding the association between PH and obesity, it is worth reviewing the interaction between the two. Indubitably, the prevalence of obesity in the USA has increased substantially in the last 10 years, yet this seems to have leveled off between the years 2003 and 2010.1-3 The purpose of this paper is to briefly discuss the association between obesity and pulmonary hypertension, postulated pathophysiological mechanisms linking obesity with PH, and general evaluation and treatment of PH in obesity.

Pulmonary hypertension

 Pulmonary hypertension is defined by a mean pulmonary artery pressure of at least 25mmHg at rest or 30mmHg with exertion based on right heart catheterization. PH is classified according to the Dana Point classification, which was developed at the 4th WHO world symposium in 2008. This classification constitutes of five different groups, as follows: Group 1 is mainly pulmonary arterial hypertension (PAH), and this group responds well to specific pulmonary vascular remodeling agents; Group II is pulmonary hypertension due to left heart disease; Group III is PH to lung diseases or chronic hypoxia; Group IV is chronic thromboembolic pulmonary hypertension (CTEPH); and Group V focuses on pulmonary hypertension related to unclear multifactorial mechanisms. Extensive discussion of this classification will not be covered in this short review paper.

Coexistence of obesity and pulmonary hypertension

Even though data are still limited on the prevalence of pulmonary hypertension as the consequence of obesity, the relationship between obesity and right ventricular dysfunction is reported as a result of pulmonary hypertension. There are multiple postulated mechanisms linking manifestations of obesity in some patients. However, it is vital to consider other potential etiologies of PH in these patients, as obesity is commonly associated with co-morbidities which could potentially be the primary case of pulmonary hypertension.

Mechanisms of pulmonary hypertension

Due to the complexity of obesity, its impact is related to the structural changes in the pulmonary vascular system. However, some reports have documented immune and vascular cell accumulation within pulmonary arterial lumen, which is believed to be the most important mechanism in all types of pulmonary hypertension.

 1. Adiponectin deficiency: With regard to pulmonary arterial hypertension (PAH), PH is thought to be as the result of an imbalance between vasodilator and vasoconstrictor markers in the pulmonary vessels. Adiponectin has direct vasodilator activity and its deficiency is associated with impairment of vasodilatation which involves the pulmonary vessels, and the development of systemic hypertension.4-7 Currently there are more data strongly demonstrating an association between adiponectin deficiency and impaired vasoreactivity.4,8

2. Obesity associated hypoventilation syndrome: Obesity hypoventilation syndrome (OHS) occurs commonly in patients with at least moderate obesity, BMI > 35kg/m2 and is very rare in those with mild obesity.9 OHS associated mediators for pulmonary hypertension include diurnal hypoxemia, hypercapnia and acidosis; however, in severe obesity secondary contributors are found, which include restrictive lung disease related to the severity of obesity, and thoracic pressure changes during the respiratory cycle due to increased upper airway resistance. Obesity hypoventilation syndrome-induced chronic hypoxemia leads to pulmonary arterial remodeling, and over a period of time the pulmonary arterial hypertension changes from vasoconstriction to one of endothelial dysfunction, arterial wall thickening and fibrosis.10 Previous small studies demonstrated that OHS is commonly associated with more severe pulmonary hypertension than in patients with obstructive sleep apnea.11

3. Obstructive sleep apnea (OSA): OSA is a well-recognized cause of PH and characterized by recurrent obstructive episodes and daytime somnolence. Postulated pathophysiological mechanisms of pulmonary hypertension in OSA are related to repeated episodes of nocturnal hypoxemia, hypercapnia, acidosis, sympathetic hyperactivity and changes in thoracic pressure. All these episodes lead to pulmonary arterial vasoconstriction with subsequent pulmonary arteriolar remodeling.12

4. Drugs and toxins: Anorexigen has been associated with the development of pulmonary hypertension which is likely not reversible after discontinuing the drug. It was first reported in 1996, when the use of methamphetamine analogues were discontinued following a sixfold increase in the risk of pulmonary hypertension.10,13 Aside from PH, these analogues PVRI Chronicle: Volume 2 Issue 1 January - June 2015 were also linked to the development of cardiac valvular pathologies and cardiac fibrosis. These drugs, particularly fenfluramine and dexfenfluramine, inhibit a specific potassium channel and inhibition of the current lead to opening of an L-type calcium channel which is associated with pulmonary arterioles vasoconstriction.10,14 Most importantly, aminorex are also linked with an excessive release of serotonin precursors from platelets, and these precursors are associated with pulmonary vasoconstriction and mediation of smooth muscle proliferation.

 5. Obesity associated myocardial dysfunction: Obesity, and particularly morbid obesity, is linked to heart failure and current reports indicate a two-fold increase of congestive heart failure in obese patients. Severe obesity is commonly associated with diastolic dysfunction or diastolic heart failure. This generally leads to elevated left ventricular filling pressures with left heart failure syndrome, which consequently may increase pulmonary venous pressure, pulmonary arteriolar remodeling and fixed pulmonary vascular resistance over time. Obesity-associated pulmonary hypertension secondary to myocardial dysfunction could be explained on the basis of myocardial steatosis, which bears some similarities to hepatic steatosis and could also be ascribed to excessive left ventricular (LV) volume load in severe obesity.10 It is very important to address other associated contributors which could explain LV myocardial dysfunction in obese patients i.e. insulin resistance, sympathetic tone overactivity, renin-angiotensin system activity and pre-existing endothelial dysfunction from other potential etiologies.10,15

6. Chronic thromboembolic disease: There are multiple postulated prothrombotic mechanisms which are linked to the occurrence of pulmonary hypertension in obesity. There is a strong literature link between obesity and insulin resistance with thrombotic and thrombo-embolic phenomenon, and these include deep venous thrombosis and pulmonary embolism.16-18 In addition, a sedentary lifestyle, chronic low grade inflammation and OSA are well recognized risk factors and are linked to obesity and venous thrombi.10,19-21

7. Associated metabolic disorders: endothelial dysfunction is a well-known link in the development of pulmonary hypertension in a handful of pathological states. Insulin resistance is one important mechanism and should be attended to, as the treatment of insulin resistance with insulin sensitizing drugs does reverse pulmonary hypertension in obese patients.10,22,23 Hyperuricemia is also associated with endothelial dysfunction, and an important pathological mediator of PH.24,25

Management

The general approach to the evaluation of PH in obese patients bears no differences to nonobese patients. Both groups will have their full medical history taken, and together with a clinical examination, this forms the crucial basis for pulmonary hypertension evaluation in these patients. A careful diagnostic approach should be applied and this includes biochemical tests, imaging modalities and invasive measures. Although echocardiography is a useful tool with reasonable sensitivity and specificity for the estimation of pulmonary arterial pressure, right heart catheterization remains the gold standard.26 Additional tests may be warranted, although the decision will be guided by findings from the initial investigations, and will subsequently help guide further treatment.

Treatment

Pulmonary hypertension in obese patients should be managed with great caution. Weight reduction by different approaches has shown to be quite beneficial in reducing pulmonary arterial pressures and improving the functional capacity in these patients. Similarly, weight reduction by lifestyle modifications and surgical means, particularly in those with morbid obesity, has shown to be beneficial in improving left ventricular diastolic dysfunction.27,28 Therefore, specific therapy directed at additional risk factors and complications have been shown to improve diastolic dysfunction in these patients.

Drug therapies targeting certain areas have shown significant improvement in patients’ symptoms and functional capacities.29 Well studied drugs include phosphodiesterase inhibitors, endothelin receptor antagonists and prostanoids. Intravenous epoprostenol have been shown to reduce mortality in pulmonary hypertension.29 It is important that specific therapies in pulmonary hypertension are directed to additional or other co-morbidities or complications, based on the clinical classification of PH.

Summary and conclusion

 Obesity is a complex condition associated with cardiovascular complications, of which pulmonary hypertension should be considered in those with dyspnoea. The diagnostic approach for pulmonary hypertension in obese patients is similar to non-obese patients, as transthoracic echocardiography should be considered for the documentation of elevated pulmonary pressures and in assessing the severity and complications of the disease, in order to guide the management of the patient. Weight reduction is the treatment of choice with a variety of means which could be very effective in the managements of these patients. Other treatment modalities should be directed to the causes of pulmonary hypertension and complications thereof.

 

 

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Topics

Obesity and Metabolic Syndrome, Diabetes and Dyslipidemias, Glucose and Glycoproteins
Pulmonary Hypertension

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January 2015

PVRI Chronicle Vol 2: Issue 1

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