Elsevier

Progress in Cardiovascular Diseases

Volume 54, Issue 2, September–October 2011, Pages 154-167
Progress in Cardiovascular Diseases

Pulmonary Hypertension Associated With Left Heart Disease: Characteristics, Emerging Concepts, and Treatment Strategies

https://doi.org/10.1016/j.pcad.2011.06.003Get rights and content

Abstract

Left heart disease (LHD) represents the most common causes of pulmonary hypertension (PH). Whether caused by systolic or diastolic dysfunction or valvular heart disease, a hallmark of PH associated with LHD is elevated left atrial pressure. In all cases, the increase in left atrial pressure causes a passive increase in pulmonary pressure. In some patients, a superimposed active component caused by pulmonary arterial vasoconstriction and vascular remodeling may lead to a further increase in pulmonary arterial pressure. When present, PH is associated with a worse prognosis in patients with LHD. In addition to local abnormalities in nitric oxide and endothelin production, gene modifiers such as serotonin polymorphisms may be associated with the pathogenesis of PH in LHD. Optimizing heart failure regimens and corrective valve surgery represent the cornerstone of the treatment of PH in LHD. Recent studies suggest that sildenafil, a phosphodiesterase-5 inhibitor, is a promising agent in the treatment of PH in LHD. Unloading the left ventricle with circulatory support may also reverse severe PH in patients with end-stage heart failure allowing candidacy to heart transplantation.

Section snippets

Methodology

A search was performed in MEDLINE and PubMed for original articles published between 1950 and 2011 that focused on left-sided PH and heart failure (HF). The search term used included “secondary pulmonary hypertension,” “pulmonary hypertension,” “heart failure,” “post capillary pulmonary hypertension,” “pulmonary remodeling,” and “valvular heart disease.” The search was limited to articles in English and French. For this review, we chose selected articles that reflect recent development in the

Definition and classification of PH in LHD

The classification of PH has gone through a series of changes since the first classification was proposed in 1973 at an international conference on primary PH endorsed by the World Health Organization (WHO).3, 4 Pulmonary hypertension is classified into 5 groups according to the pathophysiology and hemodynamic characteristics of PH (Table 1). Pulmonary hypertension associated with LHD represents group II PH in the Dana Point classification (2008).3, 4 Decades ago, mitral valve disease was the

Pathogenesis of PH in LHD

The pathogenesis of PH in LHD is complex (Fig 3). In all cases, there is a passive component associated with increased left atrial pressure. In some patients, a superimposed active component caused by pulmonary arterial vasoconstriction and vascular remodeling may lead to a further increase in PAP.38, 39, 40, 41, 42

In patients with left HF, both diastolic dysfunction and mitral regurgitation may lead to an increase in left atrial pressure.41 While diastolic dysfunction is observed in patients

Epidemiology of PH in LHD

Pulmonary hypertension in LHD has been reported in specific patient populations with variable frequency, depending on the stage of the disease, the referral population, and the definition used.1, 2, 3, 4 Also, in echocardiographic-based studies, the reported prevalence of PH is limited to patients in whom RV systolic pressure (RVSP) can be estimated. Because patients with trace tricuspid regurgitation often have lower PAP, echocardiographic-based studies may overestimate the prevalence of PH.

In

Clinical significance

When present, PH is usually associated with a poor prognosis in patients with LHD. (Table 2, Table 3, Table 4).9, 10, 11, 12, 13, 14, 15, 17, 24, 39, 40, 71 Pulmonary hypertension is regarded as a good marker of prognosis as it incorporates information on diastolic function, mitral regurgitation and pulmonary vascular disease.

In most outcome studies in left HF, PH emerged as an independent prognostic factor. In the few studies that included RV function and diastolic parameters as covariates, PH

Diagnostic approach to PH

The first step in the workup of patients suspected of PH is a comprehensive clinical and physical examination.4 Patients with PH often presents with symptoms of dyspnea, decreased exercise tolerance, or signs of congestive right or left HF. Infrequently, patients may present with hemoptysis or palpitations. The initial steps of the workup include basic metabolic panel, a chest x-ray, and an echocardiogram and occasionally cardiopulmonary exercise testing (Fig 5). The echocardiogram allows

Managing PH associated with LHD

Although PH is a strong prognostic factor in patients with LHD, it remains to be established whether PH should be a target of therapy. Several studies have in fact shown that PH usually regresses after optimization of HF or corrective valvular heart surgery.5, 8, 74, 77, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101 This explains why optimizing HF regimens and corrective valve surgery represent the cornerstone of the treatment of PH with LHD. Targeting pulmonary vascular remodeling could,

Conclusion

Heart failure is the most common cause of PH. Important determinants of PH in HF include LV diastolic dysfunction and mitral regurgitation. Imbalance in the NO pathways and ET also contribute to the pathophysiology of left-sided PH. When present, PH is associated with worse prognosis in patients with LHD. Priority in the management of left-sided disease is treating the primary cause with either medical or surgical management. Sildenafil is currently being evaluated as a potential new therapy

Statement of Conflict of Interest

All authors declare that there are no conflicts of interest.

Acknowledgments

This project was funded by educational support from the Vera Moulton Wall Center for Pulmonary Vascular Disease at Stanford Hospital.

References (122)

  • K.K. Khush et al.

    Effect of pulmonary hypertension on clinical outcomes in advanced heart failure: analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) database

    Am Heart J

    (2009)
  • J. Kjaergaard et al.

    Prognostic importance of pulmonary hypertension in patients with heart failure

    Am J Cardiol

    (2007)
  • M. Klapholz et al.

    Hospitalization for heart failure in the presence of a normal left ventricular ejection fraction: results of the New York Heart Failure Registry

    J Am Coll Cardiol

    (2004)
  • C.S. Lam et al.

    Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study

    J Am Coll Cardiol

    (2009)
  • C.S. Lam

    Heart failure with preserved ejection fraction: invasive solution to diagnostic confusion?

    J Am Coll Cardiol

    (2010)
  • C.C. Leung et al.

    Prevalence and risk factors of pulmonary hypertension in patients with elevated pulmonary venous pressure and preserved ejection fraction

    Am J Cardiol

    (2010)
  • J. Butler et al.

    Pre-transplant reversible pulmonary hypertension predicts higher risk for mortality after cardiac transplantation

    J Heart Lung Transplant

    (2005)
  • P. Botha et al.

    Acute hemodynamic effects of intravenous sildenafil citrate in congestive heart failure: comparison of phosphodiesterase type-3 and -5 inhibition

    J Heart Lung Transplant

    (2009)
  • A. Haraldsson et al.

    Comparison of inhaled nitric oxide and inhaled aerosolized prostacyclin in the evaluation of heart transplant candidates with elevated pulmonary vascular resistance

    Chest

    (1998)
  • S. Murali et al.

    Reversibility of pulmonary hypertension in congestive heart failure patients evaluated for cardiac transplantation: comparative effects of various pharmacologic agents

    Am Heart J

    (1991)
  • M.J. Semigran et al.

    Hemodynamic effects of inhaled nitric oxide in heart failure

    J Am Coll Cardiol

    (1994)
  • V.V. McLaughlin et al.

    ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association

    J Am Coll Cardiol

    (2009)
  • D.W. Kitzman et al.

    Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: failure of the Frank-Starling mechanism

    J Am Coll Cardiol

    (1991)
  • S. Capomolla et al.

    Invasive and non-invasive determinants of pulmonary hypertension in patients with chronic heart failure

    J Heart Lung Transplant

    (2000)
  • M.H. Drazner et al.

    Relationship between right and left-sided filling pressures in 1000 patients with advanced heart failure

    J Heart Lung Transplant

    (1999)
  • M. Enriquez-Sarano et al.

    Determinants of pulmonary hypertension in left ventricular dysfunction

    J Am Coll Cardiol

    (1997)
  • D.A. Kass

    Assessment of diastolic dysfunction. Invasive modalities

    Cardiol Clin

    (2000)
  • M. Guazzi

    Alveolar gas diffusion abnormalities in heart failure

    J Card Fail

    (2008)
  • S.S. Kurdak et al.

    Effect of increased duration of high perfusion pressure on stress failure of pulmonary capillaries

    Microvasc Res

    (1995)
  • C.J. Cooper et al.

    The influence of basal nitric oxide activity on pulmonary vascular resistance in patients with congestive heart failure

    Am J Cardiol

    (1998)
  • M.L. Blitzer et al.

    Endothelium-derived nitric oxide regulates systemic and pulmonary vascular resistance during acute hypoxia in humans

    J Am Coll Cardiol

    (1996)
  • T.R. Porter et al.

    Endothelium-dependent pulmonary artery responses in chronic heart failure: influence of pulmonary hypertension

    J Am Coll Cardiol

    (1993)
  • T. Tsutamoto et al.

    Relation between endothelin-1 spillover in the lungs and pulmonary vascular resistance in patients with chronic heart failure

    J Am Coll Cardiol

    (1994)
  • R.J. Rodeheffer et al.

    Increased plasma concentrations of endothelin in congestive heart failure in humans

    Mayo Clin Proc

    (1992)
  • M.R. MacLean et al.

    Serotonin and pulmonary hypertension—from bench to bedside?

    Curr Opin Pharmacol

    (2009)
  • T.P. Olson et al.

    Repeat length polymorphism of the serotonin transporter gene influences pulmonary artery pressure in heart failure

    Am Heart J

    (2007)
  • B. Ristow et al.

    Elevated pulmonary artery pressure by Doppler echocardiography predicts hospitalization for heart failure and mortality in ambulatory stable coronary artery disease: the Heart and Soul Study

    J Am Coll Cardiol

    (2007)
  • J.E. Moller et al.

    Prognostic importance of secondary pulmonary hypertension after acute myocardial infarction

    Am J Cardiol

    (2005)
  • C. Ward et al.

    Acquired valvular heart-disease in patients who keep pet birds

    Lancet

    (1974)
  • L.W. Johnson et al.

    Pulmonary hypertension in isolated aortic stenosis. Hemodynamic correlations and follow-up

    J Thorac Cardiovasc Surg

    (1988)
  • J.F. Malouf et al.

    Severe pulmonary hypertension in patients with severe aortic valve stenosis: clinical profile and prognostic implications

    J Am Coll Cardiol

    (2002)
  • S.J. Melby et al.

    Impact of pulmonary hypertension on outcomes after aortic valve replacement for aortic valve stenosis

    J Thorac Cardiovasc Surg

    (2011)
  • K. Silver et al.

    Pulmonary artery hypertension in severe aortic stenosis: incidence and mechanism

    Am Heart J

    (1993)
  • J.M. Chen et al.

    Reevaluating the significance of pulmonary hypertension before cardiac transplantation: determination of optimal thresholds and quantification of the effect of reversibility on perioperative mortality

    J Thorac Cardiovasc Surg

    (1997)
  • M.R. Mehra et al.

    Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates—2006

    J Heart Lung Transplant

    (2006)
  • A. Robitaille et al.

    Importance of relative pulmonary hypertension in cardiac surgery: the mean systemic-to-pulmonary artery pressure ratio

    J Cardiothorac Vasc Anesth

    (2006)
  • F. Haddad et al.

    Right ventricular myocardial performance index predicts perioperative mortality or circulatory failure in high-risk valvular surgery

    J Am Soc Echocardiogr

    (2007)
  • S.F. Nagueh et al.

    Recommendations for the evaluation of left ventricular diastolic function by echocardiography

    J Am Soc Echocardiogr

    (2009)
  • D. Zimpfer et al.

    Left ventricular assist devices decrease fixed pulmonary hypertension in cardiac transplant candidates

    J Thorac Cardiovasc Surg

    (2007)
  • R. John et al.

    Effects on pre- and posttransplant pulmonary hemodynamics in patients with continuous-flow left ventricular assist devices

    J Thorac Cardiovasc Surg

    (2010)
  • Cited by (0)

    Statement of Conflicts of Interest: see page 164.

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