The 5th World Symposium on Pulmonary Hypertension classified pulmonary hypertension (PH) into five groups of disorders:

• Group 1: Pulmonary arterial hypertension
• Group 2: PH due to left heart disease
• Group 3: PH due to chronic lung disease and/or hypoxia
• Group 4: Chronic thromboembolic PH
• Group 5: PH due to unclear multifactorial mechanisms¹

PH is also classified as pre-capillary and post-capillary based on hemodynamic data. The 6th World Symposium on Pulmonary Hypertension, recognizing that there can also be a combination of pre- and post-capillary PH, incorporated pulmonary vascular resistance (PVR) into the definition and emphasized the importance of differentiating between idiopathic pulmonary arterial hypertension (pre-capillary) and PH related to heart failure with preserved left ventricular (LV) ejection fraction (post-capillary) based on the pulmonary artery wedge pressure and PVR.²

Cardiac Effects of Pre-Capillary PH
In pre-capillary PH, as the disease progresses, the increases in PVR and pulmonary artery pressure result in right ventricular (RV) pressure overload and the development of RV hypertrophy (homeometric adaptation).³ As the disease progresses, heterometric adaptation occurs to maintain cardiac output but results in progressive dilation of the RV chamber leading to right heart failure.⁴ In addition to systolic dysfunction, right heart diastolic function becomes abnormal, which is thought to be caused by increasing fibrosis and stiffness of the ventricular sarcomeres.⁵

RV function has an important bearing on prognosis. Early echocardiographic studies focused on the RV and atrium to determine prognostic measures and data and ignored the role, if any, the LV played in determining prognosis, primarily because the LV, although typically small in size, exhibited normal-appearing systolic function.^6-9 In actuality, chronic PH and its effect on RV morphology and function is an excellent example of ventricular interdependence, first described by Bernheim in 1910.¹⁰ Although described in patients with severe aortic stenosis, the basic concept is that the progressive changes seen in one ventricle affect the structure and function of the other, and studies soon followed that showed this to be true.¹¹

Changes in heart size are constrained by the limitations set forth by the pericardium. As PH increases RV wall thickness and subsequently chamber size, the interventricular septum begins bowing toward and compressing the LV. The degree of distortion of the ventricle and septum, which can be quantified by the eccentricity index,¹² causes a decrease in LV chamber size due to the constraints of the pericardium, resulting in decreased filling, compliance, and stroke volume.^13-15 The diminished stroke volume explains the progression of dyspnea, edema, and hypotension. However, the impaired LV function in the setting of chronic RV pressure overload may not simply be the result of geometric effects of chamber enlargement and chamber distortion.

Echocardiography in PH
Right heart catheterization is considered the gold standard for evaluating right heart hemodynamics; however, transthoracic echocardiography is typically the first diagnostic test used (and used serially) to evaluate both the RV structure and function, although few echocardiographic parameters have demonstrated consistent reproducibility.¹⁶

Keeping in mind the interventricular dependence already mentioned, the evaluation of cardiac function in patients with PH becomes a more challenging endeavor. Historically, many of the routine echocardiography reports simply described the RV and LV function by subjective terminology, prompting the various echocardiography societies to recommend the use of objective measures,¹⁷ of particular importance in pathological states such as PH, that may produce subtle changes in cardiac size and function, both as the disease progresses and following therapeutic measures.

From the early days of qualitative assessment of right heart size and function, quantitative measurements for size (RV area, volumes, and volume index) are now readily available. Function can be assessed, typically by a combination of the ventricular fractional area change, Doppler tissue-derived tricuspid lateral annular systolic velocity wave (S' velocity), tricuspid annular plane systolic excursion, and the RV index of myocardial performance. RV, and therefore pulmonary artery systolic, pressures are typically calculated using the tricuspid regurgitation jet, and an estimation of right atrial pressure is routinely reported despite the multiple issues in achieving an accurate value.¹⁸

The development of strain rate imaging¹⁹ has improved the ability to evaluate subclinical RV and LV function, detecting ventricular dysfunction before standard measures such as fractional shortening and ejection fraction become abnormal.^20,21 Tissue-derived modalities and strain rate imaging measure the rate of regional myocardial deformation that is independent of geometric assumptions and endocardial border tracings, which are limitations known to impair adequate evaluation of the right heart assessment. Three components of strain are known:

1. Longitudinal strain measures shortening from base to apex.
2. Circumferential strain measures systolic shortening of the LV short axis.
3. Radial strain measures myocardial thickening from endocardium to epicardium.

Because of the technical limitations in acquiring circumferential and radial strain values, plus the fact that 80% of RV contraction is longitudinal, global longitudinal strain, which is able to be measured in almost all myocardial segments of both ventricles, is the preferred value to obtain. Studies have proven tissue Doppler and strain imaging can easily be incorporated into the basic echocardiographic evaluation of the RV with a prognostic power that exceeded the other parameters of ventricular function.²² In patients under treatment, serial echocardiographic RV assessment by strain imaging has been shown to independently predict clinical deterioration and mortality in patients with PH.²³

The altered mechanical function of the LV by the progressively enlarging and hypertrophied right heart has led to the standard echocardiographic reporting of a diminished size of the LV chamber, the abnormality in septal motion, the eccentricity index, and the abnormal filling pattern of mitral diastolic flow, suggesting reduced filling volumes; all are associated with a normal LV ejection fraction. However, this impaired LV function may not simply be the result of geometric effects and mechanical compression. Underlying diastolic dysfunction abnormalities have been shown to be present in PH. Slowed conduction and prolongation of the action potentials in the RV slow ventricular contraction^24,25 and thus the onset of diastolic relaxation of the left heart, depicted by reversal of the mitral E/A ratio, reduced annular tissue Doppler velocities, and higher E/e' ratios.²⁶

Attention to the "normal" LV systolic function has increased, primarily involving the use of myocardial strain imaging. Conceptually, it would be expected that the ventricular septum would show the highest degree of subclinical dysfunction. Hardegree et al.²⁷ utilized strain imaging of both the RV and LV, confirming the previously known abnormality in the right heart, but showing that despite an LV normal in size and with a normal ejection fraction, patients had a reduced strain of the free LV wall that was associated with increased mortality.

Recently, Kishiki et al. studied both LV regional and global longitudinal strain, finding that strain becomes abnormal both in the septum and the ventricular free wall, worsening as the degree of PH/right heart failure progressed. LV global longitudinal strain was an independent risk factor for mortality, and a global longitudinal strain of >-15% (less negative) had the greatest association with mortality.²⁸ Although it is unclear if this strain abnormality occurs as a result purely from mechanical compression of the left heart, LV free wall mass has been shown to decrease as the right heart enlarges, particularly when right heart failure occurred, termed hypotrophic or atrophic remodeling. Myocardial biopsy studies have shown the presence of myocyte atrophy and contractile dysfunction, which could explain the abnormality in myocardial strain. This is further complicated by studies showing the atrophied LV maintaining its energy efficiency²⁹ and rapidly regaining its mass and function following the relief of PH. Whether LV strain normalizes after treatment of PH can be used as a prognostic indicator for therapeutic trials or used as a marker of residual ventricular dysfunction post-resolution of PH needs further study.

Conclusions
Cardiac evaluation by echocardiography in patients with pre-capillary PH should not be limited to the right heart, nor based on qualitative assessment. In addition to the frequently utilized parameters of right heart function (tricuspid annular plane systolic excursion, S' velocity, and fractional area shortening), strain imaging, when available, should be incorporated on a routine basis as an objective parameter of both RV and LV systolic function. Utilizing three-dimensional volumes, calculation of three-dimensional ejection fraction is feasible with newer technology and offers another method for evaluation ventricular function, often overcoming technical limitations. Prognostic information acquired from right heart evaluations can now be enhanced by a more complete evaluation of LV diastolic and systolic function.

References

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Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Pulmonary Hypertension, Hypertension

Keywords: Hypertension, Pulmonary, Stroke Volume, Pulmonary Wedge Pressure, Endocardium, Ventricular Septum, Sarcomeres, Tricuspid Valve Insufficiency, Prognosis, Risk Factors, Action Potentials, Dilatation, Diagnostic Tests, Routine, Pulmonary Artery

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