Doppler Echocardiography

Have Noninvasive Imaging Studies Supplanted the Need for Invasive Hemodynamics?

Lessons Learned from Lymphangioleiomyomatosis

Joel A. Strom, MD, MEngCorrespondence information about the author MD, MEng Joel A. StromEmail the author MD, MEng Joel A. Strom

Florida Polytechnic University, Lakeland, Florida

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DOI: https://doi.org/10.1016/j.echo.2018.06.003

Hemodynamic measurements obtained by cardiac catheterization are considered the “gold standard” to diagnose the severity of structural cardiovascular disease. However, the indications to perform invasive measurements have greatly diminished with advances in noninvasive imaging technology. Doppler echocardiography, as well as other noninvasive imaging techniques, such as CMR, CT, and PET, are recognized as the primary modalities to assess cardiovascular anatomy and pathophysiology for many conditions, particularly those involving structural diseases of the systemic side of the heart, e.g., measurements of cardiac chamber sizes, wall thicknesses, as well as global and regional performance, valvular disease, and pericardial abnormalities.1, 2 The main clinical utility of noninvasive imaging methods is based on their accuracy, safety, and reproducibility. Relatively simple formulas can be constructed to classify disease severity, predict prognosis, and determine the timing and type of therapy.

Assessment of the pulmonary circulation is more difficult because of the complex geometry of the right heart and generally lower venous and arterial pressures, making precise and reproducible measurements critical to the accurate determination of the hemodynamic state and the alterations that result from physiologic and pathologic etiologies. Doppler echocardiography is the preferred screening technique, and multiple variables should be measured in order to provide a reliable assessment of the presence and severity of pulmonary hypertension (PH).3, 4 However, invasive hemodynamic measurements remain the definitive diagnostic approach. The 2015 ESC/ERS guidelines define PH as a resting mean pulmonary artery pressure (mPAP) of ≥ 25 mm Hg as assessed by right heart catheterization (RHC).3

Pulmonary hypertension is classified both hemodynamically and clinically. The latter is based on the modifications to the five categories made at the 5th World Symposium for PH, held in Nice, France in 2013.3, 5Patients with PH are then subdivided hemodynamically based on their mean pulmonary capillary wedge pressure (mPCWP). Precapillary PH (mPCWP ≤ 15 mm Hg) includes the clinical WHO categories: (1) pulmonary arterial hypertension, (3) PH due to lung disease and/or hypoxia, and (4) chronic thromboembolic pulmonary hypertension. An mPCWP >15 mm Hg defines postcapillary PH. Postcapillary PH is further subdivided based on calculation of the pulmonary artery diastolic pressure gradient (PADPG = diastolic PAP - mPCWP) and pulmonary vascular resistance (PVR). Isolated postcapillary PH is defined by a PADPG <7 mm Hg and/or a PVR ≤3 Wood units, while a PADPG ≥7 mm Hg and/or PVR >3 Wood units defines combined post- and precapillary PH. Postcapillary PH includes PH due to left heart disease (WHO category 2), while PH with unclear and/or multifactorial mechanisms (WHO category 5) could be assigned hemodynamically into either the pre- and/or postcapillary PH groups.

Lymphangioleiomyomatosis (LAM), a rare systemic disorder that occurs almost exclusively in women of childbearing age, is an example of a disease process involving derangements of both the pulmonary and systemic circulations. It is characterized by proliferation of benign-appearing smooth muscle cells, mainly in the lungs, that harbor tuberous sclerosis complex (TSC) inactivating gene mutations. Proliferation of the smooth muscle cells surrounding the airways induces obstruction and alveolar destruction resulting in formation of multiple cysts, while proliferation of smooth muscle cells in the walls of the pulmonary blood and lymphatic vessels results in luminal narrowing, obstruction, and disruption, which account for LAM's characteristic symptom complex. Patients can present with venous congestion, spontaneous pneumothorax, chylothorax, hemoptysis, and progressive dyspnea due to deterioration of pulmonary function.6, 7, 8 The LAM cells also express two lymphangiogenic growth factors, vascular endothelial growth factor C (VEGF-C) and vascular endothelial growth factor D (VEGF-D), and the cells can spread through lymphatic channels.9, 10 As reported by McCormack et al.,11 sirolimus, an inhibitor of the mTOR signaling pathway, a central regulator of cell metabolism, growth, proliferation, and survival, can improve both pulmonary function and biomarkers of disease activity.

Lymphangioleiomyomatosis is clinically classified in WHO category 5.2, which comprises a group of systemic disorders whose PH is due to multifactorial mechanisms. This category also includes sarcoidosis, pulmonary histiocytosis, and neurofibromatosis. LAM is a hemodynamically complex disease reflecting anatomic and physiologic abnormalities of both pre- and postcapillary pulmonary circulations.6, 7, 8 The former results from varying contributions of structural and hypoxia-induced pulmonary artery obstruction, while the latter can result from pulmonary venous occlusive disease and LV diastolic dysfunction. These abnormalities may be present at rest but are often exacerbated by exercise.12

The report by Sonaglioni et al. in this issue of JASE13 addresses a timely and very important topic: can rest and exercise Doppler echocardiography elucidate the hemodynamic mechanisms responsible for the pathogenesis of exercise-induced PH in LAM? The study employed a case-control design, comparing 15 LAM patients with 10 fairly well-matched controls. Doppler echocardiography was performed at rest and during graded exercise stress echocardiography (ESE), employing a bicycle ergometer that could be tilted for optimal imaging. Despite the relatively small number of patients, due in part to the rarity of disease, the authors were able to obtain a very large number of rest and exercise Doppler echocardiographic measurements with good-to-excellent reproducibility. Their main findings were that the LAM patients in this cohort, despite having on average normal PAP, mPCWP, and PVR at rest, experienced reduced exercise capacity accompanied by a decline in arterial O2saturation, associated with exercise-induced increases in systolic and mPAP, mPCWP, and PVR. The increase in PVR suggests the effect of hypoxia-induced pulmonary arterial vasoconstriction,12 while the elevation of mPCWP resulted from the increase in LV filling pressure and decline in stroke volume, both of which were the result of RV afterload-induced LV dysfunction as progressive RV dilation leads to bowing of the interventricular septum towards the left ventricle, thereby altering LV geometry and resulting in impaired LV filling.14

The authors performed a well-designed and carefully executed study, and they report excellent reproducibility of their measurements. However, the large number of formulas employed to estimate hemodynamic values amplifies the potential for errors caused by the physical and technical limitations of image acquisition and interpretation. The proper selection of Doppler echocardiographic formulas that accurately reflect the hemodynamic parameters remains a major limitation, especially during exercise.2, 15 While numerous reports document significant correlations between Doppler echocardiographic formulas and invasive hemodynamic measurements, a lack of robustness of those correlations, despite statistical significance, can limit their accuracy. These correlations and the formulas derived from them are dependent on the hemodynamic state of the cohort used for their derivation and validation, and thus vary among publications. Because most right-side pressures are lower than those on the left, even small discrepancies can impact the accuracy, and thus the utility, of right heart pressure estimates. In many reports, the accuracy and precision of comparisons between Doppler echocardiographic and invasive hemodynamic measurements are degraded by nonsimultaneous recordings.16 Despite the increased accuracy that results when recordings are obtained from high-fidelity catheter-tip micromanometer transducers, RHC is most often performed clinically using a double-lumen, flow-directed, fluid-filled catheter tipped with an inflatable balloon. The double-lumen catheter's small central lumen and soft walls, combined with the distance the pressure wave must travel from the catheter orifice to reach the pressure transducer, can distort the pressure wave form, and thus the phasic pressure measurements. Similarly, mPCWP is recorded by entrapping the inflated balloon in a pulmonary artery branch. It most accurately reflects the pressure in the large pulmonary veins,17 and thus the mean left atrial and mean left ventricular diastolic pressures.18 Importantly, mPCWP may be normal in patients with pulmonary venous occlusive disease involving only the small pulmonary veins.17 Invasive cardiac output measurements, required for resistance calculations, are usually obtained using the thermodilution technique, which has a ±20% accuracy compared to more rigorous methodologies.19

In the current study, mPCWP is derived from the E/e' ratio. However, despite an R2 = 0.76, the 95% confidence limit demonstrated by the Bland-Altman plot was ± 7.6 mm Hg, which is a relatively large variance that could misclassify a patient's PH.20 Others have not been able to attain that robustness of prediction, especially during exercise.21 Ommen et al.22 concluded that accurate prediction of filling pressures for an individual patient requires a stepwise approach incorporating all available data. This concept is incorporated in the most recent ASE recommendations.2 The authors calculated mPAP from a formula incorporating the right ventricular outflow tract acceleration time, but the accuracy of the formula's output was limited by significant data scatter.23Steckelberg, et al.16 derived a formula for mPAP (= 0.61 x systolic PAP + 1.95 mm Hg) which, despite a robust R2value, demonstrated considerable scatter, and thus potential for misclassification of PH. Also, the use of surrogates (such as inferior vena cava diameter and respiratory variation to estimate right atrial pressure) can induce inaccuracies in PA systolic and mean pressure estimates.

Pulmonary vascular resistance was calculated from a formula incorporating the maximal tricuspid regurgitant velocity (TRV)/right ventricular outflow tract time velocity index (TVIRVOT) ratio.24 However, in a more recent paper, Abbas et al.25 reported that the TRV2/TVIRVOT ratio better predicted PVR compared to TRV/TVIRVOT. In an accompanying editorial, Schiller and Ristow4 recommended that a set of multiple parameters be used to diagnose PH. However, a higher level of accuracy for hemodynamic values is of prime importance to assess the complex pathophysiology of a condition that involves multiple abnormalities, such as lymphangioleiomyomatosis.

Jump to SectionLessons Learned and Future DirectionsReferences

Lessons Learned and Future Directions

The most important result of the study is that two-dimensional Doppler echocardiography has the potential to elucidate the structural and physiologic changes in complex disease states. The methodology and analysis highlight their current limitations. These include the well-described inherent limitations of the physics of ultrasound, instrumentation, examination techniques, and the effect of fluid mechanical principles. Superimposed on these are the limited accuracy and precision of formulas used to estimate the hemodynamic and physical parameters, especially involving the right side of the heart. For example, the interaction of these limitations in patients with aortic stenosis have led to severity analysis protocols incorporating multiple hemodynamic measurements.26

Protocols to validate noninvasive algorithms compared to invasive hemodynamic measurements need to be more robust and standardized, as illustrated by the number of published formulas used to estimate hemodynamic variables noninvasively.4, 15 The noninvasive algorithms also must accurately reflect the change in hemodynamics that occur with exercise and other conditions affecting loading. Cutoff values, especially obtained during exercise studies, must take into account patient age, body habitus, and the disease being studied.27 Standardizing the formulas to calculate hemodynamic measurements will allow more accurate classification of clinical and hemodynamic states to improve comparability of results among studies. While the current report includes a large number of measurements, such a design can amplify the potential for Type I and II statistical errors in addition to negating the potential for reliable clinical application. Limiting the Doppler echocardiographic measurements to an accurate and reproducible number would foster more research in this area, with studies involving larger numbers of patients. Finally, incorporation of advanced techniques, such as three-dimensional Doppler echocardiography and multimodality imaging, could make studies of the type reported in the current publication more practical and robust. In conclusion, despite its multiple limitations, the report by Sonaglioni et al.13 in the current issue of JASE is an important contribution to the echocardiographic literature, since this report extends the use of Doppler echocardiography to analyze complex pathophysiologic alterations under varying hemodynamic states. If validated, this approach could transcend its application solely to patients with lymphangioleiomyomatosis.

Jump to SectionLessons Learned and Future DirectionsReferences

References

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Conflict of interest: None to disclose.

2018 by the American Society of Echocardiography.