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EDITORIAL COMMENT

Cor Pulmonale ParvusPatting the Elephant*

Nathaniel Reichek, MD

T he right ventricle has historically been poorlyunderstood terra incognita in adult cardiovas-cular imaging. Neither invasive angiography,

first-pass radionuclide imaging, nor 2-dimensional(2D) echocardiography proved sufficiently robust orwidely applicable to provide an adequate understand-ing of right ventricular (RV) pathophysiology in com-mon forms of pulmonary disease. The emergence anddevelopment of cardiac magnetic resonance (CMR)imaging and, more recently, cardiac computed tomog-raphy angiography have, for the first time, providedrobust tools with sufficient volumetric coverage andspatial and temporal resolution to fill this gap. Unfor-tunately, 3-dimensional echocardiography has playeda limited role in these disorders due to the frequentimpairment of transthoracic acoustic windows bylung disease.

SEE PAGE 2000

In this issue of the Journal, a report from MESA(Multi-Ethnic Study of Atherosclerosis) describesrelationships between chronic obstructive pulmonarydisease (COPD) and emphysema and RV size, mass,and function (1). Data on pulmonary perfusion alsowere obtained, but are not presented. The authorsreport that in individuals without overt cardiovas-cular disease, RV end-diastolic volume, stroke vol-ume, and end-systolic volume are decreased withincreasing COPD functional severity, whereas end-diastolic volume and stroke volume are also reducedwith increasing severity of emphysema in those with

*Editorials published in the Journal of the American College of Cardiology

reflect the views of the authors and do not necessarily represent the

views of JACC or the American College of Cardiology.

From St. Francis Hospital–The Heart Center, Roslyn, New York; and the

Research Department, Cardiac Imaging Program, Stony Brook University,

State University of New York, Stony Brook, New York. Dr. Reichek has

reported that he has no relationships relevant to the contents of this

paper to disclose.

centrilobular and paraseptal emphysema. In thisstudy, RV mass was unchanged by either COPDor emphysema. The authors term these patterns corpulmonale parvus.

The observations reported appear to contradictconventional wisdom that advanced COPD is associ-ated with RV hypertrophy, dilation, and, ultimately,pump dysfunction related to progressive pulmonaryhypertension. However, this profile has been drawnin the past from studies of more advanced diseaseusing small sample sizes and less robust imagingmethods. The authors suggest that selection criteriafor the main MESA population, the substudy MESA-RV, the MESA COPD study, and a cancer screeningstudy from which additional patients were drawn, aswell as the small number of patients with advanceddisease included overall, may account for these dis-crepancies. They also propose that impaired venousreturn due to a reduced pressure difference betweenthe abdomen and thorax, with a resultant reductionin central blood volume and decreased preload, maybe an important contributor to reduced RV volumes.

An earlier paper on RV from MESA actually reportsdiscrepant results, indicating that “percent emphy-sema was associated with smaller RV volumes andlower mass” (2). It is not clear to this reader how thisconclusion, derived from a larger population, and theconclusion that RV mass is unchanged in the presentpaper, can both be correct.

Additionally, given the relatively small magnitudeof the differences in RV volume reported (15% to20%), the clinical significance of the present findingsremains less than clear. Further, a number of tech-nical considerations render CMR RV quantitationsomewhat problematic. As the authors point out,CMR ventricular volume and mass quantitation havetended to include papillary muscles and protruberanttrabeculae in chamber volume. For the left ventricle,many studies have shown that this approach pro-duces very reproducible results for left ventricular

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(LV) volumes, ejection fraction, and mass. Thatmakes the method superior to 2D echocardiographicquantitation for use in clinical research (higherreproducibility equals smaller sample sizes) and inapplication to serial follow-up of individual patients.However, it likely also results in higher absolutevolumes and lower myocardial mass than actuallyexist. It is important to note that validation studiesfor CMR quantitation in human hearts are all based oncomparisons with other imaging results that areactually less reliable than CMR, not with hard phys-ical measurements. In the right ventricle, the situa-tion is more difficult, given the very thin RV wall, thehigh level of trabeculation, and the oblique orienta-tion of the tricuspid valve plane. In addition, the bodyof validation studies, such as they are, is muchsmaller than for the left ventricle.

Although the results of the present study are quiteinteresting, it is hard to avoid a sense of disappoint-ment at the paucity of pathophysiological insightsthat emerge and the highly fragmented picture of theright ventricle in lung disease that MESA has pro-vided. Indeed, this report is one of many fragments ofthe RV story provided by MESA. There are actually 2overlapping MESA studies that address RV structureand function, MESA-RV and MESA COPD. Thesestudies have produced a total of 23 previous publi-cations on the right ventricle. By and large, eachstudy focused on the relationship of a single variableto RV size, mass, and performance. Factors reportedto have significant correlations with RV differencesbetween patients with and without COPD includeC-reactive protein; interleukin-6 and fibrinogen;dyspnea; ambient air pollution; use of angiotensin-converting enzyme inhibitors and angiotensin re-ceptor blockers; von Willebrand factor; brachialartery diameter; selective serotonin reuptake inhibi-tor use; differences in obesity, race, and sex; matrixmetalloproteinase-9 and plasminogen activatorinhibitor-1; sex hormones; physical activity; cardio-vascular risk factors; and septal myocardial strain. Noefforts appear to have been made to characterizethe relationships of these factors with each other orcharacterize the mechanistic basis mediating effectson the right ventricle to provide an integratedperspective on the problem, although each studyevaluates quite a number of other potential cova-riates. Given the small population with COPD in thepresent study, analysis of all these previouslydescribed related factors certainly cannot be done,but it is easy to imagine that the concatenation ofthem may have influenced these results. Scant refer-ence is made to the bulk of this extensive body ofwork in the current paper.

Thus, there are many publications, but little path-ophysiology. Indeed, this approach seems ubiquitousin clinical cardiovascular research these days. Largesample sizes in multicenter studies combined withimproved statistical methods have resulted in muchgreater ability to demonstrate statistically significantassociations between variables. However, associationis often taken for causality, and retrospective dataoften provide the basis for claims of “predictive”value. But association is not causality, and the abilityto predict must be demonstrated prospectively. Theresult in many instances has been a more “knowing”literature that knows less than meets the eye. It isalso important to know what you do not know.

Last, the authors overlook a very familiar andplausible phenomenon, observed commonly in theleft heart that may well explain the observed results.Concentric LV remodeling, with a normal absolute LVmass but a smaller than normal LV volume, originallydescribed by Ganau et al. (3), is at least as common insystemic hypertension as overt LV hypertrophy. Suchremodeling actually normalizes myocardial afterload,often expressed as wall stress, despite increasedchamber pressure, thereby representing an importantadaptive mechanism in pressure overload states.

The same phenomenon can be found in elderlypatients with aortic stenosis and normal LV mass,especially in women. Moreover, as reported in part inMESA itself, this remodeling also occurs with aging innormal men and women in parallel with an age-related increase in average arterial systolic pressure,even in normotensive cohorts (4). Similar age-relatedchanges in the right ventricle also have beendescribed. Determination of RV pressure, dependenton either Doppler velocity of tricuspid regurgitationjets with indirect estimation of right atrial pressure orright heart catheterization, is certainly more prob-lematic than determination of cuff blood pressureand was not performed in the present study. How-ever, the authors have included age as a covariate, sopresumably it does not explain the reported findings.

Thus, it is conceivable that the results of Kawutet al. (1) reflect RV concentric remodeling in responseto mild increases in pulmonary artery pressure,whether at rest or with physical activity. This seems tome an important pathophysiological possibility thatmerits both discussion and further exploration. Al-though the RV in contemporary COPD and emphysemamaybe parvus, our understanding of it neednot be.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Nathaniel Reichek, St. Francis Hospital-The HeartCenter, 100 Port Washington Boulevard, Roslyn, NewYork 11568. E-mail: Nathaniel.Reichek@chsli.org.

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RE F E RENCE S

1. Kawut SM, Poor HD, Parikh MA, et al.Cor pulmonale parvus in chronic obstructivepulmonary disease and emphysema: the MESACOPD study. J Am Coll Cardiol 2014;64:2000–9.

2. Grau M, Barr RG, Lima JA, et al. Percent emphy-sema and right ventricular structure and function:the Multi-Ethnic Study of Atherosclerosis-Lung

and Multi-Ethnic Study of Atherosclerosis-RightVentricle Studies. Chest 2013;144:136–44.

3. Ganau A, Devereux RB, Roman MJ, et al.Patterns of left ventricular hypertrophy and geo-metric remodeling in essential hypertension. J AmColl Cardiol 1992;19:1550–8.

4. Natori S, Lai S, Finn JP, et al. CardiovascularFunction in Multi-Ethnic Study of Atherosclerosis:

normal values by age, sex, and ethnicity.AJR Am J Roentgenol 2006;186 6 Suppl 2:S357–65.

KEY WORDS cardiac MRI, chronic obstructivepulmonary disease, cor pulmonale, emphysema,right ventricle