Author + information
- Published online November 16, 2016.
- Thierry C. Gillebert, MD, PhD∗ ()
- ↵∗Reprint requests and correspondence:
Prof. Thierry C. Gillebert, Department of Cardiology, 8K12IE Ghent University Hospital, De Pintelaan, 185, 9000, Ghent, Belgium.
- excitation-contraction coupling
- leg lifting
- length-dependent activation
- mitral regurgitation
- wave reflections
This editorial highlights a careful and original clinical study that shows the added value of passive left lifting (PLL) for the prognostic stratification of patients with heart failure with reduced ejection fraction (HFrEF) (1). With PLL, forward stroke volume increased in 20 patients and paradoxically decreased in the remaining 15 patients. The findings were interpreted as related to the position on the Frank-Starling curve; patients with decreasing forward stroke volume were deemed to be on the descending limb. The 2 groups were well matched for clinical characteristics and drug treatment. The patients on the descending limb were sicker according to the echocardiographic evaluation, with higher left ventricular (LV) volumes, lower ejection fractions (EFs), higher filling pressures (E/e′), and larger inferior caval veins. Several patients had functional mitral regurgitation (MR). The mitral regurgitant fraction at baseline was a mean of 21% on the ascending limb and 35% on the descending limb.
This decrease in forward stroke volume induced by PLL may appear counterintuitive for clinical cardiologists. Nevertheless, the paradoxical decrease in forward stroke volume (“descending-limb” patients) was a univariate predictor of the primary endpoint (death or heart failure hospitalization) and increased the predictive power of all other univariate predictors in a bivariate Cox analysis. Unfortunately, the amount of data did not allow performance of a conventional multivariate prediction analysis. This was a small study (35 patients with 15 occurrences of the primary endpoint) that may be seen as a “proof-of-concept” paper, which is hypothesis-generating rather than justifying widespread clinical application. However, this is a strong stimulus to undertake a larger study to address the prognostic value of PLL in heart failure patients.
The investigators also examined the role of varying functional MR induced by PLL. With PLL, venous return and LV volumes increased, and this might have exacerbated MR. The changes in stroke volume induced by PLL correlated quite well with changes in functional regurgitation (r = −0.56), and a causal relation was postulated. In the more diseased subset of patients, leg lifting resulted in more MR, and therefore, decreased forward cardiac output. In the less diseased subset of patients, PLL resulted in less of an increase in MR. Surprisingly an absolute reduction of MR was observed in 9 of 35 patients.
The variable response of MR to PLL should be explained with the basic determinants of functional MR: the severity of MR decreases with enhanced contractility and increases with depressed contractility, as well as higher volumes and higher systolic pressures. To fully understand the results, we have to discuss the possible effects of PLL on contractile performance together with the direct volume–induced effects of PLL on the amount of MR. Contractility was assessed with EF and with global longitudinal strain (GLS). These dimension-related measurements are particularly difficult to interpret because of the confounding effect of the amount of MR and total stroke volume. More MR leads to higher EFs and GLS.
A first possible effect of PLL on contractile performance is the Frank-Starling mechanism, a concept based on the optimal overlap of actin and myosin. The energy of contraction, as reflected by the external work (rather than stroke volume) performed by the ventricle, has been shown to be dependent upon the ventricular end-diastolic fiber length; this experimental concept was validated in men (2). In chronically dilated ventricles of animal models, sarcomeres may be maximally extended (close to 2.2 μm), and there is not much room for an additional Frank-Starling response for increasing performance after increasing volume (3). Although it is still possible that the findings of the less-diseased ascending-limb patients were based at least in part on the Frank-Starling relationship, this explanation is unlikely in the descending limb patients because mid-wall sarcomere lengths cannot be forced significantly beyond the apex of the sarcomere length–tension curve, either in healthy or in diseased hearts. This resistance to stretching of cardiac tissue is dependent on the volume-restricting effect of the pericardium (4), the sarcomeric cardiac titin molecule, and the surrounding fibrous tissue (5). An alternative explanation for the descending limb is that increasing volumes will increase wall stress and blood pressure. This leads to an afterload mismatch that cannot be compensated by the use of pre-load reserve, which is exhausted (3). This then results in a fall in stroke volume.
A second possible effect is based on the excitation–contraction coupling (6). The activation of the cardiac myofibrils by calcium increases as muscle length increases (7). There is a quick response, followed by a slow response over the next several minutes. The quick response is related to the interaction between the activating calcium (Ca++) and the thin filament which is mediated by the troponin complex (8). The slow response is mediated by the amount of activating Ca++ (aequorin signal) (7). More recently, variation in lattice spacing and diastolic ordering of myosin heads have been put forward as major determinants of length-dependent changes in Ca++ sensitivity (9,10). It seems likely that an impairment of excitation–contraction coupling and length-dependent activation of cardiac tissue, rather than the Frank-Starling curve, would explain the variable responses observed in cardiac patients in response to PLL. De Hert et al. (11) studied contractility, myocardial relaxation, and filling pressures in response to PLL in hundreds of anesthetized open-chest and open-pericardium coronary artery bypass graft (CABG) patients with preserved EF. The normal cardiovascular response to PLL or volume loading was increased contractility, increased systolic pressures by 10 to 15 mm Hg, and accelerated relaxation that revealed a normal afterload dependence (see the following), but only a limited increase in filling pressures. A wide range of responses was observed, from an improvement of systolic and diastolic function, with limited increases in filling pressures to deterioration of function with marked increases in filling pressures. There was a surprisingly close coupling between the response of contraction and relaxation. The patients with deteriorating cardiac function in response to PLL were more likely to need inotropic support after extracorporeal circulation (11). In a subsequent study, the investigators compared the effects of PLL to the effects of phenylephrine, which resulted in similar increases in systolic LV pressures. The deteriorating effects induced by PLL could not be explained by increased systolic pressures and afterload mismatch, but appeared to be related to deficient length-dependent regulation of myocardial function (12). With the confounding effect of MR on EF and GLS, it is unclear to what extent deficient length-dependent activation could have influenced the results presented by Abe et al. (1). However, it is plausible that variability of length-dependent activation would have contributed to the changes in forward stroke volume and to the amount of MR observed in response to PLL (1).
A third possible effect is diastolic ventricular interdependence. The right and left ventricles are in the same pericardial space, and total cardiac volume remains unaltered. A physiological interaction occurs with each respiratory cycle and with changes in body position and venous return. Situations such as volume overload, pulmonary hypertension, and congestive heart failure may lead to a situation in which both ventricles similarly compete for the same space. When such an interaction occurs, acute volume unloading, such as that induced by vasodilators or diuretics, results in a reduction in right ventricular end-diastolic volume, a rightward shift of the interventricular septum, and an increase in LV end-diastolic volume (13). Consequently, LV performance may paradoxically increase with vasodilators or diuretics, so that in patients with HFrEF, PLL may result in a leftward shift of the interventricular septum, LV compression, and reduced performance. The data presented from Abe et al. (1) do not permit evaluation of this mechanism.
A fourth possible mechanism is afterload. With PLL, ventricular afterload increases because of increased volumes (Laplace’s law) and because of higher systolic pressures. We previously mentioned the concept of afterload mismatch with exhausted pre-load reserve (3). More recent work shed a new light on this concept. In both animal models and CABG patients, the healthy heart works at 30% to 40% of its peak isometric performance and has a huge afterload reserve (14,15). The heart is capable of developing pressures up to 250 to 300 mm Hg without delay of relaxation or increase in filling pressures. This is of paramount importance for the physiological response to exercise and stress. Smaller physiological step increases in systolic pressure cause little if any decrease in stroke volume. This tolerance to systolic load disappears when systolic function is impaired; in a patient with HFrEF, the slightest increase in systolic pressure leads to a drop in stroke volume, delayed myocardial relaxation, and increased filling pressures (14). The opposite has been observed with any decrease of systolic pressure (14,16). The filling pressures of the HFrEF ventricle, which works at >80% of its peak isometric performance, is extremely dependent on afterload. In the study by Abe et al. (1), this afterload dependence would have influenced stroke volume, diastolic function, filling pressures, and MR in response to PLL, especially in the more diseased patients.
When the cardiovascular volume increases, the properties of the arterial tree change, and wave reflections become stronger and travel faster. These wave reflections affect late-systolic wall stress and delay myocardial relaxation (17,18). This additional delay is likely to have occurred after PLL and to have affected stroke volume, diastolic function, and filling pressures.
PLL is a simple maneuver that alters pre-load, afterload, ventricular–arterial interaction, and neuro-humoral adjustments. It seems unlikely that the findings of Abe et al. (1) represent the descending limb of the Frank-Starling curve, but it remains to be investigated to what extent deficient length-dependent activation, ventricular interdependence, and afterload mismatch may have influenced the results. The main message is the pronounced effect of PLL on the amount of MR, directly through LV dilatation or indirectly through changes in contractility. A worsening amount of MR that leads to a decreased forward stroke volume has prognostic significance. Further research should document if this information improves the prognostic stratification of HFrEF patients in a multivariate analysis that includes the key clinical, laboratory, and echocardiographic variables. It will be quite useful to evaluate whether the PLL maneuver (which is easy) could supplement or replace exercise echo (which is more difficult and time-consuming).
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
The author has reported that he has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Abe Y.,
- Akamatsu K.,
- Furukawa A.,
- et al.
- Ross J. Jr..,
- Sonnenblick E.H.,
- Taylor R.R.,
- Spotnitz H.M.,
- Covell J.W.
- Katz A.M.
- de Tombe P.P.,
- ter Keurs H.E.
- Leite-Moreira A.F.,
- Gillebert T.C.
- Eichhorn E.J.,
- Willard J.E.,
- Alvarez L.,
- et al.
- Gillebert T.C.,
- Lew W.Y.