i Cardiac Performance, Ventricular-Vascular Interaction and Functional Alterations in Rheumatic Mitral Stenosis A descriptive study employing novel hemodynamic and echocardiographic modalities Ashwin Venkateshvaran Doctoral Thesis Division of Medical Engineering School of Technology and Health KTH Royal Institute of Technology
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1School for Technology and Health, Royal Institute of Technology, Stockholm, Sweden2Sri Sathya Sai Institute of Higher Medical Sciences, Bangalore, India3Karolinska Institutet, Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden4Karolinska Institutet, Department of Medicine, Solna, Sweden5Heart and Vascular Centre, Semmelweis University, Budapest, Hungary
Key points
� A hallmark of mitral stenosis (MS) is the markedly altered left ventricular (LV) loading.� As most of the methods used to determine LV performance in MS patients are influenced by
loading conditions, previous studies have shown conflicting results.� The present study calculated LV elastance, which is a robust method to quantify LV function.
We demonstrate that LV loading in MS patients is elevated but normalizes after valve repairand might be a result of reflex pathways.
� Additionally, we show that the LV in MS is less compliant than normal due to a combinationof right ventricular loading and the valvular disease itself. Immediately after valve dilatationthe increase in blood inflow into the LV results in even greater LV stiffness.
� Our findings enrich our understanding of heart function in MS patients and provide a simplereproducible way of assessing LV performance in MS.
Abstract Left ventricular (LV) function in rheumatic mitral stenosis (MS) remains an issue ofcontroversy, due to load dependency of previously employed assessment methods. We investigatedLV performance in MS employing relatively load-independent indices robust to the altered loadingstate. We studied 106 subjects (32 ± 8 years, 72% female) with severe MS (0.8 ± 0.2 cm2) and40 age-matched controls. MS subjects underwent simultaneous bi-ventricular catheterizationand transthoracic echocardiography (TTE) before and immediately after percutaneous trans-venous mitral commisurotomy (PTMC). Sphygmomanometric brachial artery pressures andTTE recordings were simultaneously acquired in controls. Single-beat LV elastance (Ees) wasemployed for LV contractility measurements. Effective arterial elastance (Ea) and LV diastolicstiffness were measured. MS patients demonstrated significantly elevated afterload (Ea: 3.0 ± 1.3vs. 1.5 ± 0.3 mmHg ml−1; P < 0.001) and LV contractility (Ees: 4.1 ± 1.6 vs. 2.4 ± 0.5 mmHg ml−1;P < 0.001) as compared to controls, with higher Ea in subjects with smaller mitral valve area (�0.8 cm2) and pronounced subvalvular fusion. Stroke volume (49 ± 16 to 57 ± 17 ml; P < 0.001)and indexed LV end-diastolic volume (LVEDVindex: 57 ± 16 to 64 ± 16 ml m−2; P < 0.001)increased following PTMC while Ees and Ea returned to more normal levels. Elevated LV stiffnesswas demonstrated at baseline and increased further following PTMC. Our findings provideevidence of elevated LV contractility, increased arterial load and increased diastolic stiffness insevere MS. Following PTMC, both LV contractility and afterload tend to normalize.
A. Manouras and A. I. Nagy contributed equally to this study.
(Received 30 June 2014; accepted after revision 9 January 2015; first published online 9 February 2015)Corresponding author Aniko Ilona Nagy: Heart and Vascular Centre, Semmelweis University, Budapest. Email:[email protected]
Abbreviations BSA, body surface area; CI, cardiac index; CO, cardiac output; Ea, effective arterial elastance; Ea INV,invasive effective arterial elastance; Ea NI, non-invasive effective arterial elastance; Ees, LV elastance; Ees NI, non-invasiveLV elastance; Ees INV, invasive LV elastance; EF, ejection fraction; E′
lat, early diastolic mitral annular velocity of the lateralLV basal wall; E′
sept, early diastolic mitral annular velocity of the IV septum; ESPVR, end-systolic pressure–volumerelationship; LA, left atrium; LAP, left atrial pressure; LV, left ventricle/ventricular; LVEDP, left ventricular end-diastolicpressure; LVESP, left ventricular end-systolic pressure; LVEDVindex, left ventricular end-diastolic volume indexed toBSA; LVESVindex, left ventricular end-systolic volume indexed to BSA; LVOT, left ventricular outflow tract; MS, mitralstenosis; MVA, mitral valve area; MVG, mean transmitral gradient; PAPd, pulmonary arterial diastolic pressure; PAPm,pulmonary arterial mean pressure; PAPs, pulmonary arterial systolic pressure; PCWP, pulmonary capillary wedgepressure; Pd, diastolic systemic arterial pressure; Pm, mean systemic arterial pressure; Ps, systolic systemic arterial pressure;PTMC, percutaneous transvenous mitral commissurotomy; PVR, pulmonary vascular resistance; RAP, right atrialmean pressure; RHC, right heart catheterization; RV, right ventricle/vetricular; RVEDP, right ventricular end-diastolicpressure; RVESP, right ventricular end-systolic pressure; RVPs, RV systolic pressure; SV, stroke volume; SVi, strokevolume index; SVR, systemic vascular resistance; TTE, transthoracic echocardiography.
Introduction
Despite numerous attempts to characterize left ventricular(LV) systolic function in the setting of mitral stenosis(MS), current evidence remains largely conflicting. Earlystudies demonstrated impaired LV systolic performance,ascribing this to mechanisms such as myocardial fibrosis(Sunamori et al. 1983), impaired inter-ventricular inter-action (Curry et al. 1972) and chronic LV under-filling(Kaku et al. 1988). However, later investigations challengedthis notion, revealing normal LV contractility in pure MS(Gash et al. 1983; Liu et al. 1992). These discrepancies mayat least in part be attributed to the fact that the majority ofthe conventional methods for LV function assessment areinfluenced by the considerably altered loading conditionsprevailing in the setting of MS. Thus, a more robustapproach would comprise the use of indices that are lessdependent on changes in LV loading and provide furtherinsight into the ventricular and arterial interaction.
The instantaneous relationship between pressure andvolume in the human heart is an expression of theintegration of arterial pressure, preload, heart rate andinotropic state of the myocardium. Sunagawa et al. (1984)proposed a comprehensive model by which LV energetics,myocardial function and ventricular performance canbe investigated taking into account their interactionwith the vascular system. Briefly, the framework ofarterio-ventricular coupling allows the characterization ofheart function in terms of effective arterial elastance (Ea),a ‘lumped index’ denoting the LV afterload in the timedomain, and LV elastance (Ees) representing the slope ofthe end-systolic pressure–volume relationship (ESPVR)and expressing the contractile force of the LV. A numberof validating studies have provided evidence that ESPVRis relatively insensitive to afterload alterations, renderingEes the gold standard for LV contractility (Suga et al. 1973;Weber et al. 1976). As this approach largely overcomes the
limitations associated with haemodynamic loading, it isof particular value in the setting of MS.
Based on the above reasoning, we undertook this studyto (1) evaluate LV performance in a large cohort of patientswith pure MS using methods that are less susceptible to thealtered haemodynamic state, (2) investigate the featuresof ventricular–arterial interaction in the setting of MSand (3) interrogate the possible alterations in LV diastolicand systolic function following the acute preload increasesecondary to valve dilatation.
Methods
Study population
Symptomatic MS patients referred for percutaneous trans-venous mitral commisurotomy (PTMC) to the Sri SathyaSai Institute were enrolled prospectively between Januaryand June 2012. Subjects were excluded if they presentedwith more than mild (grade > 1) mitral regurgitation(MR), concomitant aortic valve disease, ischaemic heartdisease, atrial fibrillation or hypertension. All patientswere on low dose β-blockers (atenolol 25 mg), and acombined regime of diuretics (amiloride + furosemide40 mg). The control group comprised 40 healthy,age-matched subjects free of any medications. The studyconformed to the ethical guidelines of the 1975 Declarationof Helsinki and was approved by the institutional reviewboard. All subjects provided written informed consent.
Echocardiographic data
All MS subjects underwent transthoracic echocardiogram(TTE) using a GE Vivid E9 system (GE Ultrasound,Horten, Norway) and a 2.5 MHz matrix array trans-ducer in keeping with current recommendations (Lang
J Physiol 593.8 Arterial load and LV performance in MS 1903
et al. 2005). LV elastance measurements were derived fromsimultaneously acquired LV volumes by echocardiographyand invasive pressures just prior the PTMC. Theechocardiographic and invasive recordings were thenrepeated within 5 min following PTMC.
LV end-systolic volume (LVESV), end-diastolic volume(LVEDV) and ejection fraction (EF) were measuredaccording to current recommendations employing theSimpsons biplane method from two-dimensional TTEfour- and two-chamber apical recordings (Lang et al.2005). Stroke volume (SVDoppler) was calculated bymultiplying the cross-sectional area of the LV outflowtract (LVOT) with the Doppler-derived velocity timeintegral (VTILVOT). Mitral valve area (MVA) was measuredby planimetry and MR was graded semi-quantitatively.Continuous (CW) and pulsed wave (PW) recordingsof the inflow mitral velocities (E and A wave) wereperformed. The mean transmitral gradient (MVGmean)was measured using the CW recordings according tocurrent recommendations (Lang et al. 2005). Spectraltissue velocities were recorded in the septal and lateralmitral annulus in the patient cohort and in controlsusing a 5 mm PW sample volume and the early myo-cardial relaxation velocity (E′) as well as the annular tissuevelocity during atrial contraction (A′) were recorded. TheWilkins score (WS) was employed to assess valve suitabilityfor the procedure (Wilkins et al. 1988). All analyseswere performed offline (EchoPac PC, GE Ultrasound,Waukesha, WI, USA).
Catheterization data
Right heart catheterization was performed using a 6FSwan-Ganz catheter in all MS patients. Right atrialmean pressure (RAPm), right ventricular systolic pressure(RVPs), pulmonary artery systolic and mean pressure(PAPs; PAPm) and mean pulmonary capillary wedgepressure (PCWPm) were measured under fluoroscopyafter careful calibration with the zero level set at themid-thoracic line. Concurrently, a 6F pigtail catheterwas advanced through the femoral artery to measuresystolic, mean and diastolic arterial pressures (Ps, Pm, Pd)with subsequent LV end-diastolic pressure (LVEDP) andend-systolic pressure (LVESP) recordings before and afterPTMC. Trans-septal puncture was performed with an 8FMullins sheath, dilator and a Brockenbrough needle. Leftatrial pressure (LAP) was subsequently recorded. Pressuretracings were stored (WITT Series III, Witt BiomedicalCorp., Melbourne, FL, USA) and analysed off-line.
PTMC was performed using a 24 to 28 mm Accuraballoon catheter (Vascular Concepts, Halstead, UK) byexperts (P.K.D., B.B.) who have individually performed>4000 procedures. The procedure was consideredsuccessful if the resultant MVA was >1.5 cm2 with less
than +1 grade increase in MR. Cardiac output (CO) andvascular resistances were measured before and after PTMCin conjunction with pressure–volume measurements. COwas calculated employing the estimated Fick’s methodwith the oxygen consumption (VO2 ) obtained from astandard nomogram.
Measurements of LV and effective arterial elastance
Ea constitutes a ‘lumped index’ of LV afterload in the timedomain and was calculated as
E a = LVESP/SVDoppler. (1)
For the study’s purposes the calculation of Ea wasperformed based on estimated LVESP values as derivedfrom the equation
LVESP = 0.9 × P s fem (2)
as this accurately approximates LVESP in pressure–volumeloop measurements and has been widely used to evaluateventriculo-arterial coupling (Kelly et al. 1992). Morespecifically, in MS patients Ea was calculated invasively(Ea INV) using the Ps recorded from the femoral artery.Additionally, non-invasive estimated Ea (Ea NI) wascalculated using the regression equation derived fromthe validation group in order for the measurement tocorrespond to the Ea NI assessment in controls.
Ees was calculated using the single-beat approachdeveloped by Chen et al. (2001). Importantly, this methoddoes not assume that the volume axis intercept of ESPVR isat the origin of the diagram (0; 0) but can be extrapolatedto intersect the volume axis at the point V0; 0 (Chen et al.2001). Briefly, Ees was calculated as:
E es(sb) = [Pd fem − (
E Nd(est) × LVESP)]
/[SVDoppler × E Nd(est)
](3)
where ENd(est) represents group-averaged normalized Ees
values as a function of EF and the ratio of diastolic (Pd fem)and systolic (Ps fem) arterial pressure at the level of thefemoral artery as described by the equation:
E Nd (est) =0.0275−0.165 × EF + 0.3656 x (Pd fem/P s fem)
+ 0.515 × E Nd (avg) (4)
In this equation, ENd (avg) is given by a seven-term poly-nomial function:
E Nd(avg) =∑
i=0
ai × tiNd
where summation is performed for i = 0 to 7, using valuesfor ai of [0.35695; −7.2266; 74.249; −307.39; 684.54;−856.92; 571.95; −159.1], respectively.
The tNd value was determined as the ratio of thepre-ejection (R-wave to flow onset) to the total systolicperiod (R-wave to flow termination), with the time atonset and termination of flow obtained from pulsedDoppler in LVOT. LVESP in eqn (3) was estimated asstated above in eqn (2), i.e. LVESP = 0.9 × Ps fem.
LV end-diastolic chamber stiffness was estimatedfrom the ratio of LVEDP and LVEDVi as describedby Kass (2000). Furthermore, the LV end-diastolicpressure–volume relationship (EDPVR) was investigatedemploying the single-beat method described by Klotz et al.(2006).
Validation study
As provided above, Ees measurements in MS patientswere based on invasive pressure measurements atthe femoral artery level. However, invasive pressuremeasurements were not performed in controls and theEes in that group was calculated based on non-invasivesphygmomanometric measurements in the brachialartery. To investigate the relationship between the twodifferent approaches we performed a validation studyon 14 MS patients referred for PTMC in whomsimultaneous pressure measurements were performedsphygmonanometrically in the brachial artery andinvasively in the femoral artery.
Stratification of subjects by severity of MS
MS subjects were dichotomized post-hoc based on MVAof � 0.8 and > 0.8 cm2. Additionally, the MS group wasstratified based upon WS (low: �9; high: >9).
Echocardiographic and haemodynamic measurementsin controls
The 40 subjects constituting the control arm of the studyunderwent TTE and simultaneous sphygmomanometricmeasurements for pressure recordings at the left arm.Systolic (Ps brach) and diastolic brachial artery pressures(Pd brach) were recorded. With regard to echocardiographicdata, volumetric and quantitative two-dimensional andDoppler measurements were performed and analysed asassessed in the patient cohort. For measurements of Ea andEes, LVESP was estimated using the systolic brachial arterypressure as recorded sphygmomanometrically and derivedfrom the equation: LVESP = 0.9 × Ps brach. Similarly, for Ees
measurements eqns (3) and (4) were modified for controlsusing the non-invasive brachial artery pressures, i.e.:
E es(sb) = [Pd brach − (
E Nd(est) × LVESP)]
/
[SVDoppler×E Nd(est)] (3a)
and
E Nd (est) = 0.0275 − 0.165 ×+ 0.3656 x (Pd brach/P s brach) + 0.515 × E Nd (avg) (4a)
In controls, PCWP was calculated according to theequation PCWP = 1.24 [E/E′] + 1.9, as proposed byNagueh et al. (1997). In this equation, E denotes the peakearly transmitral inflow velocity (E wave) and the E′ isthe early myocardial tissue Doppler velocity at the lateralmitral annulus (Nagueh et al. 1997).
Based on the assumption that PCWP equals LVEDPin healthy individuals, LV end-diastolic chamber stiffnesswas estimated in controls using the two aforementionedmethods, i.e. the end diastolic pressure–volume ratio(Kass, 2000) and the single beat approach (Klotz et al.2006).
Statistical analysis
Statistical analysis was performed using SPSS version16.0 (SPSS Inc., Chicago, IL, USA). Continuous variableswere expressed as mean ± SD and categorical variablesin absolute values and percentage. The Shapiro–Wilktest was used to check normality. Continuous variableswere compared using the paired Student t test orthe Wilcoxon test. Controls were compared with studysubjects using the Mann–Whitney test. Correlationsbetween variables were tested by the Pearson two-tailedcorrelation. Multiple regression analysis was used toidentify independent confounders of end-diastolic LVstiffness. All tests were performed at 95% confidence inter-vals, and a P-value of < 0.05 was considered statisticallysignificant. Mann–Whitney U test was performed foranalysis of the difference between the predicted elastancevalues derived from the validation study and thecorresponding non-invasive values for controls. Analysisof inter- and intraobserver variability was performed forEes in 10 patients by two observers. Methodological error(Err) in a single measurement estimated from doublemeasurements was calculated according to formula:Err = (SDdiff × 100%)/(total mean × �2), where SDdiff
is the SD of the difference between the measurements(Dahlberg, 1940)
Results
Study population
Of the 120 patients enrolled, 14 were excluded due tosevere MR following leaflet tear during PTMC (n = 6),tamponade (n = 2), unsuccessful PTMC (n = 1) andincomplete oximetry data (n = 5). In effect, 106 subjects
(age 32 ± 8 years, 72% female) were analysed. Table 1summarizes the population characteristics. In total, 46%demonstrated markedly narrowed MVA (�0.8 cm2).Despite lower EF as compared to controls, LV contractilitywas significantly higher in MS patients (Ees: 4.1 ± 1.6 vs.2.4 ± 0.6 mmHg ml−1; P < 0.001).
LV and arterial elastance in MS
Ees was inversely associated with SV in the MS group(r =−0.66; P < 0.001). LVEDV did not differ significantly,but LVESV was larger among MS subjects as was afterload(Ea: 3.0 ± 1.3 vs. 1.5 ± 0.3 mmHg ml−1; P < 0.001).Figure 1 illustrates ESPVR in controls and MS subjects.Controls demonstrated a positive association between Ea
and LVEDV (r = 0.60; P < 0.001), whereas an inverserelationship was seen in the MS group (r = −0.73;P < 0.001) with a strong positive correlation between Ea
and Ees (r = 0.74; P < 0.001). Ea in the MS group wasinversely related to EF (r = −0.54; P < 0.001), exhibitinga weak association with heart rate (r = 0.34; P = 0.005).
MS severity and elastance
Patients with MVA � 0.8 cm2 (n = 47) displayed similarLV contractility (Ees: 4.3 ± 1.6 vs. 3.8 ± 1.7 mmHg ml−1;P > 0.05) but considerably higher Ea (3.3 ± 1.3 vs.2.8 ± 1.3 mmHg ml−1; P = 0.03) compared to the rest ofthe MS group. Subjects with high WS (n = 17) had elevatedarterial load compared to those with low WS (n = 85) (Ea:3.7 ± 1.7 vs. 3.0 ± 1.2 mmHg ml−1; P = 0.04), while Ees
between the two groups did not differ significantly (Ees:4.0 ± 1.5 vs. 4.6 ± 2.2 mmHg ml−1; P > 0.05).
Normal vs. reduced EF
Twenty-five MS patients (24%) exhibited reducedEF (� 55%). They showed significantly higher Ees
(5.5 ± 2.9 vs. 3.9 ± 1.4 mmHg ml−1; P = 0.01) andEa (5.1 ± 2.3 vs. 2.9 ± 1 mmHg ml−1; P < 0.001) as wellas more extensive subvalvular fusion (SVF: 3 ± 0.4 vs.3.4 ± 0.4, P < 0.05) compared to those with normal EF(n = 81).
As shown in Table 2, all MS subjects demonstrated elevatedintracardiac pressures and reduced CO. Immediately aftercommissurotomy, LVEDP (12 ± 4 to 16 ± 4 mmHg;P < 0.001) and cardiac index (CI; 2.5 ± 0.6 to 3.2 ± 0.8l min m−2; P < 0.001) rose significantly, with concomitantSVR (27 ± 8 to 21 ± 8 Wood Units; P < 0.001) and PVRreduction (4.5 ± 4 to 3.4 ± 3 Wood Units; P < 0.001); nosignificant changes in arterial pressures were noted.
Diastolic changes
In MS patients, LVEDP correlated significantly withRVEDP (r = 0.43, P < 0.001) and CI (r = 0.24, P < 0.05)and was elevated (>16 mmHg) in 24 cases (23%).Following PTMC, LVEDP further increased (>16 mmHgin 52% of the cases). LV stiffness was significantly higherin the MS group compared to controls both whenusing the EDPVR of the operant LV stiffness and whenestimating the beta value derived from the single beatapproach (Fig. 2). In the patient cohort, a reductionin LV stiffness occurred in only 11 patients. Whencomparing the two groups, patients with a reduction inchamber stiffness following PTMC had lower MVGmean
prior to PTMC as compared to the correspondinggroup with increased LV stiffness (MVGmean 15.7 ± 10.8vs. 20.8 ± 9.1 mmHg) and lower RVPs (44 ± 10.1vs. 63.5 ± 24 mmHg). Multiple regression analysisidentified RVEDP, Ea and MVAi as constituting the onlyindependent predictors of LV stiffness both before andafter PTMC as described by the regression equation:LV stiffness = 0.165 + 0.1 × RVEDP + 0.03 × Ea
−0.147 × MVAi, with an overall model fit of r2 = 0.41,F1,94 = 21, P < 0.001. Furthermore, RVEDP at baselineacted as the sole independent predictor of the magnitude
of augmentation of the beta value following dilatation ofthe MV (r = 0.41, P < 0.001). On the other hand, nocorrelation between LV stiffness and WS, SVF or age wasfound.
Haemodynamic alterations following PTMC
MVA increased in all cases following PTMC (0.8 ± 0.2 to1.6 ± 0.2 cm2; P < 0.001) with a corresponding reductionin the transmitral gradient (19 ± 9 to 5 ± 2 mmHg;P < 0.001) (Table 3). Immediately after PTMC, both Ees
(4.1 ± 1.6 to 3.5 ± 1.3 mmHg ml−1; P < 0.001) and Ea
(3.0 ± 1.6 to 2.6 ± 1.1 mmHg ml−1; P < 0.001) returnedto more normal values with a concomitant increase inpreload (LVEDV: 82 ± 2 to 90 ± 24 ml; P < 0.001), EF(60 ± 8 to 64 ± 8%; P < 0.001) and SVDoppler (49 ± 16to 57 ± 17 ml; P < 0.001). Importantly, both methods forassessing LV stiffness revealed a significant reduction inchamber compliance following PTMC, with higher betaand lower alpha values following PTMC, indicating rightand upward change in EDPVR following intervention.
Validation measurements
In the validation group comprising 14 MS patients,simultaneous pressures were acquired sphygmomanom-etrically at the brachial artery level and invasively atthe femoral artery level (Table 4). The non-invasiveEes measurements (Ees NI) were highly correlated tothe invasively derived Ees (Ees INV) (r2 = 0.94,Ees NI = 0.16 + 0.86 × Ees INV) although significantlylower (P = 0.005). Using the regression equationderived from the validation study, we calculated the pre-dicted Ees NI in our patient cohort to verify that theobserved difference between the Ees INV and non-invasive
Figure 1. Left ventricular end-systolicelastance (Ees) and arterial elastance (Ea) insevere rheumatic mitral stenosis (MS) ascompared to normal subjectsMS patients demonstrated significantly elevatedEes and Ea as compared to controls. Values shownhere represent the mean for the two study groups.
PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure, LAPm, left atrial mean pressure; LVEDP, left ventricularend diastolic pressure; LVESP; left ventricular end systolic pressure; RVEDP, right ventricular end diastolic pressure CI, cardiac index;PVR, pulmonary vascular resistance; SVR, systemic vascular resistance; Ees INV, invasively derived LV elastance; Ees NI, non-invasivelyderived estimated LV elastance; Ea INV, invasively derived arterial elastance; Ea NI, non-invasively derived estimated arterial elastance;EDPVR, end diastolic pressure–volume relation. P values indicate the significance of differences between pre- and post-PTMC data inthe MS group. Significant differences between the control and pre- or post PTMC MS group values are indicated by asterisks.
measurements in controls was valid. As shown in Table 4,the predicted Ees NI values in MS patients both before(Ees NI pre = 3.7 ± 1.4 mm Hg ml−1) and after PTMC(Ees NI post = 3.2 ± 1.1 mm Hg ml−1) were higher ascompared to the controls (Ees NI controls = 2.4 ± 0.6)(z = −4.4 and z = −2.2, respectively) with the meanEes NI pre and Ees NI post being 38 and 28% higher than thecorresponding values in controls.
Similarly, we calculated the predicted Ea valuesbased on the validation study. An excellent correlationbetween invasive (Ea INV) and non-invasively derived Ea NI
(r2 = 0.97, P < 0.001) was found in the validation group.As shown in Table 4, the Ea NI was lower as compared toEa INV (Ea NI = 0.04+0.87 × Ea INV, P < 0.001). Based onthat equation, the predicted Ea NI was calculated in ourpatient group both before and following PTMC (Table 3).We also inferred that MS patients showed significantlyhigher Ea values compared to controls, and this was validfor the measurements both before and after PTMC.
Inter- and intraobserver variability analysis showedrelatively low error for repeated measurements of Ees (7.7and 12.8% for intra- and interobserver measurements,respectively).
Discussion
To our knowledge, this is the largest invasive studyevaluating LV performance in patients with purerheumatic MS. Contrary to some previous reports,we demonstrate augmented LV contractility along withreduced LV compliance in severe MS. Our data indicatethat EF poorly describes the inherent LV performancein this patient population. The elevated arterial load isstrongly associated with LV stiffness and MS severity.Finally, the elevated LV contractility and afterload at base-line returned to more normal levels immediately followingPTMC, along with a further increase in LV stiffness.
LV performance in rheumatic MS has been an issueof debate with conflicting observations that might partlybe attributed to the load susceptibility of the variousmeasurements employed for the quantification of LVfunction (Ahmed et al. 1977; Kaku et al. 1988). Indeed,based on the analysis of indices such as EF, strokework as well as ESPVR and wall motion scoring, earlierstudies reported evidence of impaired LV function inMS patients (Heller & Carleton 1970; Curry et al. 1972;Hildner et al. 1972). Reduced SV in relation to LV
end-diastolic pressures at rest and during exercise aswell as depressed EF have been previously interpretedas indicative of impaired LV function in these patients(Horwitz et al. 1973). Regardless, given the limited pre-load recruitment secondary to MS, lower LV outputper se may not imply impaired ventricular performance.Similarly, circumferential fibre shortening rate (Vcf)was found to be reduced, thus arguing for myocardialdysfunction in this patient population (Holzer et al.1973). However, experimental studies demonstrated thatVcf varies inversely with afterload alterations (Covellet al. 1966; Urschel et al. 1968). In contrast, Ahmedand colleagues (Ahmed et al. 1977) assessed dP/dt/Pmax
and reported preserved LV contractile function in MSpatients, although later studies have shown that even thisapproach is subjected to load dependency, thus providingunreliable results in the setting of MS (Schmidt and Scheer,1981).
In the present report, LV function was assessed byESPVR, a relatively load-independent approach well suitedfor MS (Suga et al. 1973; Suga and Sagawa, 1974). Ourfindings refute the notion of impaired LV contractileperformance in severe MS advocated in previous studies.Instead, they indicate a state of elevated LV contra-ctility, as demonstrated by a roughly 40% higher Ees inMS patients compared to that of age-matched controls.A direct comparison of the single beat Ees with otherthan EF LV performance indices was not performedin the current study, and thus a detailed physiologicalexplanation of the discrepancy compared to previous
findings is not appropriate. However, in an attempt toapproach a constructive appreciation of the current resultswe suggest that they might reflect a less pronounced loadsensitivity of Ees as compared to other previously employedLV function measurements. Increased sympathetic activityhas been demonstrated in patients with MS and has beenascribed to the decreased SV secondary to the reducedspace of the mitral valve (Ashino et al. 1997). The depressedLV ventricular output would yield a reduction in afferentactivity of the baroreceptors, which has been consideredas a possible cause of sympathetic activation in thesepatients (Ashino et al. 1997). Apart from the elevated Ees,we demonstrate increased arterial load and systemic peri-pheral vascular resistance in MS patients as compared tocontrols, a constellation of findings that might advocateincreased sympathetic activity in our patient cohort.A significant association between sympathetic activityand systemic vascular resistance has been previouslydemonstrated (Ashino et al. 1997). The elevated LVelastance in MS patients as compared to controls in thepresent study stands in contrast to the findings of Liu et al.(1992) showing similar Ees values in MS patients comparedto controls. A plausible explanation for this disparity mightlie in the discrepancy of haemodynamic findings betweenthe two cohorts; in our study, MS subjects demonstratedlower CO (3.0 ± 1.0 vs. 3.7 ± 0.9 l min−1), higher LAP(26 ± 7 vs. 18 ± 7 mmHg) and higher PAPm (58 ± 24 vs. 41±13 mmHg). These haemodynamic discrepancies suggestlower baroreceptor sensitivity (Ferguson et al. 1990) andincreased atrial stretch (Koizumi et al. 1977; Ashino et al.
Figure 2. Left ventricular (LV) diastolic stiffness asexpressed by the ratio of LV end-diastolic pressure to LVend-diastolic volumePatients with MS demonstrated elevated LV stiffnesscompared to controls. Following percutaneous transvenousmitral commissurotomy (PTMC), a further significant increasein LV stiffness was documented.
HR, heart rate; LVEDV, left ventricular end diastolic volume; LVESV, left ventricular end systolic volume; SVDoppler, Doppler-derivedstroke volume; EF, ejection fraction; MVA, mitral valve area; MVG, mitral valve gradient.
1997), which in turn imply increased sympathetic toneand hence elevated contractility.
LV systolic function and arterial load
Consistent with previous results, our MS patientsdemonstrated significantly increased afterload (Liu et al.1992) with 24% of them showing reduced EF (< 55%)(Kennedy et al. 1970; Gash et al. 1983). Ees, however,was not significantly different in these patients, whereasarterial load was higher (Ea: 4.1 ± 1.9 vs. 2.8 ± 0.9,P < 0.001) compared to those with preserved EF. Theconcept of ventriculo-arterial coupling posits that EFis determined by the interaction between LV contra-ctility and afterload (Sunagawa et al. 1985). Providingthere are no alterations in contractility, PV loop analysissuggests that a 33% afterload reduction (representing themeasured difference between mean Ea in the two MSgroups) yields an EF increase of roughly 20%, consistentwith our results (Kass et al. 1990). Furthermore, with thereduction of Ea observed following PTMC (from 4.1 ± 1.9to 3.5 ± 1.7 mmHg ml−1), EF normalized (EF: 60±9%) inall cases with depressed LV performance at baseline. This,together with the significant inverse correlation betweenEa and EF, suggests that employing EF to describe LVperformance in severe MS can be misleading.
MS subjects demonstrated significantly higher LVESV,but not LVEDV, suggesting afterload mismatch (Ea vs.LVEDV, r = −0.75; P < 0.001) only partially compensatedfor by an increase in contractility (Ees vs. LVEDV, r = 0.61;P < 0.001). In normal hearts, afterload elevation iscountered by preload increase to prevent SV reduction.However, MS hinders adequate preload recruitment (MVAvs. LVEDV, r = 0.4; P < 0.001), thereby limiting preloadreserve. Hence, despite elevated Ees, the raised arterial loadcannot be overcome owing to a hampered Frank–Starlingmechanism, yielding lower SV. Although in normal heartsincreased LVESV often indicates reduced inotropy, a more
applicable explanation in MS could be a state of exhaustedcontractile reserve, or the LV’s inability to further increaseEes. This ‘ceiling effect’ in contractility may also beattributed to the inhibiting impact of β-blockers, partiallypreventing further increases in LV contractility.
LV performance and MS severity
Previous studies have demonstrated a rapid rise intension in the subvalvular apparatus (Salisbury et al.1963; Semafuko & Bowie, 1975) during isovolumetric LVcontraction, and a considerable reduction in Ees when thechordae were severed (Hansen et al. 1986). To investigatethe influence of mitral apparatus on LV performance,we sub-grouped our patients based on WS, degree ofchordal fusion and length separately. Although LV contra-ctility did not differ between these groups, subjects withEF < 55% displayed a significantly higher degree of sub-valvular fusion. Our results also suggest that LV afterloadis related to the degree of valvular deformation, as reflectedby increased Ea in patients with higher valve scores.
LV diastolic function in MS
Previous studies have shown reduced LV compliancein MS patients (Liu et al. 1992; Mayer et al. 1999).A number of possible mechanisms for this observationhave been proposed, including a mechanically mediatedincrease in LV stiffness by the rigid mitral apparatus(Heller & Carleton 1970; Curry et al. 1972), inherentmyocardial alterations due to rheumatic disease, aswell as altered RV loading and inter-ventricular inter-action with this condition (Mayer et al. 1999). Ourresults provide important details regarding the possibleunderlying mechanisms of the reduced end-diastolic LVcompliance in MS patients. First, we show that thedegree of MV stenosis could independently predict the
Ees, LV elastance; Ea, effective arterial elastance.
degree of LV compliance. In that sense a more rigid andimmobile valvular apparatus could act in a constrainingmanner reducing the distensibility of the LV duringdiastolic filling, as suggested by Liu et al. (1992). Moreimportantly, RVEDP was identified as a strong predictorof end-diastolic LV stiffness. The role of inter-ventricularinteraction in the setting of EDPVR has been suggestedby Curry et al. (1972). In their study, MS patients withenlarged RV, reflecting increased RV preload, displayedimpaired anterolateral wall motion and LV function; thisobservation was ascribed to the mechanical influenceof the RV. Another group of investigators showed thatRVEDP was associated with LV diastolic conditions in MSpatients (Mayer et al. 1999). It has been suggested thata right to left interaction in MS might be secondary toalterations in anterolateral wall motion due to RV pressureoverload (Nagel et al. 1996).
Acute haemodynamic alterations following PTMC
Following PTMC, SV and LVEDV rose significantly,while Ees returned to more normal values. SV elevationwas directly related to the effect of the Frank–Starlingmechanism (�LVEDV vs. �SV; r = 0.73, P < 0.001),suggesting that following MV dilatation, the LV counter-acts afterload mismatch by recruiting preload reserve.Hence, the fall of LV elastance following PTMC canbe assigned partly to SV increase after the inter-vention (�SV vs. �Ees; r = −0.37, P < 0.001) as theincreased SV is expected to yield afferent parasympatheticbaroreceptor stimulation. This in turn would inhibitsympathetic systemic output, resulting in lower arterialtonus (Ea reduction) and less pronounced LV contra-ctility. Normalization of the baroreceptor reflex functionhas been attributed to CI increase and occurs within1 week following PTMC (Ashino et al. 1997). Ourfindings imply that the arterial pressor reflexes maybe reactivated immediately following valve dilatation,supporting the notion that their function is impaireddue to haemodynamic rather than structural alterations(Ferguson et al. 1989). An intriguing finding of the pre-sent study is that LV end-diastolic stiffness showed astatistically significant albeit slight increase immediatelyafter dilatation of the MV when employing two separate
non-invasive measurements of chamber stiffness. In fact,an elevation of chamber stiffness was noted in roughly 90%of the patients. Our data provide a plausible explanationfor this finding as we have identified RV preload as the onlyindependent predictor of the increases in EDPVR slopefollowing PTMC. The presence of a non-distensible peri-cardium surrounding the two ventricles and the commonseptal wall shared by the two chambers contribute to thehaemodynamic interaction between the two ventricles.In particular, the diastolic interaction between the twochambers has been increasingly recognized recently. Inthe setting of MS, the increased RVEDP occurring inMS due to pulmonary hypertension might be a plausibleexplanation for the increased LV stiffness. The observationthat RVEDP did not change significantly following inter-vention, despite a significant fall in systolic RV pressures,adds weight to this hypothesis as after opening of the MVthe LV has to accommodate larger volumes (increase inLVEDV). This would add a further constraint and thuslead to elevated LV stiffness. Although the present studydid not investigate possible changes in myocardial stiffnessfollowing PTMC, it appears not to provide a plausibleexplanation for the altered LV chamber stiffness observedafter MV dilatation.
Clinical implications
EF is misleading when studying LV performance inpatients with MS as a result of the elevated LV after-load. The single-beat approach to measuring Ees providesa feasible, more comprehensive evaluation of LV function.Optimal pharmacological inhibition of the adrenergicactivation might have a beneficial effect in MS patients.
Limitations
In the present study, non-invasive indices of LV andarterial function were used. LV end-diastolic stiffness andLV elastance as well as arterial elastance are optimallyrecorded using conductance catheters. However, all theaforementioned non-invasive measurements are validatedagainst gold standard invasive methods (Kelly et al.1992; Kass, 2000; Chen et al. 2001). Additionally, inour study, we calculated Ees and Ea using the invasively
J Physiol 593.8 Arterial load and LV performance in MS 1911
derived pressures, whereas in the controls non-invasivepressure measurements were performed for the samereason. This limitation of the study was addressed bya validation study. The predicted values for the patientcohort, although different from the invasive data, did notalter the results of the study. Furthermore, in controlsLV chamber stiffness was measured using PCWP valuesestimated using a previously proposed equation (Naguehet al. 1997). As the authors in that study reported astandard error of approximately 4 mmHg, this wouldresult in overlap in LV stiffness between MS patients andcontrols. To resolve this concern we proceeded by usinga PCWP value of 11 mmHg for all healthy controls (thegenerally accepted upper normal value in young healthysubjects). Measurements of LV stiffness thus revealed thateven in that extreme case LV stiffness in controls wassignificantly lower (0.2 ± 0.03 mmHg ml−1) as comparedto MS patients (P < 0.001). Doppler and two-dimensionalechocardiographic measurements entail an inherentlylarger variability compared to invasive measurements. Onthe other hand, measurements of intra- and interobservervariation performed for Ees show a rather low variationfor repeated single measurements. Finally, patients in ourstudy had advanced rheumatic MS (WS > 8 in 56% ofcases) and may not represent the haemodynamic statein less severe degrees of stenosis. However, the study addsimportant physiological insight into severe rheumatic MS.
Conclusion
Subjects with severe MS exhibit a hypercontractile LV,most probably reflecting an increased sympathetic tone.With preload recruitment immediately following PTMC,LV afterload and contractility tend to normalize in mostpatients. Finally, we demonstrate that heightened arterialload is associated with MS severity.
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Additional information
Competing interests
No extramural funding was used to support this work. None ofthe authors have any conflict of interest to disclose. The authorsare solely responsible for the design and conduct of this study,all study analyses and drafting and editing of the paper. Allauthors take responsibility for all aspects of the reliability andfreedom from bias of the data presented and their discussedinterpretation.
Author contributions
A.M., A.V., A.I.N., S.S. and R.W. designed the study; A.V.,A.M., B.B. and P.K.D. performed invasive and echocardiographicmeasurements; A.V., A.M., A.I.N., K.S., S.C.G., A.S., R.W., B.B.and P.K.D. contributed to analysis and interpretation of thedata; A.V., A.M. and A.I.N. wrote the manuscript. K.S., S.C.G.,A.S., R.W., B.B. and P.K.D. revised the manuscript critically. Allauthors have read and approved the final manuscript.
Methods and results Invasive hemodynamic and echo-cardiographic data of 120 patients with PH due to severe rheumatic mitral stenosis before and immediately after per-cutaneous valvulotomy, along with 40 age-matched healthy controls, were analyzed. Effective arterial (Ea) and ven-tricular elastance (Ees) were measured. PH patients dem-onstrated elevated LV afterload (Ea) along with AV uncou-pling, and these derangements were more evident in the Cpc-PH group [Ea: 3.3 (2.3–5.4) vs 2.6 (2.1–3.5) mmHg/mL, Ea/Ees: 0.73 (0.6–0.9) vs 0.88 (0.7–1.2), p < 0.05]. In addition, PH was associated with reduced LV deforma-tion, which was mainly determined by elevated Ea, while the effect of interventricular interaction was limited to the septal wall.Conclusions Our results suggest that in addition to the interventricular interaction, an abnormal AV coupling con-tributes to the altered LV mechanics that has been associ-ated with adverse prognosis in Cpc-PH.
AbbreviationsAV Arterial-ventricularBSA Body surface areaCI Cardiac indexCpc-PH Combined pre- and post-capillary pulmonary
hypertensionDPG Diastolic pulmonary pressure gradientEa Effective arterial elastanceEDV End-diastolic volumeEes Left ventricular elastanceEF Ejection fractionESV End-systolic volumeLA Left atrium
Abstract Background Isolated post-capillary pulmonary hyperten-sion (Ipc-PH) is characterized by elevated left atrial pres-sures that are passively transmitted upstream, whereas com-bined pre- and post-capillary PH (Cpc-PH) demonstrates additional reactive changes in pulmonary vasculature. The increased load imposed on the right ventricle (RV) influ-ences left ventricular (LV) mechanics by means of inter-ventricular interaction. However, there is lack of evidence to substantiate the effect of possible additional alterations in the arterio-ventricular (AV) coupling and their effect on LV function. Considering the discrepant RV load in Cpc-PH and Ipc-PH, we sought to investigate whether these two conditions are also characterized by differential alterations in AV coupling.
Communicated by Keith Phillip George.
A. I. Nagy and A. Manouras contributed equally to this work.
Electronic supplementary material The online version of this article (doi:10.1007/s00421-016-3393-z) contains supplementary material, which is available to authorized users.
LAP Left atrial mean pressureLHD Left heart diseaseLS Longitudinal strainLV Left ventricleLVEDP Left ventricular end-diastolic pressureLVESP Left ventricular end-systolic pressureLV-LS Global left ventricular longitudinal strainLV-LSlat Longitudinal strain of the LV lateral wallLV-LSsept Longitudinal strain of the septal wallMS Mitral stenosisPAPd Pulmonary arterial diastolic pressurePAPm Pulmonary arterial mean pressurePAWP Pulmonary artery wedge pressurePd Diastolic systemic arterial pressurePH Pulmonary hypertensionPm Mean systemic arterial pressureIpc-PH Isolated post-capillary pulmonary hypertensionPs Systolic systemic arterial pressurePTMC Percutaneous transvenous mitral
commissurotomyPVR Pulmonary vascular resistanceRV Right ventricleRVEDP Right ventricular end-diastolic pressureRVSP Right ventricular end-systolic pressureRV-LS Longitudinal strain of the RV free wallSV Stroke volumeTAPSE Tricuspid annular plane systolic excursionTPG Transpulmonary gradient
Introduction
Pulmonary hypertension (PH) is frequently associated with left heart disease and carries an independent prog-nostic impact on mortality (McGoon and Kane 2009; Ghio et al. 2001; Grigioni et al. 2006). Elevated left atrial pres-sure (LAP) due to left ventricular (LV) dysfunction or val-vular disease is passively transmitted through the pulmo-nary capillaries yielding pulmonary artery pressure (PAP) increase. In the setting of isolated post-capillary PH (Ipc-PH), this is governed solely by LAP rise. However, in cer-tain patients, reactive functional and structural alterations in the pulmonary vasculature result in a disproportionate PAP elevation, inadequately explained by a post-capillary pressure rise alone. This condition, currently referred to as combined post- and pre-capillary PH (Cpc-PH), results in a further aggravated right ventricular (RV) afterload. The current PH guidelines suggest that the diastolic pulmonary gradient (DPG) is a reliable index to differentiate these two PH sub-groups (Galie et al. 2016). Considering the inverse association of RV function with RV outflow impedance and the fact that RV dysfunction is an established independent determinant of outcome in PH, (Ghio et al. 2001; Meyer
et al. 2010; Abramson et al. 1992) Cpc-PH is known to showcase a worse prognosis as compared to Ipc-PH (Miller et al. 2013; Gerges et al. 2013). In addition, considering the inherent interdependence between the left and right ventricle, an elevated right-sided pressure might influence LV performance and, subsequently, impact systemic ven-tricular-arterial interaction. Given the maladaptive changes in the pulmonary vasculature of Cpc-PH subjects and the increased RV impedance, we hypothesized that these two PH groups might also demonstrate distinctive patterns in systemic arterial circulation. Hence, we aimed to investi-gate systemic AV coupling in a large homogenous cohort of young individuals, free from comorbidities, with PH secondary-to-rheumatic MS.
Methods
Study population
120 consecutive MS patients in sinus rhythm, referred to the Sri Sathya Sai Institute for percutaneous transvenous mitral commissurotomy (PTMC) and 40 age-matched healthy individuals, were enrolled prospectively. Subjects with concomitant aortic valve disease, >1 grade mitral regurgitation, ischemic heart disease, systemic hyperten-sion, or diabetes mellitus were not included. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. It was approved by the local insti-tutional review board [Sri Sathya Sai Institute of Higher Medical Sciences Ethics Committee (ESC/12/187/02)]; all subjects provided written informed consent.
Echocardiography
All MS subjects underwent transthoracic echocardio-gram (TTE) using a GE Vivid E9 system (GE Ultrasound, Horten, Norway) and a 2.5 MHz matrix array transducer in keeping with the current recommendations (Lang et al. 2005). LV elastance measurements were derived from simultaneously acquired LV volumes by echocardiography and invasive pressures just prior to the PTMC. The echo-cardiographic and invasive recordings were then repeated within 5 min following PTMC.
LV end-systolic (LVESV) and end-diastolic volumes (LVEDV), and ejection fraction (EF) were measured according to the current recommendations, employing the Simpsons biplane method from 2D TTE 4- and two-cham-ber apical recordings (Lang et al. 2005). Stroke volume (SVDoppler) was calculated by multiplying the cross-sec-tional area of LV outflow tract (LVOT) with the Doppler-derived velocity time integral (VTILVOT). Mitral valve area (MVA) was measured by planimetry and MR graded
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semi-quantitatively. Continuous-wave (CW) and pulsed-wave (PW) recordings of the inflow mitral velocities (E and A wave) were performed. The mean transmitral gradient (MVGmean) was measured using the CW recordings accord-ing to the recommendations. The Wilkins score (WS) was employed to assess valve suitability for the procedure (Palacios et al. 1988). All analyses were performed offline (EchoPac PC, GE Ultrasound, Waukesha, Wisconsin).
Invasive hemodynamics
Patients underwent simultaneous RV and LV catheteri-zation. A 6F Swan-Ganz and a 6F pigtail catheter was advanced from femoral access to the pulmonary artery and LV, respectively. Right-sided pressures were measured under fluoroscopic guidance after careful catheter calibra-tion. Systolic, mean, and diastolic arterial pressures (Ps, Pm, and Pd, respectively) at the femoral artery level were meas-ured. The zero-pressure level was set at the mid-thoracic line. Trans-septal puncture was performed with an 8F Mul-lins sheath, dilator, and a Brockenbrough needle. Left atrial pressures (LAP) were subsequently recorded. Pressure tracings were stored (WITT Series III, Witt Biomedical Corp., Melbourne, FL) and analyzed offline. PTMC was performed using a 24-to-28-mm Accura balloon catheter (Vascular Concepts, Essex, UK) by an expert (PKD) who has performed >4000 procedures. The procedure was con-sidered successful if the resultant MVA was >1.5 cm2 with less than +1 grade increase in MR. No anesthetics were used apart from local subcutaneous lidocaine. All pres-sure recordings were performed in a minimum of five heart cycles at end-expiration and stored for the offline analysis. Subsequently, pressures were assessed manually at end-expiration by a single investigator, limiting possible erro-neous computerized PAPD measurements and preventing potential underestimation of PAWP resulting from averag-ing pressures throughout the respiratory cycle (Ryan et al. 2012).
Cardiac output (CO) was calculated employing the esti-mated Fick’s method; Pulmonary vascular resistance was assessed as PVR = (PAPm − PAWP)/CO; transpulmonary gradient as TPG = PAPm − PAWP; and diastolic pulmo-nary gradient as DPG = PAPd − PAWP.
Definitions and subset classification
Post-capillary PH was defined as PAPm ≥ 25 mmHg and PAWP > 15 mmHg, and was subdivided into Ipc-PH and Cpc-PH based on the DPG (DPG < 7 mmHg as Ipc-PH, DPG ≥ 7 mmHg as Cpc-PH). An additional analysis of the sub-groups, as defined by the TPG (TPG ≤ 12 mmHg as Ipc-PH, TPG > 12 mmHg as Cpc-PH), was also performed; the results of this are presented in Supplementary Tables 1 and 2.
Indices of estimated arterial‑ventricular coupling
Measurements of LV contractility (Ees) and effective arte-rial afterload (Ea) were derived from simultaneously acquired echocardiographic volumes and catheterization-derived pressures in patients; while in controls, non-inva-sive cuff pressure measurements were used.
Ea constitutes a “lumped index” of LV afterload in the time-domain and was calculated as Ea = LVESP/SVDoppler . For the study’s purposes, the calculation of Ea was per-formed based on the estimated LVESP values, as derived from the equation LVESP = 0.9× Ps fem, as this accurately approximates LVESP in pressure–volume loop measure-ments, and has widely been used to estimate ventriculo-arterial coupling (Kelly et al. 1992). More specifically, in MS patients, Ea was calculated invasively (Ea INV) using the Ps recorded from the femoral artery. In addition, non-inva-sive estimated Ea (Ea NI) was calculated using the regres-sion equation derived from the validation group for the measurement to be corresponding to the Ea NI assessment in controls.
Ees was calculated as Ees(sb) = [Pd − (ENd(est)×
LVESP)]/[SVDoppler × ENd(est)] where ENd(est) represents group-averaged normalized Ees values obtained as a func-tion of EF and the ratio between diastolic (Pd) and systolic (Ps) arterial pressure as described by the equation:
ENd(est) = 0.0275− 0.165× EF+ 0.3656× (Pd/Ps)+
0.515 × ENd(avg) . In this equation, ENd(avg) is given by a seven-term polynomial function:
where summation is performed for i = 0–7, using values for ai of [0.35695; −7.2266; 74.249; −307.39; 684.54; −856.92; 571.95; and −159.1], respectively. tNd was calculated as the ratio of the pre-ejection period and the total systolic period, with time intervals determined from Doppler measurements. The ratio of the arterial elastance (Ea) to the ventricular elastance (Ees) describ-ing the AV coupling, as proposed by Suga (1969), was calculated to evaluate the mechanical efficiency of the cardiovascular system and the interaction between car-diac performance and vascular function. LV stiffness, defined as the instantaneous relationship between LV end-diastolic pressure and volume, was estimated as: LVEDP/LVEDV.
Validation study
Ees and Ea values were based on invasively measured pres-sures in MS patients, while in controls on sphygmomano-metric measurements. To document the relationship between the two approaches, we performed a validation
ENd(avg) =∑
i=0
ai × tiNd
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study on 14 PTMC candidates with simultaneous sphyg-momanometric and invasive pressure measurements. Based on those results, a regression equation was created, and estimated non-invasive Ees and Ea values for the whole study patient cohort were calculated.
Statistical analysis
SPSS version 16.0 for Windows (SPSS Inc., Chicago, Ill. USA) was used. Continuous variables are expressed as mean ± SD and categorical variables in absolute val-ues and percentage. The Shapiro–Wilk test was used to check normality. Continuous variables were compared using the paired Student t-test or the Wilcoxon test. Con-trols were compared with study subjects using the Man-Whitney test. For multiple comparisons between controls, Ipc-PH and Cpc-PH groups, we employed the non-para-metric Kruskal–Wallis H, and proceeded with a one-way ANOVA using the Bonferroni correction. Correlations between variables were tested by the Pearson 2-tailed correlation. All tests were performed at 95 % confidence intervals, and a p value of <0.05 was considered as statis-tically significant.
Results
Study population and demographics
We enrolled 120 patients, of which 14 were excluded due to procedural complications. 94 subjects fulfilled the cri-teria of post-capillary PH; 74 were classified as Ipc-PH and 20 as Cpc-PH based on the DPG. 58 % of the patients displayed NYHA Class II and 42 % NYHA Class III heart failure symptoms. No significant differences in age or gender were observed between Cpc-PH and Ipc-PH sub-jects (p > 0.05). Cpc-PH subjects demonstrated higher heart rates as compared to the Ipc-PH group and controls (p < 0.05 for both comparisons), and lower EF as compared to controls (p < 0.05). No significant differences were observed in mitral stenosis severity as far as MAVA, mean gradient or LA volume was concerned. Demographic and clinical parameters are summarized in Table 1.
Right ventricular indices in PH subjects
Cpc-PH patients displayed higher right heart pressures and more pronounced impairment of RV function com-pared to Ipc-PH. More specifically, these subjects dem-onstrated larger RA area and RV diameter than controls (p < 0.01 and p < 0.001, respectively) and Ipc-PH (p < 0.01 and p < 0.001, respectively). RV strain was significantly lower in Cpc-PH as compared to Ipc-PH (p < 0.016), while TAPSE did not significantly differ between the two PH groups (p > 0.05). In addition, TAPSE and RV strain were higher in controls compared to both Cpc-PH (p = 0.003 and p < 0.001, respectively) and the Ipc-PH (p < 0.001 for both comparisons).
Left ventricular indices in PH subjects
As seen in Table 2, PH subjects demonstrated lower SVi than controls, with significantly lower values in Cpc-PH. Although the patient group showcased lower EF, contrac-tility, represented by Ees, was significantly higher as com-pared to controls. LV afterload, as described by Ea, was ele-vated in PH subjects, with significantly higher values in the Cpc-PH cohort (Tables 2, 3; Fig. 1). LVEDP was slightly elevated in the PH cohort with increased LV diastolic stiff-ness compared to controls. Measurements of LV diastolic stiffness were similar in the two PH groups. Both Ea/Ees ratio (r = 0.27, p < 005) and Ea (r = 0.30, p < 0.05) were found to be significantly associated with DPG employing linear regression analysis.
Table 1 Demographics and MS characteristics
Ipc-PH isolated post-capillary pulmonary hypertension (PH), Cpc-PH combined post- and pre-capillary PH, BSA body surface area, HR heart rate, EF ejection fraction, MS mitral stenosis, MAVA mitral valve area, MVG mean mitral valve pressure gradient, LA-ESVi left atrial end-systolic volume indexed to body surface area
* indicates significant difference (p < 0.05) compared to control, † indicates significant difference (p < 0.05) between patient groups, n indicates patient number
Controls (n = 40)
Ipc-PH (n) Cpc-PH (n)
Age (years) 31 ± 6 32 ± 9 (74) 31 ± 9 (20)
Female (%) 70 71 75
BSA (m2) 1.4 ± 0.2 (74) 1.4 ± 0.2 (20)
Medication
Beta blockers 100 % 100 %
Diuretics 100 % 100 %
HR (bpm) 76 ± 10 73 ± 13† (74) 82 ± 14* (20)
EF (%) 66 ± 6 60 ± 8* (74) 58 ± 11* (20)
MS severity
MAVA (cm2) 0.90 ± 0.2 (74) 0.85 ± 0.2 (20)
MVG (mmHg) 19.9 ± 8.4† (74) 24.5 ± 9.8 (20)
Wilkins score 8.8 ± 0.8 (74) 8.8 ± 0.9 (20)
LA-ESVi (mL/m2)
68 ± 20 (74) 66 ± 15 (20)
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Ventricular interaction in PH subjects
Multivariate regression analysis was performed to study the association between LV afterload, which is directly influ-enced by SV, and degree of LV inflow obstruction and RV
function. Importantly, this analysis revealed no associa-tion between mitral valve area and Ea (p < 0.05). Instead, Ea correlated with the degree of PH and RV function (Ea = 4.61+ 0.2× PAPm − 0.13× TAPSE, r = 0.43, p < 0.001) ). SVR demonstrated similar associations
Table 2 Echocardiographic and hemodynamic measurements in Ipc-PH and Cpc-PH, as defined by DPG
Ipc-PH isolated post-capillary pulmonary hypertension (PH), Cpc-PH combined post- and pre-capillary PH, EDVi LV end-diastolic volume index, ESVi LV end-systolic volume index, SVi stroke volume index, LV-LS LV longitudinal strain in the septal and lateral wall, respectively, V0 estimated LV volume at zero pressure, Ees INV invasively derived LV elastance, Ees NI non-invasively derived estimated LV elastance, Ea INV invasively derived arterial elastance, Ea NI non-invasively derived estimated arterial elastance, RA right atrium, RVIDb RV basal internal diameter, TAPSE tricuspid annular systolic excursion, RV-LSlat RV lateral wall longitudinal strain, PAWP pulmonary arterial wedge pressure, PAPs, PAPd, and PAPm pulmo-nary artery systolic, diastolic, and mean pressure, respectively, RVEDP right ventricular end-diastolic pres-sure, RAP right atrial pressure, PVR pulmonary vascular resistance, CI cardiac index, SBP and DBP sys-tolic and diastolic systemic blood pressure, respectively, SVR systemic vascular resistance
† indicates significance at the level of p < 0.05 between patients and controls, * indicates significance at the level of p < 0.05 between Cpc-PH and Ipc-PH patients
(SVR = 40.1+ 0.6× PAPm − 0.89× TAPSE, r = 0.34, p < 0.001) . Furthermore, the sole independent predictor of Ees was Ea, which accounted for 55 % of Ees variance (r = 0.63, p < 0.001). As revealed in Table 2, the Ea/Ees ratio was sig-nificantly higher in the PH cohort as compared to the con-trol group, with a more pronounced elevation in the Cpc-PH than Ipc-PH subgroup (p < 0.001).
We proceeded to separately investigate the effect of AV and interventricular influence on LV myocardial mechanics in PH patients. Ea was identified as the single factor indepen-dently associated with LV systolic deformation as expressed by global LV-strain (r = 0.47, p < 0.05). The differential effect of RV function and AV interaction on the septal and lateral LV wall mechanics was subsequently investigated. Interestingly, in a linear regression model, Ea and RV-LS cor-related with LV-LSsept (r = 0.43, p < 0.001), whereas RV-LS
Table 3 Hemodynamic measurements in Ipc-PH and Cpc-PH, before and immediately after PTMC
PTMC percutaneous transvenous mitral commissurotomy, Ipc-PH isolated post-capillary pulmonary hyper-tension (PH), Cpc-PH combined post- and pre-capillary PH, HR heart rate, LAP left atrial pressure, PCWP pulmonary capillary wedge pressure, ∆LAP pre- vs post-PTMC left atrial pressure difference, PAPs, PAPd, and PAPm pulmonary artery systolic, diastolic, and mean pressure, respectively, RVEDP right ventricular end-diastolic pressure, RAP right atrial pressure, PVR pulmonary vascular resistance, RVSWi Right ventric-ular stroke work index, CI cardiac index, LVEDP left ventricular end-diastolic pressure, LVESP left ventri-cle end-systolic pressure, SVR systemic vascular resistance, Ees INV invasively derived LV elastance, Ea INV invasively derived arterial elastance
* indicates significance at the level of p < 0.001 between the Cpc-PH and the Ipc-PH before and after PTMC
Fig. 1 Left ventricular end-systolic pressure–volume relationship (ESPVR) in Ipc-PH (red) vs Cpc-PH (blue) patients. Cpc-PH patients demonstrated significantly elevated end-systolic elastance (Ees) and arterial elastance (Ea) compared to Ipc-PH. Values shown here repre-sent the mean for the two study groups
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did not significantly correlate with LV-LSlat (p > 0.05). How-ever, Ea retained its prognostic ability and together with Ees were the only independent correlates of the LV-LSlat (r = 0.38, p < 0.001). PAPm correlated inversely with RV-LS (r = −0.36, p < 0.001) and LV-LSsept (r = −0.26, p = 0.009), whereas it was not significantly associated with LV-LSlat.
Reversibility of Cpc‑PH following PTMC
In 6 of the 20 patients with Cpc-PH, the pre-capillary com-ponent was reversed (DPG < 7 mmHg) immediately fol-lowing PTMC. Compared to the corresponding group with-out significant reversibility, patients with DPG < 7-mm Hg after PTMC had less pronounced increase of LV contractil-ity (Ees: 2.6 ± 1.6 vs 4.9 ± 2.3; p < 0.05) and demonstrated a tendency to lower systemic afterload (Ea: 4.4 ± 2.4 vs 3.0 ± 0.8, p = 0. 055). There were no significant differ-ences between the two groups in regard to pulmonary pres-sures and TAPSE (p > 0.05).
Discussion
To our knowledge, this is the first large-scale prospec-tive study investigating distinctive hemodynamic features of Cpc-PH and Ipc-PH in patients with severe MS. We demonstrate that (1), in conjunction with the markedly elevated RV afterload, patients with Cpc-PH show sig-nificantly higher systemic arterial load than Ipc-PH; and (2) previously demonstrated impairment in LV mechanics is determined in major part by an increased arterial load and to a lesser degree by the direct effect of ventricular interdependence.
Hemodynamic alterations in Ipc‑PH vs Cpc‑PH
Roughly 20 % of the patients exhibited Cpc-PH, compa-rable to the prevalence of Cpc-PH among patients with impaired LV function, and in keeping with the analogous histological pulmonary vascular alterations observed in MS- and LV dysfunction-derived PH (Delgado et al. 2005). There is conflicting evidence regarding potential hemody-namic disparities between Cpc-PH and Ipc-PH. Our find-ings contrast those of a recent retrospective study which did not demonstrate significant hemodynamic differences between the two PH sub-groups (Berger et al. 2012). Simi-lar to the results of Miller and colleagues, Cpc-PH patients in our cohort exhibited more pronounced hemodynamic derangements than Ipc-PH. In Miller’s report, however, PAWP did not differ between the two PH groups, (Miller et al. 2013) which opposes our findings of significantly higher PAWP in Cpc-PH compared to Ipc-PH. Differences in patient profiles might explain this discrepancy. In the
afore-mentioned study, age was an independent determi-nant of Cpc-PH, indicating more longstanding LAP eleva-tion, thus potentially more pronounced structural changes in the pulmonary capillaries (Miller et al. 2013). Our patients were younger and age failed to exert any discrimi-native effect on the PH subtypes, which advocates for more reactive pre-capillary responses to LAP elevation rather than structural alterations. Hence, it could be argued that at early stages of PH, LAP contributes to the degree of pre-capillary vasoreactivity, while later, the structural vascular changes being more fixed, LAP elevations have a less pro-nounced effect on PVR.
Importantly, we demonstrate that Cpc-PH in MS sub-jects is characterized by increased resistance not only in the pulmonary, but also in the systemic circulation as indicated by elevated Ea and SVR as compared to Ipc-PH and controls. In addition, the inherent LV contractility, as described by Ees, was elevated in PH patients. Esti-mated AV coupling, described by the ratio of the arterial elastance (Ea) to the ventricular elastance (Ees), is known to be a reliable measure of mechanical efficiency of the cardiovascular system (Suga 1969; Sunagawa et al. 1983). The significant elevation of Ea/Ees in the PH cohort with higher values in the Cpc-PH group suggests an associa-tion between PH status and a state of arterial-ventricular uncoupling. Aberrant interaction between the left ventri-cle and vascular system demonstrates a relationship with more pronounced changes in the pulmonary vascular tree. Moreover, we show that the Ea/Ees demonstrates a weak, albeit a significant association with measurements of the pulmonary arterial changes as expressed by DPG, and this association was driven by Ea. Previous experimen-tal studies have demonstrated reflex-mediated systemic vasoconstriction in response to pressure elevation sensed by the pulmonary baroreceptors (McMahon et al. 2000; Moore et al. 2004). Furthermore, LV under-filling due to MS implies a relative deactivation of aortic baroreceptors, resulting in elevated efferent sympathetic stimulation. Although the current study was not designed to investi-gate the neurohumoral discrepancies between Ipc-PH and Cpc-PH, altered baroreceptor reflex activity might also contribute to the increased resistance in the pulmonary circulation, in addition to the increased systemic after-load (Aviado et al. 1967). Similar to our results, Miller et al. demonstrated higher SVR in Cpc-PH patients with PH due to left heart disease (LHD) (Miller et al. 2013). Evidently, the effects of severe MS on the pulmonary and the systemic hemodynamics differ in many ways from the other types of left heart dysfunction. In addition, patients with primary diastolic LV impairment are generally older with multiple comorbidities significantly influencing the vascular elasticity. Although the afore-mentioned dispari-ties between patient cohorts must be acknowledged, the
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finding of increased systemic load in the state of Cpc-PH is intriguing and warrants further studies to investigate potential differences in adrenergic activity between the two sub-groups of PH due to LHD (Chatterjee and Lewis 2011; Miller et al. 2013).
Determinants of LV mechanics in MS‑derived PH
Evidence regarding the influence of PH on LV function is conflicting (Hardegree et al. 2013; Puwanant et al. 2010). Elevated PAP has been shown to affect LV geom-etry, resulting in reduced myocardial deformation of the septal (Huez et al. 2007; Puwanant et al. 2010), but not the lateral LV wall (Puwanant et al. 2010). Conversely, other investigators demonstrated reduced LV-LSlat in PH patients, the degree of which entailed a significant prog-nostic value on mortality (Hardegree et al. 2013). We found a significant association between LV contractility and RV function (RV-LS) that indicates an interaction between the two ventricles during systole (Belenkie et al. 1995). In our cohort, myocardial strain reduction was not restricted to the septal, but was also evident in the lat-eral LV wall. More importantly, the LV-LS reduction was mainly ascribed to elevated LV afterload; whereas in line with the findings of Punawant and colleagues (2010), the impact of RV afterload on the LV function was confined to the septum.
As myocardial strain might be influenced by loading conditions, (Burns et al. 2010), we chose to evaluate LV function using the end-systolic pressure–volume relation-ship, a method relatively robust to load changes. Interest-ingly, despite a lower LV-LS and EF, the inherent LV con-tractility was elevated in PH patients compared to controls.
A plausible physiological explanation for the elevated systemic arterial load and increased inotropic state in our patient cohort might lie in hampered baroreceptor activity due to SV reduction (Ferguson et al. 1990) in PH patients (Fig. 2). Further studies involving direct measurement of sympathetic activity are needed to confirm this hypothesis, both in this patient population, as well in patients with PH due to the other causes of left heart disease.
Limitations
Ees was measured using the non-invasive single-beat approach. However, this method has been well validated against conductance catheters; (Chen et al. 2001) in addi-tion, Ees in our control group was similar to the reported reference values, which confirms the method’s validity (Chen et al. 1998). Ees and Ea in patients were calculated using invasive pressure measurement, while in controls non-invasive pressure measurement. This discrepancy was
addressed by the validation study (supplementary Table 3) (Venkateshvaran et al. 2015).
Importantly, the hemodynamics in MS, as well as the patient profile of the present study differ from the other forms of PH due to LHD; thus, the current findings can-not directly be generalized. However, we believe that the investigated cohort provides a good model due to the homogeneous pathophysiological basis of PH and the lack of comorbidities.
Direct measurement of sympathetic activity employing techniques, such as microneurography or noradrenaline radiotracer methods, was not performed. Therefore, the proposed role of neuro-hormonal factors remains specula-tive and needs to be further investigated.
Compliance with ethical standards
Conflict of interest No conflict of interest to be declared.
Funding This study was not supported by extramural funding. We certify that this work has not previously been published/presented in any form.
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point, DPG calculated using z-point of the PAWP curve; SD, standard deviation.
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Typewritten text
Figure 1. Correlations between V-wave amplitude and A) DPG, B) TPG, C) PAWPm, D) PAPD in patients with low and high PVR E) Correlation between V-wave amplitude and Delta PG in MS and PH-LHD. Legend details provided in manuscript.
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Figure 2A, Kaplan Meier analysis for the three diastolic pulmonary pressure gradient (DPG) groups. Group I, DPG < 0 mmHg; Group II, 0 ≥ DPG < 7 mmHg; Group III, DPG ≥ 7 mmHg.
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B, Hazard ratio for death and/or transplantation for patients with positive normal DPG (0 ≤ DPG < 7 mmHg) and negative DPG. Due to few patients in Group III, only the statistical comparison between Group I and II is presented.
1
3D Echocardiographic evaluation of the Mitral Annulus in Rheumatic Mitral Stenosis &
alterations after Percutaneous Transvenous Mitral Commissurotomy
Authors: Ashwin Venkateshvaran,1, Srikanth Sola
2, Pravat Kumar Dash
2, Aristomenis Manouras
3
Reidar Winter1, Lars-Ake Brodin
1, Satish Chandra Govind
4
Affiliations: 1School for Technology and Health, Royal Institute of Technology, Stockholm, Sweden;
2Sri Sathya Sai Institute of Higher Medical Sciences, Bangalore, India;
3Department of Cardiology,
Karolinska University Hospital, Stockholm, Sweden; 4Narayana Institute of Cardiac Sciences,
Bangalore.
Corresponding author:
Ashwin Venkateshvaran MSc, RDCS
Sri Sathya Sai Institute of Higher Medical Sciences, Bangalore
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