Methods

From 2005 to 2012, any patients with secondary MR and chronic LV systolic dysfunction (LV ejection fraction <45%) referred to our heart valve clinic to undergo exercise stress echocardiography were screened for ischemia, exercise tolerance, and dynamic hemodynamic alterations (increase in MR severity, PH, increase in LV filling pressures) (n = 315). Patients fulfilling the following inclusion criteria were eligible to be included in this study: (1) chronic secondary MR, (2) sinus rhythm, (3) narrow QRS interval (<120 ms), and (4) measurable SPAP during exercise echocardiography. Of note, 19 patients (6%) were excluded from the final analysis according to this last exclusion criterion, resulting in a feasibility rate in the measurement of exercise SPAP of 94%. The final studied population was composed of 159 consecutive patients with heart failure (mean LV ejection fraction 36 ± 7%, range 20% to 44%). All had been stable for ≥2 months, and none met the following exclusion criteria (1) technically inadequate echocardiogram, (2) more than trivial aortic regurgitation or mild or greater aortic stenosis or severe tricuspid regurgitation, (3) history of myocardial infarction <6 months, (4) atrial fibrillation or flutter, (5) evidence of inducible ischemia, and (6) extensive myocardial ischemia requiring coronary angiography and revascularization. None of the patients were in New York Heart Association functional class IV. All patients gave their informed consent, and the local ethics committee approved the protocol.

The presence of hypercholesterolemia was defined as total plasma cholesterol level >6.2 mmol/L or the use of cholesterol-lowering medications. Systemic hypertension was defined as the use of antihypertensive medications or having known but untreated hypertension (blood pressure ≥140/90 mm Hg).

All echocardiographic parameters were obtained at rest and at peak exercise in the same cycling semisupine position (Vivid 7 or 9; GE Healthcare, Little Chalfont, United Kingdom). All Doppler echocardiographic recordings were stored on a dedicated workstation for subsequent off-line analysis. For each measurement, ≥2 cardiac cycles were averaged. MR was quantified as previously described ( Figure 1 ). Regurgitant volume (RV) and effective regurgitant orifice area (EROA) area were calculated with standard formulas. The biplane method of discs summation (modified Simpson’s rule) was applied to quantify LV end-diastolic and end-systolic volumes and the LV ejection fraction. From the mitral inflow, the E- and A-wave velocities, E-wave deceleration time, and E/A velocity ratio were measured. Left atrial maximal volume was measured using the modified Simpson’s rule. Using color tissue Doppler imaging, peak velocities during early (e′) diastole obtained at the level of septal and lateral annulus were averaged. The E/e′ ratio was then calculated. SPAP was derived from the regurgitant jet of tricuspid regurgitation using the systolic transtricuspid pressure gradient ( Figure 1 ) and the addition of 10 mm Hg for right atrial pressure, as previously performed. Resting PH and exercise PH were defined as SPAP >50 and >60 mm Hg, respectively. Right atrial pressure was assumed to be constant from rest to exercise.

Exercise-induced increase in MR and in SPAP. EF = ejection fraction.

Beta blockers were withdrawn on the day of the test. A symptom-limited graded bicycle exercise test was performed in the semisupine position on a tilting exercise table. After an initial workload of 25 W maintained for 2 minutes, the workload was increased every 2 minutes by 25 W. Blood pressure and a 12-lead electrocardiogram were recorded every 2 minutes. Two-dimensional and Doppler echocardiographic recordings were available throughout the test.

Follow-up information was obtained from interviews with the patients, their relatives, or their physicians. Clinical management was determined independently by the patient’s personal physician using all information available. The primary end point was cardiac mortality. The combined end point included the following: cardiac-related death, heart failure decompensation (worsening heart failure requiring hospitalization, acute pulmonary edema), need for cardiac resynchronization therapy or implantable cardiac defibrillator, or heart transplantation. Nonfatal myocardial infarction was reported in the population with histories of ischemic heart disease but was not considered a PH-related event.

Continuous variables are expressed as mean ± SD, unless otherwise specified. Group comparisons for categorical variables were obtained with chi-square tests and for continuous variables with Student’s t tests. Probabilities of event-free survival were obtained by Kaplan-Meier estimates for the 2 groups and then compared using a 2-sided log-rank test. The impact of exercise PH on the occurrence of the end point was assessed with Cox proportional hazards models in univariate and multivariable analyses. Variables with a univariate p values <0.10 were incorporated into the multivariate models. We used penalized smoothing splines to illustrate the association of SPAP as a continuous variable and the risk for cardiac event. A p value <0.05 was considered to indicate statistical significance.

Results

The demographic and clinical data of the 159 included patients are listed in Table 1 . None of the patients, at the time of the study, had suspected significant coronary artery disease requiring myocardial revascularization. The prevalence of exercise PH was significantly higher than resting PH (40% vs 13%, p <0.0001). There was no significant difference between patients with exercise PH and those without exercise PH regarding demographic and clinical data, as well as baseline medication ( Table 1 ).

In the whole cohort, SPAP significantly increased from rest to exercise (+19 ± 13 mm Hg, p <0.0001). Patients with exercise PH had statistically lower resting E- and e′-wave velocities but higher E/e′ ratios ( Table 2 ). Resting SPAP was significantly higher in the exercise PH group. Of note, there was no significant difference between the 2 groups regarding resting MR severity ( Table 2 ). During exercise, e′-wave velocity was lower in exercise PH group compared with the no exercise PH group, resulting in significantly higher exercise E/e′ ratios. During exercise, MR severity was available (i.e., quantifiable) in 120 patients (75%); MR increased significantly in the whole cohort (EROA +8.5 ± 11 mm ² , p <0.0001, and RV +12 ± 15 ml, p <0.0001). Exercise ( Table 2 ) and exercise-induced increase in MR severity were significantly higher in patients with exercise PH than in those with no exercise PH (EROA +14 ± 11 vs +5 ± 10 mm ² , p <0.0001, and RV +19 ± 16 vs +8 ± 14 ml, p <0.0001).

In simple linear regression, exercise SPAP was significantly correlated ( Table 3 ) with resting and exercise e′-wave velocity, resting SPAP, exercise E/e′ ratio, and exercise EROA and RV. Of note, exercise-induced changes in SPAP were well correlated with exercise-induced changes in RV and in EROA ( Figure 2 ) Using multiple linear regression analysis, resting SPAP, exercise EROA, and e′-wave velocity were identified as independent determinants of exercise SPAP ( Table 4 ). Similar results were found when exercise RV was included in the model instead of exercise EROA (β = 0.26 ± 0.05, p <0.0001).

Relation between exercise-induced changes in SPAP and exercise-induced changes in RV (A) and in EROA (B) , stratified according to resting MR severity ( light blue dots denote resting EROA >20 mm ² ; dark blue dots denote resting EROA ≤20 mm ² ).

Table 4

Multivariable determinants of exercise systolic pulmonary arterial pressure

Variable	Exercise systolic pulmonary arterial pressure
	β	Standard error	p
Age	0.099	0.091	0.277
Male gender	1.931	2.073	0.353
Resting systolic pulmonary arterial pressure	0.947	0.096	<0.0001
Exercise effective regurgitant orifice area	0.578	0.089	<0.0001
e’-wave velocity	-1.258	0.429	0.004

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