Diastolic Dysfunction Is Unmasked on Exercise in Patients With Asymptomatic, Severe Aortic Stenosis: An Invasive Hemodynamic Study
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Abstract
Background:
Optimal timing of aortic valve replacement remains difficult in patients with asymptomatic, severe aortic stenosis (AS). More accurate diagnostic methods are warranted for the detection of subtle ventricular impairment. We aimed to evaluate diastolic function in asymptomatic patients with severe AS.
Methods:
In this cross-sectional study, patients with asymptomatic, severe AS were evaluated with right heart catheterization at rest and during moderate exercise. The patients also underwent cardiopulmonary exercise testing to objectify functional capacity and confirm the absence of symptoms.
Results:
Between February 2019 and May 2021, we included 50 patients aged 70±12 years. The patients had severe AS with peak velocity 4.4±0.4 m/s, mean gradient 46±9 mm Hg, and an indexed valve area of 0.47±0.08 cm2 at rest. All patients were asymptomatic and had normal left ventricular ejection fraction. Five patients had postcapillary pulmonary hypertension at rest. During exercise, 44 patients (88%) had an increase in the mean pulmonary artery pressure per increase in cardiac output of >3 mm Hg/L per minute, of whom 93% had a concomitant increase in the pulmonary artery wedge pressure per increase in cardiac output >2 mm Hg/L per minute, suggesting exercise-induced pulmonary hypertension due to left heart disease. Female gender and increasing age were associated with a higher increase in the pulmonary artery wedge pressure per increase in cardiac output ratio. The catheterization was well tolerated, and there were no adverse events.
Conclusions:
A large proportion of asymptomatic patients with severe, degenerative AS have exercise-induced postcapillary pulmonary hypertension.
What Is New?
We report a high prevalence of pulmonary hypertension on exercise in patients with asymptomatic severe aortic stenosis.
Although only 10% had elevated pulmonary pressures at rest, 86% had an increase in pulmonary artery wedge pressure per increase in cardiac output >2 mm Hg/L per minute, indicating exercise-induced pulmonary hypertension due to left heart disease.
What are the Clinical Implications?
Our results show that there are signs of diastolic dysfunction on exercise in most patients with asymptomatic, severe aortic stenosis, in line with 2 clinical trials that show that early intervention may be preferable in these patients.
An abnormal hemodynamic response to exercise may indicate incipient heart failure and illustrates that a pathological response to the aortic stenosis starts before symptoms or overt left ventricular dysfunction appear.
Aortic stenosis (AS) is the most common valvular heart disease. It affects ≈5% of the population older than 65 years.1 The only effective treatment is aortic valve replacement (AVR). The main indications for AVR are severe stenosis in combination with symptoms due to the AS or reduced left ventricular systolic function caused by the AS.1,2 The development of symptoms signifies a dramatic change in the natural history of AS. Untreated, symptomatic patients with severe AS face a dismal prognosis.3–5 For the majority of patients with severe AS who remain asymptomatic, the prevailing guidelines recommend a strategy of watchful waiting. However, whether the patients are truly asymptomatic, and whether the symptoms presented are due to the AS, can be difficult to determine, especially in older individuals.6,7 Furthermore, recent observational studies and 2 randomized controlled trials have challenged the notion that the lack of symptoms signifies a benign condition.8–11 The challenge is to find objective markers of myocardial dysfunction at an early stage.
Patients with severe AS are at risk of developing diastolic dysfunction due to compensatory hypertrophy and myocardial fibrosis. Diastolic dysfunction is associated with elevated left ventricular filling pressures as a result of impaired ventricular relaxation and reduced compliance.12,13 The development of diastolic dysfunction occurs before the development of systolic failure and represents incipient heart failure. Studies suggest that diastolic failure in patients with AS is associated with increased mortality and adverse events, even after AVR.13–15 It is reasonable to assume that the detection of subtle signs of diastolic dysfunction could potentially identify patients who may benefit from early AVR.
The gold standard for estimating diastolic function is invasive measurements of end-diastolic left ventricular pressure or, in the absence of pulmonary vein stenosis, pulmonary artery wedge pressure (PAWP).16 These measurements, however, are rarely performed during the diagnostic work-up of patients with AS. We aimed to assess diastolic function at rest and during moderate exercise by right heart catheterization (RHC) in 50 patients with asymptomatic, severe, and degenerative AS. Our hypothesis was that diastolic dysfunction is prevalent in asymptomatic patients with severe AS and that exercise can unmask post capillary pulmonary hypertension that is not apparent at rest.
Materials and Methods
Due to the sensitive nature of the data collected for this study, the material will not be made publicly available. Excerpts of deidentified data relevant to the study are available from the corresponding author upon reasonable request.
Patient Population
In this cross-sectional study, we included patients with asymptomatic, high gradient, degenerative AS, and left ventricular ejection fraction >50%. We excluded patients with moderate or severe valvular heart disease other than AS; severe extracardiac disease; poorly controlled hypertension; other cardiopulmonary diseases that might influence pressure measurements by RHC (eg, cardiomyopathy, previous myocardial infarction, or pulmonary embolism); or other contraindications to AVR.
Eligible patients were either referred directly for study participation from their private cardiologists or local hospitals, or identified among patients who were scheduled for follow-up at Oslo University Hospital due to an asymptomatic, severe AS. The absence of cardiopulmonary symptoms was confirmed on the date of enrollment with a 3 floors stair walk and a cardiopulmonary exercise test.
Informed consent was obtained from all patients in accordance with the Declaration of Helsinki, and the study was approved by the appropriate Regional Committee for Medical and Health Research Ethics.
Clinical Examination
All patients went through a full clinical work-up with physical examination, resting blood pressure measurement, an ECG, and routine biochemistry.
Echocardiography
A transthoracic echocardiography was performed in all patients to assess the severity of the AS and to identify potential exclusion criteria. The examination was conducted according to guidelines17 using Vivid E9 or E95 ultrasound scanners (GE Vingmed Ultrasound AS, Horten, Norway). At least 3 consecutive cycles were recorded.
Exercise Test and Gas Exchange Measurements
All patients underwent a maximal, upright, symptom-limited exercise test on an electrically braked bicycle ergometer (Cardiovit CS-200 Excellence ErgoSpiro, Schiller, Baar, Switzerland). The test was performed at a constant cadence of 60 to 70 rotations per minute. The load was incrementally increased every minute. An expected maximum load was estimated for each patient according to the standard equation on the Schiller machines. We obtained gas exchange data by breath-by breath analysis (Ganshorn PowerCube gas analyser, Ganshorn, Niederlauer, Germany). Peak VO2 was defined as the VO2 achieved at maximum load at the end of the exercise. Expected values for peak VO2 was calculated according to the formula provided by Wasserman et al.18
All patients performed a 3 floors stair walk. The absence of cardiopulmonary symptoms was confirmed as the ability to perform this test without symptoms of limiting dyspnea, dizziness, or chest pain.
Right Heart Catheterization
Right-sided heart catheterization was performed with a 7 French Swan-Ganz pulmonary artery thermodilution catheter via the internal jugular vein. No sedatives were administered. The zero reference level was set at mid axillary line consistent with the left atrial level. We measured right atrial pressure, right ventricular pressure, mean pulmonary artery pressure (mPAP), and PAWP. The wedge position was verified by observing the typical changes in waveforms, and by fluoroscopy. Pressures were measured at end-expiration. Cardiac output (CO) was measured by the thermodilution technique, and a minimum of 3 measurements of CO was performed. Mixed vein oxygen saturation was measured in the pulmonary artery. Cardiac index was calculated by dividing CO with body surface area. Brachial blood pressures were obtained from an oscillometric arm cuff sphygmomanometer.
After assessment of resting hemodynamics, the patients performed a supine cardiopulmonary exercise test on a bicycle ergometer. The workload was gradually increased to a moderate load (20–75 Watts) at a cadence of 60 rotations per minute. When the patients’ heart rate had increased by a minimum of 20 beats per minute, a new complete set of pressure measurements, mixed vein oxygen saturation, CO measurements, and brachial blood pressure was taken.
We defined exercise pulmonary hypertension as a change in the mPAP from rest to peak exercise divided by the change in CO (ΔmPAP/ΔCO) >3 mm Hg/L per minute.19–22
To differentiate exercise pulmonary hypertension related to left heart disease from precapillary forms of pulmonary hypertension, we defined exercise-induced postcapillary pulmonary hypertension as a change in the mean PAWP from rest to peak exercise divided by the change in CO (ΔPAWP/ΔCO) >2 mm Hg/L per minute.23 Since there is no consensus definition of pulmonary hypertension during exercise, we also assessed 2 other proposed definitions as secondary assessment of exercise-induced postcapillary pulmonary hypertension: (1) PAWP at exercise ≥25 mm Hg and (2) mPAP >30 mm Hg, total pulmonary resistance >3 Wood, and PAWP ≥20 mm Hg.24–26 Total pulmonary resistance was calculated as mPAP at exercise divided by the CO at exercise.26 We measured the height of the v-wave from the baseline PAWP in end diastole to the peak of the v-wave.
Statistical Analysis
We performed all data analyses in IBM SPSS V.26. Baseline data are expressed as means±SD, medians (interquartile range), or numbers (percentages) depending on distribution. Between-group differences were tested using the Student t test, the Mann-Whitney U test‚ or the Pearson χ2 test when appropriate. We used the Shapiro-Wilk test, histograms‚ and Q-Q plots to test for normality. We used linear regression to evaluate associations between patient characteristics and the steepness of the ΔPAWP/ΔCO slope. Potential explanatory variables were identified a priori and assessed by univariable linear regression analysis as presented in Table 3. Variables with a P<0.20 were included in the multivariable regression analysis, with a stepwise removal of the variable with the highest P value, resulting in the final model. The relationships between PAWP at rest and exercise and between PAWP at rest and the ΔPAWP/ΔCO were investigated using the Pearson product-moment correlation coefficient and the nonparametric Spearman ρ correlation coefficient, respectively. A P≤0.05 was considered statistically significant. All P values were 2-tailed.
Results
Study Population
From February 2019 to May 2021, we screened 157 patients to include 50 participants (Figure 1). Demographic characteristics are shown in Table 1. All patients had severe, high gradient, degenerative AS. The average peak valve velocity was 4.4±0.4 m/s, the mean gradient 46±9 mm Hg, and the indexed valve area 0.47±0.08 cm2/m2. Nineteen patients (38%) had bicuspid aortic valves. Two patients had documented paroxysmal atrial fibrillation, both of whom had sinus rhythm throughout the examination. One patient had had surgery for coarctation of the aorta >30 years earlier. This patient had no significant residual coarctation and normal blood pressure. Four patients had previous percutaneous coronary intervention due to stable angina with no troponin elevation and no history of myocardial infarction. Two patients had a body mass index >30 kg/m2.
| Demography | |
|---|---|
| Age, y | 70±12 |
| Male sex, n (%) | 32 (64) |
| Smoker, current/previous, n (%) | 7 (14)/15 (30) |
| Married or cohabiting, n (%) | 39 (78) |
| Body surface area, m2 | 1.93±0.22 |
| Body mass index, kg/m2 | 23±4 |
| Systolic blood pressure, mm Hg | 140±16 |
| Diastolic blood pressure, mm Hg | 77±10 |
| Heart rate, beats per minute | 69±11 |
| Left ventricular hypertrophy in ECG (Socolow-Lyon), n (%) | 9 (18) |
| Medical history | |
| Hypertension, n (%) | 21 (42) |
| Obesity, BMI>30 kg/m2, n (%) | 2 (4) |
| Diabetes (type 2), n (%) | 8 (16) |
| Prior myocardial infarction, n (%) | 0 (0) |
| Previous percutaneous coronary intervention due to stable angina, n (%) | 4 (8) |
| Previous stroke or TIA, n (%) | 5 (10) |
| Previous cardiac surgery, n (%) | 0 (0) |
| Peripheral vascular disease, n (%) | 0 (0) |
| Chronic obstructive pulmonary disease (GOLD 1–2), n (%) | 2 (4) |
| Medication | |
| Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, n (%) | 19 (36) |
| β-Blocker, n (%) | 7 (14) |
| Platelet inhibitor, n (%) | 15 (30) |
| Anticoagulation (warfarin or direct oral anticoagulation), n (%) | 1 (2) |
| Cholesterol lowering agent, n (%) | 20 (40) |
| Biochemistry | |
| Hemoglobin, g/dL | 14.3±1.4 |
| Cholesterol, mg/dL | 188±49 |
| LDL cholesterol, mg/dL | 116±38 |
| Creatinine, µmol/L | 80±20 |
| Estimated glomerular filtration rate, mL/min | 79±16 |
| NT-proBNP, ng/L | 163 (112–319) |
| P-Troponin T, ng/L | 10 (8–14) |
| Echocardiography | |
| Left ventricular ejection fraction, % | 59±4 |
| Bicuspid aortic valve, n (%) | 19 (38) |
| Aortic valve peak velocity, m/s | 4.4±0.4 |
| Mean aortic pressure gradient, mm Hg | 46±9 |
| Aortic valve area, cm2 | 0.91±0.22 |
| Indexed aortic valve area, cm2/m2 | 0.47±0.08 |
| Left ventricular end-diastolic diameter, mm | 48±5 |
| Interventricular septum diastolic diameter, mm | 11±2 |
| Left atrium volume indexed, mL/m2 | 37.3±11.6 |
| E/e′ | 11.5±3.9 |
| E/A ratio | 0.81 (0.63–0.99) |
| Cardiopulmonary exercise test | |
| Basal heart rate, beats per minute | 80±12 |
| Peak heart rate, beats per minute | 147±18 |
| Peak workload, Watts | 141±43 |
| % Watt | 104±15 |
| Peak VO2, mL/min per kg | 23.1±5.8 |
| % maxVO | 107±24 |
| RER | 1.05±0.3 |
| BORG scale at peak exercise | 17±1 |
| Peak respiratory volume, L/min | 61±18 |
Figure 1. Flow chart illustrating patient selection. AF indicates atrial fibrillation; AR, aortic regurgitation; AS, aortic stenosis; AVR, aortic valve replacement; CPET, cardiopulmonary exercise test; EF, ejection fraction; MR, mitral regurgitation; MS, mitral stenosis; Vmax, peak aortic jet velocity; and VSD, ventricular septal defect.
The mean peak VO2 during cardiopulmonary exercise test was 23.1±5.8 mL/min per kg, representing 107±24% of the expected peak VO2. The mean maximal load was 104±15% of the expected maximal load. No patient experienced a hypotensive response to the exercise test.
Right Heart Catheterization
All patients performed the test according to protocol. There were no adverse events. Hemodynamic data are shown in Table 2. At rest, 16 patients (32%) had a mPAP >20 mm Hg, which is the upper limit of normal at rest.27,28 All patients had a pulmonary vascular resistance <3 Wood. Five patients (10%) had a resting mPAP ≥25 mm Hg, and they all had PAWP >15 mm Hg at rest, indicating postcapillary pulmonary hypertension related to left heart disease.
| Rest | Exercise | |
|---|---|---|
| Heart rate, bpm | 75±12 | 106±12 |
| Systolic blood pressure, mm Hg | 136±20 | 157±25 |
| Diastolic blood pressure, mm Hg | 82±12 | 91±15 |
| Mean right atrial pressure, mm Hg | 4.3±2.0 | 8.0±3.6 |
| Systolic pulmonary artery pressure, mm Hg | 27.1±6.5 | 53.3±11.1 |
| Diastolic pulmonary artery pressure, mm Hg | 11.3±4.6 | 24.1±7.0 |
| Mean pulmonary artery pressure, mm Hg | 18.7±5.1 | 39.2±8.0 |
| Mean pulmonary artery wedge pressure, mm Hg | 11.0±3.9 | 27.2±6.9 |
| Transpulmonary gradient, mm Hg | 7.8±2.5 | 11.0±3.9 |
| PaO2s, % | 73.8±4.5 | 48.7±6.5 |
| Spo2, % | 95.6±1.6 | 94.3±2.1 |
| Pulmonary vascular resistance, Wood | 1.29±0.44 | 1.26±0.60 |
| Systemic vascular resistance, Wood | 15.3 (13.0–17.7) | 9.9 (8.3–12.0) |
| Cardiac output, L/min | 6.2±1.4 | 10.4±2.7 |
| Cardiac index, L/min per m2 | 3.2±0.6 | 5.3±1.2 |
| Workload, Watt | … | 39±15 |
| ΔmPAP, mm Hg | 20.0 (17.0–24.0) | |
| ΔPAWP, mm Hg | 17 (13.3–19.0) | |
| ΔCO, L/min | 4.2±1.9 | |
| ΔmPAP/ΔCO, mm Hg/L per minute | … | 4.6 (3.5–7.1) |
| ΔPAWP/ΔCO, mm Hg/L per minute | … | 3.8 (2.9–5.8) |
During exercise, 44 patients (88%) met the criterion for exercise pulmonary hypertension with a ΔmPAP/ΔCO >3 mm Hg/L per minute. Forty-three patients (86%) met the primary criteria for postcapillary pulmonary hypertension during exercise with ΔPAWP/ΔCO >2 mm Hg/L per minute. The second definition with a PAWP ≥25 mm Hg at exercise was met by 33 patients (66%). The third definition, with a mPAP >30 mm Hg, total pulmonary resistance >3 Wood, and a PAWP ≥20 mm Hg, was met by 29 patients (58%). There was a positive correlation between the PAWP at rest and during exercise, r=0.49, P<0.01. There was a positive correlation between the PAWP at rest and the ΔPAWP/ΔCO, r=0.28, P=0.047.
Of the 44 patients with ΔmPAP/ΔCO >3 mm Hg/L per minute, 41 patients (93%) had concomitant ΔPAWP/ΔCO >2 mm Hg/L per minute. Figure 2 shows the relationships between the mPAP (A) and the PAWP (B) and CO at rest and during exercise. Figure S1 shows the relationship between peak VO2 during cardiopulmonary exercise test and the ΔPAWP/ΔCO.
Figure 2. Pulmonary pressures and cardiac output (CO) at rest and during exercise for 50 patients with asymptomatic, severe aortic stenosis.A, The relationship between the mean pulmonary artery pressure (mPAP) and CO. B, The relationship between the pulmonary artery wedge pressure (PAWP) and CO.
All 3 criteria of pulmonary hypertension related to left heart disease were met in 26 patients (52%). Concordance of the 3 criteria, meaning that either 0/0 or 3/3 criteria were met, was found in 62 % of patients (Figure 3). Table S1 shows patient characteristics according to how many hemodynamic criteria of exercise pulmonary hypertension related to left heart disease the patients met.
Figure 3. Performance of the 3 hemodynamic criteria for exercise-induced postcapillary pulmonary hypertension. In 62% of the patients, there were concordance between the 3 definitions, defined as either 0/0 or 3/3 definitions being met. ΔCO indicates difference in cardiac output from rest to exercise; ΔPAWP, difference in pulmonary capillary wedge pressure from rest to exercise; mPAP, mean pulmonary artery pressure; and TPR, total pulmonary resistance.
Factors associated with a higher ΔPAWP/ΔCO slope were female sex and higher age as shown in Table 3.
| Explanatory variable | Univariable analysis | Multivariable analysis | ||||
|---|---|---|---|---|---|---|
| B | 95% CI for B | P value | B | 95% CI for B | P value | |
| Age, y | 0.15 | 0.046 to 0.26 | 0.006 | 0.14 | 0.037 to 0.24 | 0.009 |
| Male sex | −3.2 | −5.85 to −0.56 | 0.018 | −2.8 | −5.3 to −0.34 | 0.027 |
| Body mass index, kg/m2 | −0.28 | −0.64 to 0.087 | 0.13 | |||
| Systolic blood pressure, mm Hg | 0.98 | 0.016 to 0.18 | 0.021 | |||
| Bicuspid aortic valve | −2.75 | −5.40 to −0.092 | 0.043 | |||
| Indexed aortic valve area, cm2/m2 | −5.48 | −22.01 to 11.05 | 0.51 | |||
| Mean aortic pressure gradient, mm Hg | 0.013 | −0.13 to 0.16 | 0.86 | |||
| Aortic valve peak velocity, m/s | −0.012 | −3.75 to 3.73 | 0.99 | |||
| Smoker, current or previous | −0.85 | −3.55 to 1.85 | 0.53 | |||
In 42 patients, the v-wave on the PAWP pressure curve was discernible. The average height of the v-wave on exercise was 15±5 mm Hg. The v-wave correlated with the indexed left atrial volume (r=0.39; P=0.03) but was not associated with peak VO2.
Thirteen patients had a mean pressure gradient on echocardiography just below 40 mm Hg. Nine of these patients had a ΔPAWP/ΔCO >2 mm Hg/L per minute versus 34/37 of the patients with a pressure gradient >40 mm Hg (P=0.27). Due to the small number of patients, this subgroup analyses must be interpreted with caution.
Discussion
Our study shows that many patients with asymptomatic, severe AS have elevated pulmonary pressures during exercise (Figure 4). While only 5 patients (10%) had isolated postcapillary pulmonary hypertension at rest, the majority of patients (90%) fulfilled 1 or more of the proposed criteria for postcapillary pulmonary hypertension on exercise.
Figure 4. We evaluated 50 patients with asymptomatic severe aortic stenosis with right heart catheterization at rest and during moderate exercise. During exercise, 86% of patients had an increase in pulmonary artery wedge pressure per increase in cardiac output (ΔPAWP/ΔCO) >2 mm Hg/L per minute, indicating exercise-induced pulmonary hypertension due to left heart disease.
The assessment of pulmonary pressures during exercise gives insight into stress physiology and has the potential to provide additional information for the management of asymptomatic AS by identifying patients who are hemodynamically decompensated during exercise. Previous studies have shown that when diastolic dysfunction is present, improvement in diastolic function after AVR for AS is delayed or incomplete.13 Moreover, several studies suggest that diastolic dysfunction in patients with AS is associated with worse outcomes.13 In a study on 105 patients with asymptomatic‚ severe AS, exercise pulmonary hypertension assessed by stress echocardiography was associated with a 2-fold increased risk of cardiac events after 3 years.14 Another study on 39 patients with asymptomatic, severe AS, demonstrated that PAWP was remarkably elevated during exercise in 85% of patients. Furthermore, changes in mPAP and PAWP during exercise were associated with increased risk of a composite outcome of AVR, unplanned hospitalization or death.15
The AVATAR trial (Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis) showed that early valve replacement may improve patient outcomes in low-risk, asymptomatic severe AS.11 Our findings provide a possible explanation for why early intervention may be beneficial. After left sided valve surgery, 2 out of 3 patients have heart failure with preserved ejection fraction, an independent predictor of mortality.29 This suggests that in many patients who undergo valve replacement, the pathological processes leading to heart failure have developed too far, and are irreversible. In our patients, hemodynamic assessment revealed an abnormal response to exercise even in the face of preserved exercise capacity and a lack of symptoms. This may represent a preclinical condition in which a pathological process has started. Our data suggest that during exercise, the heart is unable to compensate for the increased hemodynamic load induced by a severe AS, potentially inducing myocardial changes that may in time become irreversible. Adaptation to higher pulmonary capillary pressures, redundancy in cardiac function, or an increased capacity for peripheral oxygen extraction may explain why the patients remain asymptomatic despite the abnormal hemodynamic response to exercise.
There is no consensus on how to define abnormal pulmonary hemodynamic responses during exercise.30,31 The most promising definitions of exercise pulmonary hypertension is the mPAP/CO slope, when multipoint mPAP/CO relationships are available, or a 2-point measurement of the ΔmPAP/ΔCO slope from resting and peak exercise >3 mm Hg/L per minute.26,31 In our study 88% had ΔmPAP/ΔCO >3 mm Hg/L per minute, indicating that a pathological increase in mPAP occurs on exercise in the majority of patients with asymptomatic, severe AS.
To discriminate precapillary from postcapillary exercise pulmonary hypertension, different exercise hemodynamic definitions have been proposed, of which 3 were assessed in our study. Our primary definition, the ΔPAWP/ΔCO >2 mm Hg/L per minute, has been associated with worse clinical outcomes in patients with dyspnea,23 and appears to be the most sensitive. The other 2 definitions, both of which use single threshold values, are at greater risk of being confounded by the complexity of physiological responses that are particularly complicated with concomitant AS. Due to the moderate workload, the PAWP may not have exceeded 25 mm Hg in some patients with a pathological ΔPAWP/ΔCO slope. During exercise, 86% of the patients in our study had a ΔPAWP/ΔCO slope >2 mm Hg/L per minute. Among the 44 patients who had a ΔmPAP/ΔCO slope >3 mm Hg/L per minute, 93% had ΔPAWP/ΔCO slope >2 mm Hg/L per minute, suggesting that the elevated pulmonary pressures are driven by left heart filling pressures. Female gender and increasing age were associated with a steeper ΔPAWP/ΔCO slope. However, this association must be interpreted with caution due to the limited number of patients in this study.
Adjusting the absolute values of mPAP and PAWP for CO accounts for the variable increases in flow that occur during exercise.31 However, none of the proposed definitions account for differences that occur with age. According to a review from 2012, age did not affect resting mPAP significantly. However, during exercise, mPAP was age-dependent, especially in older individuals.27 Consequently, it may not be possible to define a single upper limit of the ΔmPAP/ΔCO and ΔPAWP/ΔCO relationships that fit all individuals across all ages. Small studies have suggested that the ΔmPAP/ΔCO ratio in healthy controls over the age of 50 is in the range of 1.4 to 2.8 mm Hg/L per minute27,32,33 which is significantly lower than in our study, where the median ΔmPAP/ΔCO was 4.6 mm Hg/L per minute (interquartile range: 3.5–7.1).
Up to 16% of patients with AS have amyloid deposition which may lead to diastolic dysfunction.34,35 We did not perform bone scintigraphy. However, none of the study participants had red flags suggestive of amyloid disease apart from 1 patient who had a history of carpal tunnel syndrome.
In our experience, RHC is safe and feasible in asymptomatic patients with severe AS. More studies are warranted to evaluate the prognostic implication of elevated filling pressure during exercise in asymptomatic severe AS. The DANAVR trial (Danish National Randomized Study on Early Aortic Valve Replacement in Patients With Asymptomatic Severe Aortic Stenosis) will be of particular interest in this regard (URL: https://www.clinicaltrials.gov; Unique identifier: NCT03972644).
Limitations
This was a single-center study with a limited number of patients. The lack of standardized exercise hemodynamic measurements and consensus criteria to define elevated left ventricular filling pressures limits the ability to obtain reproducible assessments of diastolic function across laboratories. Heterogeneous procedural practices are used in different studies, for example, related to supine or upright positions during exercise, methods for CO measurements, exercise protocols and averaged versus end-expiratory measurements, which may limit comparison across studies. We defined the ΔmPAP/ΔCO and ΔPAWP/CO slope by 2 measurements. Multiple measurements of mPAP, PAWP, and CO during exercise would have increased the accuracy of the slope. However, the concordance between the mPAP/CO slope and the ΔmPAP/ΔCO is high.36 This is a cross-sectional study. Whether pulmonary hypertension on exercise is associated with long-term outcomes must be tested in a properly designed longitudinal study. The present study did not provide exercise hemodynamic data for a healthy age- and sex-matched control group, which is a limitation to the interpretation of the hemodynamic data. Comparable data on hemodynamic exercise responses in historical controls have been published, albeit with a limited numbers of individuals in the population aged >50 years. We did not measure end-systolic systemic blood pressure, a prerequisite for calculating arterial elastance, which is associated with cardiac performance in patients with AS.37 Finally, we do not have data on pulmonary function tests.
Conclusions
Exercise RHC is feasible and safe in true asymptomatic patients with severe, degenerative AS. Exercise hemodynamics unmask diastolic dysfunction in a large proportion of this population. Future research must be directed at understanding whether RHC has a place in the decision-making for patients with asymptomatic AS.
Article Information
Acknowledgments
The authors thank the staff at the catheterization laboratory for their help. They also thank Jørgen Westby, Svend Aakhus, Lars Øivind Krafft Sande, Lars Erik Gevelt, Per Anton Sirnes, Rune Ask, and Guro Storsul for helping to find patients for this study.
Sources of Funding
This work has been partly funded with a grant from the Bergesenstiftelsen.
Disclosures
None.
Supplemental Material
Figure S1
Table S1
| AS | aortic stenosis |
| AVR | aortic valve implantation |
| CO | cardiac output |
| mPAP | mean pulmonary artery pressure |
| PAWP | pulmonary artery wedge pressure |
| RHC | right heart catheterization |
| VO2 | oxygen consumption |
| ΔmPAP/ΔCO | increase in the mean pulmonary artery pressure per increase in cardiac output |
Footnotes
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