Diagnostic, prognostic and differential-diagnostic relevance of pulmonary haemodynamic parameters during exercise: a systematic review

Abstract

Background: The cardiopulmonary haemodynamic profile observed during exercise may identify patients with early-stage pulmonary vascular and primary cardiac diseases, and is used clinically to inform prognosis. However, a standardised approach to interpreting haemodynamic parameters is lacking.

Methods: We performed a systematic literature search according to PRISMA guidelines to identify parameters that may be diagnostic for an abnormal haemodynamic response to exercise and offer optimal prognostic and differential-diagnostic value. We performed random-effects meta-analyses of the normal values and report effect sizes as weighted mean±sd. Results of diagnostic and prognostic studies are reported descriptively.

Results: We identified 45 eligible studies with a total of 5598 subjects. The mean pulmonary arterial pressure (mPAP)/cardiac output (CO) slope, pulmonary arterial wedge pressure (PAWP)/CO slope and peak cardiac index (or CO) provided the most consistent prognostic haemodynamic parameters during exercise. The best cut-offs for survival and cardiovascular events were a mPAP/CO slope >3 Wood units (WU) and PAWP/CO slope >2 WU. A PAWP/CO slope cut-off >2 WU best differentiated pre- from post-capillary causes of PAP elevation during exercise. Upper limits of normal (defined as mean+2sd) for the mPAP/CO and PAWP/CO slopes were strongly age-dependent and ranged in 30-70-year-old healthy subjects from 1.6 to 3.3 WU and 0.6 to 1.8 WU, respectively.

Conclusion: An increased mPAP/CO slope during exercise is associated with impaired survival and an independent, prognostically relevant cut-off >3 WU has been validated. A PAWP/CO slope >2 WU may be suitable for the differentiation between pre- and post-capillary causes of PAP increase during exercise.

FIGURE 1

a) Mean pulmonary arterial pressure (mPAP)/cardiac output (CO) slope (Wood units (WU) and b) pulmonary arterial wedge pressure (PAWP)/CO slope (WU) by age group in the supine position. Each line represents an individual study group or a subgroup according to stratification to age in one study (see figure 2 for details). Older subjects (blue line) had a steeper mPAP/CO and PAWP/CO slope and tended to have higher mPAP at rest. During exercise, older subjects reach higher mPAP and PAWP at lower CO values as than younger individuals. The solid black lines show the age-adjusted mean slopes (estimated by mean age across the included studies). Exercise values in healthy subjects did not exceed mPAP >30 mmHg in combination with exercise total pulmonary resistance >3 WU (dashed line in figure 1a).

FIGURE 2

Forrest plots of the identified studies in healthy subjects in the supine position for a) mean age (years), b) mean pulmonary arterial pressure (mPAP)/cardiac output (CO) slope (Wood units (WU)) and c) pulmonary arterial wedge pressure (PAWP)/CO slope (WU). Estimates were computed using the Knapp–Hartung correction due to the low number of available studies. The study of Wolsk et al. [65] assessed different age groups that are separately displayed in the Forrest plot, showing the influence of age on cardiopulmonary haemodynamic parameters during exercise. Wolsk et al. 2017­_1 provided the youngest age group (<40 years) and Wolsk et al. 2017­_3 the oldest ( >60 years) [65].

FIGURE 3

Mean pulmonary arterial pressure (mPAP)/cardiac output (CO), pulmonary arterial wedge pressure (PAWP)/CO and trans-pulmonary gradient (TPG)/CO slopes for the characterisation of pulmonary haemodynamic parameters during exercise. Abnormal pulmonary haemodynamic parameters during exercise may be defined by an increased mPAP/CO slope. This slope is strongly age-dependent and its upper limit of normal (ULN) (mean+2sd) ranges from 1.6 Wood units (WU) (in ∼30-year-old healthy subjects) to 3.3 WU (in ∼70-year-old healthy subjects) in the supine position (table 2). The ULN based on the weighted mean and sd of all healthy subjects included in this analysis was 2.7 WU in the supine position. An increased mPAP/CO slope with a cut-off above >3 WU is independently associated with poor survival and heart failure-related hospitalisations. The mPAP/CO slope corresponds to the sum of the TPG/CO slope and the PAWP/CO slope. Like the mPAP/CO slope, the PAWP/CO slope is also strongly age-dependent and its ULN ranges from 0.6 to 1.8 WU. An increased PAWP/CO slope with a cut-off >2 WU is associated with impaired survival and increased cardiovascular (CV) events and may be diagnostic for a post-capillary cause of PAP elevation during exercise. The ULN for the TPG/CO slope is 1.2 WU and age-independent. An increased TPG/CO slope is also associated with impaired survival and may be suggestive of pulmonary vascular disease (PVD). Studies reporting on the prognostic relevance of the mPAP/CO, TPG/CO and PAWP/CO slopes are indicated in the footnotes. LHD: left heart disease. ^#: for validating mPAP/CO >3 WU cut-off [31], and [12, 42, 44, 45, 48]; ^¶: for validating mPAP/CO >3 WU cut-off [31]; ⁺: [31, 48]; ^§: [31]; ^ƒ: [, , –63]; ^##: for validating PAWP/CO >2 WU cut-off [32], and [31, 33]; ^¶¶: for validating PAWP/CO >2 WU cut-off [32], and [31]; ⁺⁺: for validating PAWP/CO >2 WU cut-off [32], and [54].