Systemic vascular distensibility relates to exercise capacity in connective tissue disease

Abstract

Objective

Exercise intolerance is a common clinical manifestation of CTD. Frequently, CTD patients have associated cardio-pulmonary disease, including pulmonary hypertension or heart failure that impairs aerobic exercise capacity (pVO₂). The contribution of the systemic micro-vasculature to reduced exercise capacity in CTD patients without cardiopulmonary disease has not been fully described. In this study, we sought to examine the role of systemic vascular distensibility, α in reducing exercise capacity (i.e. pVO₂) in CTD patients.

Methods

Systemic and pulmonary vascular distensibility, α (%/mmHg) was determined from multipoint systemic pressure-flow plots during invasive cardiopulmonary exercise testing with pulmonary and radial arterial catheters in place in 42 CTD patients without cardiopulmonary disease and compared with 24 age and gender matched normal controls.

Results

During exercise, systemic vascular distensibility, α was reduced in CTD patients compared with controls (0.20 ± 0.12%/mmHg vs 0.30 ± 0.13%/mmHg, P =0.01). The reduced systemic vascular distensibility α, was associated with impaired stroke volume augmentation. On multivariate analysis, systemic vascular distensibility, α was associated with a decreased exercise capacity (pVO₂) and decreased systemic oxygen extraction.

Conclusion

Systemic vascular distensibility, α is associated with impaired systemic oxygen extraction and decreased aerobic capacity in patients with CTD without cardiopulmonary disease.

impaired systemic oxygen extraction, systemic vascular distensibility, CTD

Rheumatology key messages

• Impaired systemic vascular distensibility reduces systemic oxygen extraction and decreases aerobic capacity in CTD.

• Reduced systemic vascular distensibility is major determinant of exercise capacity in CTD without pulmonary hypertension/heart failure.

Introduction

Pulmonary vascular stiffness is known to cause decreased exercise capacity in patients with pulmonary arterial hypertension, heart failure with or without pulmonary hypertension and even in healthy subjects [1, 2]. However, the effects of systemic vascular stiffness to exercise capacity is not well understood.

Systemic vascular resistance (SVR) is dictated mainly at the level of the arterioles, meta-arterioles and pre-capillary sphincter. These vessels dilate or constrict, in response to different neuronal and hormonal signals, when either the rate of tissue metabolism or the availability of tissue oxygenation changes [3]. Hence, during exercise, the greater need for local tissue metabolism coupled with reduced availability of tissue oxygen results in greater production of local vasodilatory substances such as adenosine, nitric oxide and histamine. Conversely, when there is an increase in blood flow and systemic arterial pressure, these vasodilatory substances are ‘washed out’ and there is an increase in vasoconstrictor substances such as endothelin or epinephrine, as well as a baroreflex mediated vascular constriction resulting in reduced local blood flow [3]. Therefore, similar to pulmonary vascular stiffening, an exaggerated systemic vascular stiffening could eventually limit maximum cardiac output and thus also aerobic capacity.

Patients with CTD may present with latent pulmonary vascular disease [4] but are also known to present with altered endothelial regulation of the systemic circulation [5]. Thus, both central and systemic circulatory factors could play a role in limiting peak aerobic exercise capacity (i.e. peak oxygen consumption, pVO₂) in CTD. In the current study, we sought to determine the relative contribution of systemic vessel distensibility to reduced exercise capacity in patients with CTD without evidence of cardiopulmonary disease.

Methods

Forty-two consecutive CTD patients without cardiopulmonary disease and 24 age/sex-matched controls referred for combined right heart catheterization and invasive cardiopulmonary exercise testing (CPET) due to unexplained dyspnoea between March 2011 and September 2018 were retrospectively analysed.

Cardio-pulmonary diseases were excluded based on the following criteria: patients with resting or exercise pulmonary hypertension [6]; patients with left heart disease defined by moderate/severe mitral and/or aortic valvular disease, and/or left ventricular ejection fraction <0.50 on resting echocardiography; patients with parenchymal lung disease based on pulmonary function and radiological findings. Additionally, patients with physical or musculoskeletal limitation (including contracture deformity of the limbs) that precludes satisfactory invasive CPET were also excluded from the study. Controls were selected based on the identification of a physiological response to exercise (i.e. no cardiopulmonary nor peripheral limitation to exercise), defined by a pVO₂ and peak cardiac output ≥80% predicted and peak arterial to mixed-venous oxygen content difference (Ca-vO₂) corrected for haemoglobin >1.0 ml/dl. All included patients and controls achieved a maximum exercise effort based on a peak heart rate ≥85% predicted and/or a peak respiratory exchange ratio >1.10. There was no elite athlete in the control group. Prior to invasive CPET, all subjects were advised to continue their current medications for the procedure including b-adrenergic blocker, calcium channel blocker, angiotensin converting enzyme and diuretic therapy.

Our right heart catheterization and invasive CPET techniques have been described previously [2, 7–10] and are detailed in the Supplementary Material, available at Rheumatology online. The study protocol was approved by Partners Healthcare Human Research Committee (2011P000272). Included patients agreed to have their clinical and invasive CPET data used for research purposes and informed consent was obtained at time of invasive CPET.

Systemic vascular distensibility, α was determined from nonlinear squares fitting (i.e. least squares fitting) of multi-point mean systemic arterial pressure and right atrial pressure vs cardiac output relationships. An expanded description of systemic vascular distensibility, α calculation as well as pulmonary vascular distensibility calculation is described in the Supplementary Material, available at Rheumatology online.

Statistical analyses were performed using GraphPad Prism 7 (GraphPad Software) and SAS 9.4 (SAS Institute Inc., Cary, NC, USA). Results are expressed as mean (s.d.), assessed by t test. The relationship between stroke volume index augmentation to systemic vascular distensibility, α was examined using linear regression. Non-colinear variables (i.e. Pearson correlation r<0.6) with a significant P-value (P <0.05) on univariate analysis were incorporated into multivariate models to identify independent predictors of peak exercise capacity, pVO₂ (%predicted).

Results

CTD patients were aged 53 ± 17 years, and 36 of them were female. Sub-diagnoses were SSc (n = 14), rheumatoid arthritis (n = 7), mixed CTD (n = 3), undifferentiated CTD (n = 3), Sjögren’s syndrome (n = 9), systemic lupus erythematosus (n = 5) and polymyositis (n = 1). Amongst those with SSc, 12 out of 14 (86%) of patients had associated Raynaud’s phenomenon. Co-morbidities included hypertension (n = 16), hyperlipidaemia (n = 9) and diabetes (n = 4). Treatments included β adrenergic receptor blockers (n = 7), calcium channel blockers (n = 3), angiotensin converting enzyme inhibitors (n = 7), diuretics (n = 6) and oral hypoglycaemics (n = 4).

Controls were aged 50 ± 13 years; 17 of them were female. These characteristics were all statistically non-significant compared with CTD patients.

CTD patients had a resting mean pulmonary arterial pressure ≤20mmHg, resting pulmonary vascular resistance <3 Woods Unit, and peak exercise total pulmonary resistance <3 Woods Unit, thus no resting or exercise pulmonary hypertension. Resting right atrial pressure, mean pulmonary arterial pressure, cardiac output, stroke volume index, pulmonary arterial wedge pressure, pulmonary vascular resistance and SVR index were not significantly different between controls and CTD (Table 1). At peak exercise, CTD had reduced pVO₂ and reduced oxygen extraction ratio (calculated by Ca-vO₂/CaO₂) compared with controls (Table 1). Additionally, peak stroke volume index and peak bi-ventricular filling pressures (right atrial pressure and pulmonary arterial wedge pressure) were also reduced compared with controls (Table 1). Dynamic pulmonary distensibility factor, α was 1.33 ± 0.75%/mmHg (95% CI 1.07, 1.58) in the CTD patients and 1.37 ± 0.29%/mmHg (95% CI 1.24, 1.50) in controls (P >0.05).

Table 1

Resting hemodynamics, maximum CPET data, and peak exercise hemodynamics

	CTDs (n = 42)	Controls (n = 24)	P-value
Baseline characteristics
Age, years	53 (17)	50 (41)	0.45
Female, n (%)	36 (87)	17 (71)	0.10
BMI, kg/m2	25 (5)	28 (6)	0.03
Caucasian, n (%)	38 (90)	24 (100)
Hispanic, n (%)	2 (5)	0
African American, n (%)	2 (5)	0
Duration of CTD disease, years	5 (5)	n/a
Co-morbidities, n (%)
Systemic hypertension	16 (39)	11 (45)	0.59
Hyperlipidaemia	9 (22)	6 (25)	0.78
Diabetes	4 (9)	2 (8)	0.84
Medications, n (%)
Beta adrenergic receptor blocker	7 (17)	5 (21)	0.71
Calcium channel receptor blocker	3 (7)	1 (4)	0.61
ACE inhibitor or ARB	7 (17)	3 (13)	0.62
Diuretics	6 (14)	3 (12)	0.81
Oral hypoglycaemics	4 (9)	1 (4)	0.41
Resting RHC
Heart rate, bpm	78 (13)	82 (15)	0.28
Systolic SAP, mmHg	141 (19)	152 (30)	0.08
Diastolic SAP, mmHg	78 (9)	81 (14)	0.25
Mean SAP, mmHg	99 (11)	105 (17)	0.09
CO, l/min	5.6 (1.8)	5.1 (2.1)	0.29
SV index, ml/m2	37.3 (11.9)	37.7 (15.8)	0.91
RAP, mmHg	2 (2)	3 (2)	0.65
mPAP, mmHg	14 (3)	14 (3)	0.31
PAWP, mmHg	6 (3)	6 (2)	0.89
PVR, Wood units	1.5 (0.5)	1.7 (0.6)	0.44
SVR index, dynes/s/cm5/m2	2853 (1021)	3130 (985)	0.30
Maximum CPET data
Watts achieved	85 (26)	142 (81)	0.0001
Peak VO2 (% predicted)	66 (8)	115 (33)	<0.0001
Heart rate, bpm	140 (22)	144 (33)	0.62
Peak heart rate (% predicted)	82 (10)	85 (15)	0.31
Peak SAP, mmHg	184 (32)	187 (32)	0.79
Peak SAP, mmHg	86 (14)	83 (22)	0.41
Peak mean SAP, mmHg	119 (18)	118 (22)	0.73
Peak arterial pH	7.40 (0.05)	7.37 (0.05)	0.01
Peak PaCO2, mmHg	31.9 (6.0)	32.2 (3.8)	0.85
Peak lactate, mmol/l	5.1 (1.4)	6.3 (1.9)	0.03
Peak MvO2, %	42.7 (7.1)	23.3 (4.2)	<0.0001
Peak exercise hemodynamics
CO, l/min	11.4 (2.2)	12.9 (5.3)	0.10
SV index, ml/m2	43.1 (6.9)	50.5 (12.7)	0.01
RAP, mmHg	4 (3)	8 (4)	<0.0001
mPAP, mmHg	25 (6)	27 (5)	0.07
PAWP, mmHg	9 (4)	12 (5)	0.02
PVR, Wood units	1.36 (0.52)	1.36 (0.61)	0.99
SVR index, dynes/s/cm5/m2	1575 (340)	1303 (448)	0.03
Ca-vO2 corrected for Hgb, ml/dl	0.75 (0.1)	1.07 (0.05)	< 0.0001
EO2	0.56 (0.07)	0.77 (0.04)	<0.0001

Data presented as mean (s.d.).

BP: blood pressure; bpm: beats per min; Ca-vO₂: arterial to mixed venous oxygen content difference; CO: cardiac output; CPET: cardiopulmonary exercise test; EO₂: systemic O₂ extraction ratio; Hgb: haemoglobin; mPAP: mean pulmonary arterial pressure; MvO₂: mixed venous oxygen content; PaCO₂: partial pressure of carbon dioxide in systemic arterial blood; PAWP: pulmonary arterial wedge pressure; PVR: pulmonary vascular resistance; RAP: right atrial pressure; RHC: right heart catheterization; SAP: systemic arterial pressure; SV: stroke volume; SVR: systemic vascular resistance; VO₂: oxygen consumption.

The dynamic systemic vascular distensibility factor α, was 0.20 ± 0.12%/mmHg (95% CI 0.17, 0.23) in CTD patients and 0.30 ± 0.13%/mmHg (95% CI 0.25, 0.36) in the controls (P =0.01) (Fig. 1A). Patients with Sjogren’s syndrome and SSc tended to have lower dynamic systemic vascular distensibility, α amongst CTD patients, but this did not reach statistical significance (P >0.05) (Supplementary Table S1, available at Rheumatology online). Reduced systemic vascular distensibility, α was associated with failure of stroke volume index augmentation during exercise (r = 0.82, P <0.0001) (Fig. 1B). On multivariate analysis, systemic vascular distensibility, α emerged as an independent predictor of peak exercise capacity, pVO₂ (β coefficient of 10.75; 95% CI 3.59, 17.89; P =0.004) and of peak oxygen extraction (β coefficient of 0.04; 95% CI 0.01, 0.06; P =0.003). The use of cardiovascular or diuretic medications did not affect the systemic vascular distensibility, α (Supplementary Table S2, available at Rheumatology online).

Fig. 1

Systemic vascular distensibility in CTD

(A) Characterization of systemic vascular distensibility in connective disease (CTD) and controls groups. (B) A scatter plot of stroke volume index augmentation vs systemic vascular distensibility is shown.

Discussion

Impaired exercise capacity (i.e. pVO₂) in CTD patients without cardiopulmonary disease was shown to be related to both reduced systemic vascular distensibility, α and impaired oxygen extraction by exercising muscles.

Reduced systemic vascular distensibility, α was associated with higher SVR, and impaired stroke volume increase during exercise (i.e. failure of stroke volume index augmentation), suggesting afterload limited left ventricular flow output adaptation to peripheral demand. Decreased oxygen extraction was likely related to parasympathetic impairment and sympathetic overactivity seen with CTD [11]. During exercise, skeletal muscle capillary beds dilate in the face of increased muscle sympathetic activity from increased local vasodilator production to facilitate oxygen transfer. These regulatory factors override the opposing sympathetic vasoconstrictor forces allowing for increased tissue oxygen delivery during exercise. Failure of this functional sympatholysis impairs systemic microvasculature dilation [12]. It is unclear why patients with CTD have impaired sympatholysis during exercise with resulting reduced systemic vascular distensibility. We speculate that this may relate to the imbalance between endogenous vasoconstrictor and vasodilatory substances. Indeed, in patients with SSc, reduced nitric oxide bioavailability and increased expression of the vasoconstrictive peptide, endothelin has been implicated in scleroderma associated micro-circulatory endothelial dysfunction [5, 13].

While micro-vascular dysfunction in patients with SSc has been previously described, circulatory impairment to whole-body exercise in SSc has not been fully characterized [5, 14, 15]. Prior studies examining exercise limitation in SSc using non-invasive CPET utilizing indirect estimates of a ‘peripheral’ limit to exercise suggest a high prevalence of limits not attributable to cardio-pulmonary disease [16]. Our study, using direct invasive hemodynamic and gas exchange measurements, is able to further elucidate the functional and physiological impact of microvascular circulatory dysfunction in patients with CTD by direct and accurate assessment of systemic oxygen extraction and the hemodynamic variables that constitute systemic vascular distensibility, α and its implications on the primary determinants of peak exercise aerobic capacity, pVO₂ (i.e. systemic oxygen extraction and stroke volume index).

We previously demonstrated that in a cohort of patients with unexplained dyspnoea, pulmonary vascular distensibility, α represents a sensitive hemodynamic marker for pulmonary vascular disease that is associated with reduced exercise capacity (peak VO₂) [2]. In the current study consisting of CTD patients without cardiopulmonary disease, we showed that impaired systemic rather than pulmonary vascular distensibility, α is associated with reduced exercise capacity (i.e. peak VO₂). This adds further to the diagnostic utility of invasive CPET in the assessment of patients with unexplained dyspnoea. Furthermore, the findings highlight the importance of recognizing the role of an abnormal systemic vasculature in patients with CTD.

The reduced systemic vascular distensibility, α and the increase in SVR impedes systemic blood flow, increasing the left ventricular afterload and therefore reduces the normal or expectant increase in stroke volume index (i.e. impaired stroke volume index augmentation). This in turn impairs the obligatory increase in blood flow and tissue oxygen delivery to exercising muscles resulting in earlier attained anaerobic threshold with lactic acidemia with resulting increased fatigability, dyspnoea and reduced exercise capacity [17].

Our study has several limitations. The study sample is relatively small and was retrospectively derived from invasive CPET evaluation at a tertiary centre and, therefore, the studies’ subjects may not be representative of an overall CTD population. Hence, generalization of findings needs caution. Controls who underwent invasive CPET for unexplained exertional dyspnoea may not be representative of a completely healthy population. However, the control subjects were selected based on objective exercise physiologic criteria. Therefore, they represent a studied population with a normal physiologic response to exercise and reflect ‘symptomatic normal’ subjects. Additionally, this was a retrospective study of consecutive patients that performed invasive CPET during their clinical investigation of unexplained dyspnoea and no sample size or power calculation was performed prior to study data analysis. Nonetheless, despite this limitation, which would be better addressed in a prospective study design, we believe our data provide helpful insight for the understanding of reduced peak exercise capacity in CTD patients without cardiopulmonary diseases. Finally, diabetes, which can lead to arterial stiffening, was observed in 7% of all studied patients. However, the presence of diabetes was not statistically different comparing CTD vs controls (Table 1). Therefore, the presence of diabetes is unlikely to explain the differences in systemic vascular distensibility observed in CTD vs controls in the current study.

In conclusion, reduced systemic vascular distensibility, α in CTD patients without cardiopulmonary disease is associated with reduced exercise capacity (i.e. reduced peak VO₂), which in turn is related to paradoxical combination of reduced systemic oxygen extraction and oxygen delivery to the exercising muscle. Further studies encompassing larger CTD cohorts to examine the impact of dynamic systemic vascular distensibility, α across the different CTD groups is warranted.

Acknowledgements

All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript.

Disclosure statement: The authors have declared no conflicts of interest.

Supplementary data

Supplementary data are available at Rheumatology online.