Abnormal cardiac and metabolic measures correlate significantly with lower performance and activity in overweight chronic liver disease

Abstract

People with Hepatitis C (HCV) and non‐alcoholic fatty liver disease (NAFLD) in the United States follow national trends toward a sedentary lifestyle and are increasingly at risk for hypertension. The intent of this study was to identify potential correlates of exercise tolerance in people with two types of chronic liver disease (CLD)‐NAFLD and HCV. Measures included cardiac output, oxygen consumption and stroke volume, blood pressure, distance walked in 6 minutes, clinical laboratory tests, and medications influencing the autonomic nervous system, patient self‐reports of activity, fatigue, and health‐related quality of life (HRQL). A total of 67 patients completed the 6‐minute walk test [45.1% Female, Age 51.7 ± 8.0 years, Body Mass Index 32.8 ± 5.9, 60% HCV]. At baseline, 70% had either diastolic (DBP) or systolic blood pressure outside normal range. Performance and cardiorespiratory measures correlated strongly with one another, but not with activity. Patients with abnormal DBP reported significantly lower maximum activity (MAS; r = −.254, P = .041, CI = −0.51 to −0.010; MAS 70.6 vs 82.5), significantly higher DBP post‐6‐minute walk test (r = .524, P = .0001, CI = 0.287‐0.762) and significantly lower overall HRQL items related to physical domains (r = .273, P = .029, CI = −0.518 to −0.029). Mental‐domain HRQL and depression measures did not correlate significantly with blood pressure. This study reports a significant correlation between both pre‐hypertensive and hypertensive DBP, poor physical‐domain self‐reports, HRQL, and performance in CLD patients.

1. INTRODUCTION

Hypertension is directly associated with increased cardiovascular disease risk, renal insufficiency, and stroke as well as mortality. ¹ Patients with hepatitis C (HCV) and non‐alcoholic fatty liver disease (NAFLD) in the United States follow national trends toward a sedentary lifestyle and are increasingly at risk for hypertension ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ and its complications. NAFLD in particular is rising in prevalence—between 13.48% and 31.79% of the global population, depending upon continent—and is the most rapidly increasing indication for liver transplant. ¹² , ¹³ , ¹⁴ , ¹⁵ In addition to physiological and metabolic abnormalities, patients with chronic liver disease (CLD) are likely to have symptoms that favor a sedentary life style. ¹⁶ Associations between hypertension/pre‐hypertension and physical activity and performance have been studied in people with diabetes and metabolic syndrome, but have not been well studied in NAFLD and HCV.

Previous work has shown that high resting diastolic blood pressure in patients with liver disease is associated with low physical performance levels. ¹⁶ Anti‐hypertensive medications and some other commonly prescribed anti‐depression medications can influence the autonomic nervous system (ANS) and, in part, may be able to explain these findings. ¹ We sought to further explore these relationships to determine whether the strongest correlations occur between low physical performance levels and cardiovascular measures, hypertension, or usual activity level. We undertook this study in part, because control of hypertension is a therapeutic goal relatively easy to achieve and may contribute to a higher level of participation in physical activity in this population.

The intent of this exploratory, prospective study was to identify potential correlates of exercise tolerance in people with two types of CLD (NAFLD and HCV). We first assessed cardiovascular and cardiorespiratory findings in the two populations and then compared them to determine whether the two different diagnostic groups present different findings through examination of correlations between cardiorespiratory measures, patient self‐reports of activity, 6‐minute walk distance; and resting diastolic (DBP)/systolic blood pressure (SBP). Secondary outcomes include impact of use of medications potentially affecting factors that contribute to blood pressure regulation via the ANS.

2. METHODS

2.1. Study population

Patients diagnosed with either NAFLD or HCV and seen at a liver disease clinic were invited to participate in this study. Data for this descriptive study were collected prospectively. To be included, participants must have had ultrasound or histologically proven NAFLD, active, or recent chronic HCV with positive HCV antibody and HCV RNA viral load for actively infected individuals. Patients with HCV were not receiving anti‐viral therapies at time of study. HCV patients could have previously been treated and achieved sustained virologic response (SVR). Previous research has suggested that some HCV‐associated symptomatology such as fatigue can linger after SVR has been achieved. Approximately one‐third of HCV patients post‐SVR may still experience fatigue outside of population norms with non‐interferon‐based treatments. ³ Subjects were 18 years of age or older and provided informed consent. Patients with a recent myocardial infarction, poorly controlled hypertension, unstable angina, arthritis, or exercise intolerance were excluded. This study was approved by the hospital internal Institutional Review Board and study procedures were in accordance with institutional guidelines.

2.2. Clinical data

Baseline clinical, demographic, laboratory data, and medication use were prospectively collected from subjects and clinical records (Tables 1 + 2). At enrollment, a brief physical examination including hip and waist circumference, height, grip strength, and weight were collected. Serum‐based laboratory alanine aminotransferase (ALT) and aspartate aminotransferase (AST) measures were obtained (Table 2).

TABLE 1.

Performance variables of interest defined

Measure	Purpose
6‐Min Walk‐time Test (6MWT)	Self‐paced performance measure of distance in feet (or meters) covered during 6 min of purposeful walking
Borg Rating of Perceived Exertion (RPE)	A subject‐reported rating of perceived exertion
Human Activity Profile (HAP)	Measures Maximum Activity Level (MAS) and Adjusted/Average Activity Level (AAS). Scores can be assessed by age and gender, translated into level of impairment and metabolic equivalents (1 MET = 3.5 mL O2 kg−1 min−1)
Center for Epidemiological Studies Depression Scale (CESD)	Frequently used measure of depression in population of interest
Chronic Liver Disease Questionnaire (CLDQ)	Disease‐specific measure of health‐related quality of life, including the following domains: Fatigue, Activity, Emotional Functioning, Abdominal Symptoms, Systemic Symptoms, Worry
Medical Outcomes Survey Short Form 36 (SF‐36)	Global measure of health‐related quality of life, including the following subscales: Physical Function (PF), Role‐Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Role‐Emotional (RE), Social Functioning (SF), Mental Health (MH), Physical Component Score (PCS), Mental Component Score (MCS)

TABLE 2.

Descriptive Variables for Subjects with HCV and NAFLD

	CLD (N = 67)	HCV (N = 46)	NAFLD (N = 21)	HCV‐NAFLD P = value, (CI)
Female (%)	67	33	38	.667 (23‐46)
Age in years (Mean ± SD)	51.45 ± 9.29	52.67 ± 8.72	48.76 ± 10.14	.111 (−49.18 to 53.71)
Cirrhosis, (%)	12.0	17.4	0	.001 (0‐45)
Body Mass Index (BMI) (Mean ± SD)	30.8 ± 5.6	29.9 ± 5.2	33.0 ± 5.8	.031 (29.48‐32.19)
Obesity (%)	51	43	67	.080 (38‐63)
Stride length, inches (Mean ± SD)	28.1 ± 2.2	27.9 ± 2.5	28.4 ± 1.6 (20)	.379 (27.51‐28.62)
Hypertension (%)	30	24	43	.147 (19‐41)
Hyperlipidemia (%)	30	13	67	.000 (19‐41)
Diabetes Mellitus (DM) (%)	24	17	38	.101 (13‐34)
Metabolic Syndrome (MET SYN) (%)	16	9	33	.039 (7‐26)
AST (IU/L, Mean ± SD)	49.5 ± 33.5	48.4 ± 36.8	51.8 ± 25.6	.710 (39.28‐58.00)
ALT (IU/L, Mean ± SD)	58.5 ± 37.4	54.8 ± 39.7	66.3 ± 31.1	.248 (47.06‐67.83)
6‐Min Walk‐time Distance (meters, Mean ± SD)	1892 ± 292 (576.7 ± 89.0)	1928 ± 292 (587.7 ± 89.0)	1797 ± 278 (547.7 ± 84.7)	.116 (1818.03‐1896.05 feet; 554.1‐577.9 m)
Resting Heart Rate (RHR) Pre 6‐Min Walk‐time (beats per min, Mean ± SD)	71 ± 12	70 ± 13	72 ± 8	.704 (69.13‐74.03)
Heart Rate Post‐6‐Min Walk‐Time (HR post‐6MWT; bpm Mean ± SD)	91 ± 20	91 ± 20	92 ± 21	.837 (85.82‐96.64)
Cardiac Output Pre 6‐Min Walk Time (CO pre 6MWT; L/min, Mean ± SD)	6.14 ± 1.98	6.20 ± 2.13	6.02 ± 1.60	.748 (5.73‐9.26)
Cardiac Output Post‐6‐Min Walk Time (CO post‐6MWT; L/min, Mean ± SD)	8.33 ± 3.03	8.59 ± 3.26	7.71 ± 2.34	.307 (7.62‐9.26)
Oxygen Saturation Pre 6‐Min Walk Time (% SPO2, Mean ± SD)	98 ± 2	97 ± 2	98 ± 1	.135 (97.24‐98.13)
Oxygen Saturation Post‐6‐Min Walk Time (SPO2 post‐6MWT; %, Mean ± SD)	96 ± 2	96 ± 3	96 ± 1	.837 (97.51‐98.45)

2.3. Physical performance assessment

Performance assessments included both objective and self‐reported measures (Tables 2, 3, 4). Subjects completed a series of questionnaires pertinent to function, mood, activity level, fatigue, health‐related quality of life. Self‐reports examined were as follows: Borg Ratings of Perceived Exertion (RPE), Human Activity Profile Maximum Activity Scale (MAS) and Adjusted Activity Scale (AAS), Medical Outcomes Survey Short Form 36 (SF‐36), Fatigue Severity Scale (FSS), Chronic Liver Disease Questionnaire (CLDQ), and Center for Epidemiological Studies Depression Scale (CESD) (Table 1). These instruments have been used and validated in this population. ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷

TABLE 3.

Cardiorespiratory data summary from results (Mean ± Standard Deviation (SD))

	Pre‐Exertion		Post Exertion		Change Score Post – Pre
	Male	Female	Male	Female	Male	Female
Heart Rate (bpm), 1 Min Post	73 ± 11	69 ± 14	86 ± 19	99.2 ± 19	17 ± 21	22 ± 19
Oxygen Saturation (%)	97 ± 2	98 ± 2	98 ± 2	98 ± 2	1 ± 2	0 ± 2
Mean Arterial Pressure (mmHG)	92.05 ± 10.31	93.01 ± 11.48	102.04 ± 10.86	102.88 ± 10.67	9.99 ± 9.47	9.87 ± 10.02
Cardiac Output (Q) (L/min)	6.3 ± 2.1	5.8 ± 1.8	8.1 ± 3.0	8.7 ± 3.1	1.8 ± 1.6	2.9 ± 1.8
Total Peripheral Resistance (TPR) (mmHG×min/L)	14.6 ± 4.9	16.0 ± 6.4	12.6 ± 3.6	11.8 ± 3.4	5.6 ± 5.9	3.4 ± 5.6

TABLE 4.

Correlates (Spearman Rank‐order sum, r‐values) of metabolic & cardiovascular measures in chronic liver disease: r, (P‐values)

	High RHR	MET SYN	# METSYN Components	Obesity	High BMI	DM	Low Walk Distance	High Base‐line SBP	Low Base‐line SBP
High Resting Heart Rate (RHR)	—	0.393 ** (0.008)	0.455 ** (0.002)	0.431 * (0.044)	0.599 *** (0.0001)	−0.305 * (0.047)	−0.325 * (0.033)
Metabolic Syndrome (METSYN)	0.393 ** (0.008)	—						0.321 * (0.034)
# METSYN Components	0.455 ** (0.002)		—					0.341 * (0.034)
Obesity	0.431 * (0.044)			—
High BMI	0.599 *** (0.0001)				—			0.229 * (0.048)
Diabetes Mellitus (DM)	−0.305 * (0.047)					—		0.329 ** (0.009)	−0.305 * (0.047)
Low Walk Distance	−0.325 * (0.033)						—
High Base‐line SBP		0.321 * (0.034)	0.341 * (0.034)		0.229 * (0.048)	0.329 ** (0.009)		—
Low Base‐line SBP						−0.305 * (0.047)			—

Abbreviations: BMI, Body Mass Index; DM, Diabetes Mellitus; METSYN, Metabolic Syndrome; # METSYN Components, Number of Metabolic Syndrome Components; RHR, Resting Heart Rate; SBP, Systolic Blood Pressure.

^*Significant at P ≤ 0.05.

^**Significant at P ≤ 0.01.

^***Significant at P ≤ 0.0001.

To study cardiorespiratory measures related to physical performance, we assessed cardiac and vascular contributors to a 6‐minute walk time (6MWT). This was used both as a physiological “stress” test and a performance measure. Measures include heart rate, blood pressure, cardiac output (CO, L/min), and oxygen consumption. This was then correlated with other cardiovascular performance and capacity measures (Tables 3, 4). Capacity was defined as the ability to accomplish or maintain activity at a certain level in a controlled setting.

All subjects performed hand dynamometry as a strength measure and underwent a non‐invasive multi‐channel bioimpedance test used to measure percent body fat and body composition (Maltron BioScan 920‐2). Next, subjects completed a 6‐minute walk test (6MWT) ²² along a straight 100 foot (30.48 m) long corridor. For two and a half minutes at baseline and immediately post‐walk, CO and stroke volume were obtained using a single channel bioimpedance instrument (Physioflow^® Mantec Biomedical). ²⁵ Additional cardiopulmonary fitness measures were collected pre and post‐6MWT, including: oxygen (O₂) saturation (O₂ sat pre, O₂ sat post), heart rate (HR resting, HR immediate post, HR recovery, ΔHR), CO, and percent maximum oxygen volume (VO₂ max). The Borg scale ¹⁰ performed at 2, 4, and 6 minutes during 6MWT was used to measure perceived exertion.

Activity and fitness levels were determined using Maximum and Adjusted Activity Scores (MAS, AAS) of the Human Activity Profile (HAP) a standardized frequently used self‐report designed for use in the cardiac population. Correlations between performance (ie, CO and oxygen consumption) and activity level measured by maximum activity score (MAS) have been established. ⁹ To measure fitness level, CO and oxygen volume were measured pre and post‐6MWT using Physioflow^®, a non‐invasive single channel, alternating current bioimpedance CO measure. While CO and oxygen consumption were calculated values, these measures generated by Physioflow^® have been validated against other cardiac and oxygen measures across a wide variety of conditions, including exercise of untrained subjects. ²⁴

2.4. Statistical analysis

Descriptive analyses were performed to assess correlative relationships among diagnosis, hematologic markers, medication, performance measures, and subjects’ self‐reports on symptoms and perceived ability. Performance measures analyzed were average velocity and distance walked. Spearman rank sum correlations were performed. Mann‐Whitney U test was used to compare normal range DBP and SBP measures (diastolic 60‐79, systolic 90‐119 mm mercury) at baseline to those in the pre‐hypertensive range (diastolic 80‐89, and/or systolic 120‐139 mm mercury). Pearson's correlation and regression of DBP and medication were also run using SPSS version 23 (SPSS, Inc). Standard deviations (SD) and confidence intervals (CI) were calculated where applicable.

3. RESULTS

Sixty‐seven patients completed the 6MWT [34.0% Female, Age 51.45 ± 9.29 years, Body Mass Index (BMI) 30.8 ± 5.6, 49% HCV, 51% NALFD] and were able to provide all measures of interest for analysis. Nine of 33 HCV subjects (32%) had previously been treated and achieved SVR. MAS and AAS were correlated with walk distance (Pearson r = .316, P = .012, CI = 0.071‐0.558; r = .369, P = .004, CI = 0.121‐0.618). MAS was also correlated with VO2 (r = .306, P = .016, CI = 0.059‐0.545). VO2 max was highly correlated with resting heart rate (r = −.939, P = .0001, CI = −1.028 to −0.850), HR 1 min post (r = −.297, P = .021, CI = −0.537 to −0.045), walk distance (r = .262, P = .042, CI = 0.010‐0.514) and MAS (r = .306, P = .016, CI = 0.059‐0.545). Correlations between cardiorespiratory measures, patient activity self‐reports, exertion to 6MWT, and resting DBP/SBP are reported below grouped by primary variable of interest. These findings are followed by secondary outcomes reporting on medication use possibly affecting the ANS. High SBP was strongly associated with diagnosed hypertension (r = .293, P = .027, CI = 0.034‐0.553).

3.1. Cardiorespiratory

Average cardiorespiratory data for the entire cohort were obtained and performance was highly correlated with cardiorespiratory data (Table 3). No patient self‐reports correlated significantly with performance or cardiorespiratory data. Furthermore, BMI was not significantly correlated with performance measures or self‐reports. Self‐reports (FSS or SF‐36) were not correlated with physiological measures except SF‐36 vitality subscale, which validates its previously demonstrated relationship to physiological measures. ²⁸ , ²⁹

3.2. Heart rate

Overall, resting heart rate (RHR) was evenly distributed among the 67 subject cohort. Metabolic abnormalities were highly correlated with high resting heart rate (Table 4). Ten subjects failed to return to RHR within 7 minutes post‐6MWT. Notable population descriptors compared to overall CLD cohort are as follows: 70% were female, BMI 34.1 ± 7.8, 70% obese, slightly shorter stride length (27.1 ± 6 inches), 60% hypertension, 30% hyperlipidemia, 60% diabetes, 40% metabolic syndrome, a 20 point elevation in heart rate post‐exertion (109.9 ± 13.2 bpm), higher baseline systolic (132.7 ± 15.3 mm Hg) and diastolic (81.0 ± 9.1 mm Hg), and lower baseline CO (5.7 ± 2.4). AST, ALT, age, walk distance, oxygen saturation, MAS, AAS, and CO post‐exertions were comparable to the overall group.

Seven subjects returned to baseline in less than a minute post‐exertion. Notable group descriptors include: 14% female, BMI 27.6 ± 5.0 SD, 43% obese, 43% hyperlipidemia, wide variability in AST and ALT (66.0 ± 29.5 and 73.8 ± 36.3, respectively), average baseline systolic of 115.5 ± 6.4, average baseline diastolic of 70.3 ± 6.7, increased walk distance (2035 ± 142 feet), low heart rate 1 minute post‐exertion (67 ± 11), and increased CO post‐exertion (8.79 ± 0.98). No one in this group had a hypertension, diabetes or metabolic syndrome diagnosis. Oxygen saturation at rest, age, baseline CO and heart rate did not differ from the overall group.

3.3. Blood pressure

Seventy percent of patients at baseline had either DBP or SBP outside normal range and 18.2% had abnormal values for both. In 94% of patients previously diagnosed with hypertension, either DBP or SBP was abnormal; and 29% had both abnormal DBP and SBP. Metabolic abnormalities were highly correlated with high resting systolic blood pressure. (Table 4) Baseline SBP was negatively correlated with walk distance (r = −.293, P = .025, CI = −0.547 to −0.038) and positively correlated with baseline DBP (r = .352, P = .005, CI = 0.112‐0.592). One minute post‐SBP was correlated with HR 1 minute post (r = .349, P = .008, CI = 0.095‐0.604). Baseline and post‐DBP were highly correlated with one another (r = .700, P = .0001, CI = 0.478‐0.922) and pre and post‐SBP were also correlated (r = .336, P = .005, CI = 0.117‐0.616). Diastolic and systolic 1 minute post were also highly correlated with one another (r = .295, P = .045. CI = 0.006‐0.584).

Significant differences were found between subjects with normal range DBP and those with pre‐hypertension range DBP. The latter reported significantly lower MAS than patients whose DBP was within normal range (r = −.288, P = .023, CI = −0.535 to −0.041; MAS 70.6 vs 82.5).

Subjects with pre‐hypertensive DBP scored significantly worse on the Bodily Pain (r = −.344, P = .006, CI = −0.585 to −0.103) and Vitality (r = −.283, P = .024, CI = −0.526 to −0.039) SF‐36 subscales, as well as overall Physical Component Score (PCS; r = −.273, P = .029, CI = −0.528 to −0.029). Patients with pre‐hypertensive DBP also scored significantly worse on CLDQ Fatigue (r = −.326, P = .05, CI = −0.586 to −0.067). Neither depression nor SF‐36 mental component scales correlated significantly with blood pressure. In subjects with pre‐hypertensive DBP, as in the full cohort, measures of performance and activity were significantly correlated with one another (Table 5). Also consistent with the overall cohort, pre‐hypertensive DBP subject fatigue scores tracked well with the Vitality subscale of SF‐36 but not with any of the activity or performance measures (Table 5).

TABLE 5.

Correlates of performance, and patient reported outcomes among subjects with pre‐clinical diastolic hypertension (Spearman Rank‐order sum, P‐values)

	Velocity	VO2 Max	Walk Distance	MAS	AAS	SF‐36 Vitality	FSS	HR post	Pre‐CO	Post‐CO	SF‐36 GH a
Velocity	—	0.264*	1.000**	0.307*	0.369*
VO2 Max	0.264*	—	0.262*	0.306*				−0.297*	−0.300*	−0.305*
Walk Distance	1.000**	0.262*	—	0.316*	0.369*
MAS	0.307*	0.306*	0.316*	—	0.812**						0.305*
AAS	0.369*		0.369*	0.812**	—	0.350*					0.435*
SF‐36 Vitality					0.350*	—	−0.527**	0.454*		0.292*
FSS						−0.527**	—
HR post		−0.297*				0.454*		—
Pre CO		−0.300*							—
Post CO		−0.305*				0.292*				—
SF‐36 GH a				0.305*	0.425*						—

Abbreviations: AAS, Adjusted Activity Score; FSS, Fatigue Severity Scale; HR post, HR 1 min post exertion; MAS, Maximum Activity Score; Post‐CO, Post‐exertion Cardiac Output; Pre CO, Pre‐exertion Cardiac Output; SF‐36 GH, Short Form 36 Global Health Subscale; SF‐36 Vitality, Short Form 36 Vitality Subscale; VO2 Max, Maximum Oxygen Volume.

^aSF‐36 GH = SF‐36 General Health subscale.

4. DISCUSSION

Patients with CLD (NAFLD and HCV) have a high prevalence of hypertension or pre‐hypertension. They have been shown to participate in a low activity level and experience relatively high perceived exertion level for this level of activity. The combination of inactivity and high perceived exertion level for a given workload or activity level, may help explain findings of low aerobic capacity and lack of adherence to exercise regimens. A prior study comparing physical activity in normal blood donors and patients with HCV, found the presence of hypertension to be predictive of lower daily/adjusted activity score (AAS) in both volunteer blood donors and patients with HCV. ³⁰ Blood pressure abnormalities are frequently associated with vessel stiffness, abnormal cytokine response to physiological demand, increased angiotensin, pain, and illness, all of which are associated with poor cardiovascular outcomes (eg, infarct, stroke etc). When cardiovascular disease (CVD) is present‐ regardless of cause‐lower exercise tolerance results. ³¹

This study also provides evidence about hypertension and pre‐hypertension prevalence in patients with NAFLD and HCV. The 70% frequency of abnormal blood pressure values in the group at time of study visit was somewhat surprising because this population of patients is receiving state‐of‐the‐art management for NAFLD and HCV, and many participate in clinical trials by attending a referral clinic for CLD management. It is possible that the elevated blood pressure is a temporary response to anticipation of testing, hence labile or pre‐clinical. An increased frequency of mortality risk from coronary artery disease (CAD) has also been associated with chronic liver disease patients, and recently highlighted in patients with non‐alcoholic fatty liver disease (NAFLD) particularly in cases of comorbid diabetes mellitus (DM) and NAFLD. ³² , ³³ , ³⁴ , ³⁵

Hepatitis C patients post‐sustained virologic response (SVR) still report fatigue, which is often associated with persistent systemic inflammation. Dysregulation of the renin‐angiotensin system (RAS) may contribute particularly to the fibrosis and necroinflammation processes associated with fatty infiltration of the liver. ³⁶ All components of metabolic syndrome have been associated with systemic inflammatory processes. Increased DBP in particular may be indicative of sustained upregulation of systemic inflammation, and potentially, an early warning sign of accumulating inflammation‐mediated damage to the vasculature. Inflammation‐related scarring could increase in blood vessel stiffness and impair the ability for the smooth muscle of the vessel to respond and adapt appropriately to a challenge such as exercise. Targeting of the renin‐angiotensin system (RAS) using angiotensin receptor blockers (ACE/ARBs) has been proposed as a means to both control hypertension and to reduce liver fibrosis and nercroinflammatory processes within the liver. ³⁷

This study indicates that subjects with normal resting DBP differ from those with abnormal resting DBP in terms of their self‐reported activity level, global and disease‐specific quality of life. Increased diastolic blood pressure is a measure of high peripheral resistance, and associated with increased heart rate and inotropic response. Patients with NAFLD and HCV who have baseline elevation of either SBP or DBP had poorer physical performance and higher metabolic symptom burden than patients who had normal blood pressure. In this study, it is more likely to be associated with pre‐hypertensive DBP (Tables 3, 4, 6). Diastolic hypertension is a major concern for chronic kidney and heart damage, which can be further exacerbated by alcohol, smoking, aging, and high cholesterol‐related harm. ³⁸ , ³⁹ The Framingham Study suggested that chronic damage over time through elevated diastolic blood pressure may still be a primary driver of disease in subjects younger than 45 years. ³⁸ , ⁴⁰ Even mildly elevated DBP in CLD patients is associated with fatigue and lower physical activity levels. This is in keeping with previous studies indicating that a slow recovery of heart rate in the first minute after an exercise stress test (<10 bpm) is associated with a prognosis of mortality. ⁴¹ , ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² Perceived exertion and general self‐reports (FSS) did not correlate with physiological self‐reports or performance measures in this study.

TABLE 6.

Primary significant differences between cohorts (Mean ± Standard Deviation (SD), Range; P = value, Confidence Interval (CI))

	Baseline Normal Range Diastolic Blood Pressure	Baseline Pre‐hypertensive Diastolic Blood Pressure	P‐values(CI)
Maximum Activity Score (MAS) a	82.2 ± 8.28 (79.62‐84.63)	75.8 ± 9.8 (73.07‐82.82)	.049 * (78.46‐83.12)
Adjusted Activity Score (AAS) *	78.5 ± 8.3 (73.42‐79.76)	85.4 ± 4.3 (66.65‐79.90)	.001 ** (72.85‐78.64)

^aHigher scores are better.

^*Significant at p ≤ 0.05.

^**Significant at p ≤ 0.001.

One of the goals of this study was to determine if there might be specific, routine office‐based measures useful in evaluating an individual with liver disease that would help direct safe exercise/activity recommendations. This study supports the idea that resting heart rate and blood pressure, especially paired with activity level self‐report and calculated requirements of energy for daily activity (METS) (eg, HAP‐derived metabolic equivalents or METs; 1 MET = 3.5 mL O2 kg⁻¹ min⁻¹) can provide an estimate of VO2 max and daily/maximal METs expenditure estimate. MET requirements for self‐care are 1‐3 METs, daily activity such as walking and leisure activities are 4‐8 METs, have been well established. ⁵³ These routine office‐based measures and an activity level questionnaire will provide valuable information about an individual's status from which a judgment about exercise tolerance can be made. It is important, we believe, to be able to determine what is safe for an individual to do and whether they are likely to tolerate recommendations for increased activity. Addressing their resting heart rate, DBP, current level of activity and its impact on symptoms of shortness of breath, aches/pains will help form a successful approach to activity/exercise recommendations.

Our study did have limitations. The primary study focus was to determine the role of cardiovascular, physical activity, and fitness‐related parameters on performance in patients with either HCV or NAFLD. Many other factors are likely to influence performance—including degree of inflammation, metabolic status, mood, motivation, nutrition—not all of which were measured in this study. Motivation and degree of effort are always important contributors to a self‐directed activity such as 6MWT. A VO2 estimate was calculated based on CO data, taking gender and age into consideration, and was in keeping with overall cardiac measures. Multiple calculation options were applied, yielding similar results. The Uth–Sørensen–Overgaard–Pedersen estimate method was ultimately chosen based on its validation studies. ⁵⁴ The sample size is small, yet provides valuable information about a patient population that has a large inflammatory burden, significant metabolic difficulties, and is generally under‐reported in terms of their activity profiles.

In summary, this study reports a significant correlation between blood pressure abnormalities—particularly diastolic hypertension—and low performance. When added to known associations with metabolic and inflammatory abnormalities, this patient group has a significant physical performance deficit for their age and gender, and a decreased level of participation in higher energy activities. Low performance indicates reduced capacity to engage in higher MET requiring activities of daily living, limiting some types of engagement in daily and social activities, as well as engagement in the kinds of aerobic exercise recommended for maintenance and improvement of heart health. They self‐report low vitality level. Together, these findings paint a picture of an individual with pre‐ to full hypertension and lowered capacity to engage in the kinds of aerobic exercise recommended for improvement and maintenance of cardiovascular health. Careful blood pressure assessment and management may remove one barrier to participation in increased exercise intensity and may help reduce the perceived exertion level. Patients with this profile would likely benefit from close monitoring of hypertension and the introduction of additional, lower MET aerobic exercise to their daily routines, to be increased gradually over time. There may be opportunity for early correction of clinical trajectory toward functional impairment, cardiovascular disease, and increased mortality risk.”

CONFLICT OF INTEREST

None.

AUTHOR CONTRIBUTIONS

Jillian Price, PhD‐designed the study, collected and managed the data and wrote the manuscript. Carey Escheik BS‐designed and coordinated the study, monitored the protocol and edited the manuscript. Ali Weinstein PhD‐designed the study and contributed the manuscript. Patrice Winter. PhD‐designed the study, visited the study coordination, collected the data and reviewed the manuscript. Lynn Gerber MD‐designed the study, collected the data and wrote the manuscript. Zobair Younossi, MD, MPH‐designed the study and developed the manuscript.

Price J, Escheik C, Weinstein A, Winter P, Gerber L, Younossi Z. Abnormal cardiac and metabolic measures correlate significantly with lower performance and activity in overweight chronic liver disease. J Clin Hypertens. 2020;22:1915–1923. 10.1111/jch.13938