Carotid Arterial Stiffness and Its Relationship to Exercise Intolerance in Older Patients with Heart Failure and Preserved Ejection Fraction

Abstract

Heart failure with a preserved ejection fraction (HFpEF) is the dominant form of heart failure in the older population. The primary chronic symptom in HFpEF is severe exercise intolerance, however, its pathophysiology and therapy are not well understood. We tested the hypothesis that older patients with HFpEF have increased arterial stiffness beyond that which occurs with normal aging and that this contributes to their severe exercise intolerance.

Sixty-nine patients ≥ 60 years with HFpEF and 62 healthy volunteers (24 young healthy subjects ≤ 30 years (YHC) and 38 older healthy subjects ≥ 60 years old (OHC) were examined. Carotid arterial stiffness was assessed using high-resolution ultrasound and peak exercise oxygen consumption (VO₂) was measured using expired gas analysis.

Peak VO₂ was severely reduced in the HFpEF patients compared to OHC (14.1±2.9 vs. 19.7±3.7 ml/kg/min; p<0.001) and in both was reduced compared to YHC subjects, (32.0±7.2 ml/kg/min; both p<0.001). In HFpEF compared to OHC, carotid arterial distensibility was reduced (0.97±0.45 vs. 1.33±0.55 × 10⁻³ mmHg⁻¹, p=0.008) and Young’s elastic modulus (YEM) was increased (1320±884 vs. 925±530 kPa, p<0.02). Carotid arterial distensibility was directly (0.28; p=0.02) and YEM was inversely (−0.32; p=0.01) related with peak VO_2.

Carotid arterial distensibility is decreased in HFpEF beyond the changes due to normal aging and is related to peak VO₂. This supports the hypothesis that increased arterial stiffness contributes to exercise intolerance in HFpEF and is a potential therapeutic target.

Introduction

Approximately 50% or more of heart failure (HF) patients have preserved left ventricular ejection fraction (HFpEF), and the proportion is greater among women and the elderly.^1,2 The primary symptom in patients with chronic HFpEF, even well-compensated, is severe exercise intolerance, which can be measured objectively as decreased peak exercise pulmonary oxygen uptake (peak VO₂).^3-8

It has been shown in population-based studies that increased arterial stiffness is associated with cardiovascular morbidity and mortality, including in older populations.^9-12 We and others have shown that increased stiffness of the aorta is associated with exercise intolerance in older patients with either HFpEF or HF and reduced ejection fraction (HFrEF).^13,14 It is known that arterial function may have substantial regional variation.¹⁵ In HFrEF, it has been shown that the increase in arterial stiffness is generalized and is observed in the peripheral arteries as well as the aorta, and has been shown to be modifiable with angiotensin receptor antagonism.¹⁶ Moreover, the pulsatile components of arterial afterload are greater in HFpEF compared with HFrEF and may play a greater role in the pathophysiology of HFpEF than HFrEF.¹⁷ It is known that normal aging alone is associated with increased arterial stiffness, and that this can be exacerbated in the setting of systemic hypertension¹⁸. In addition, Borlaug et al^5,6,19 and others^20,21 reported in older HFpEF patients that systemic vascular resistance was increased and appeared to contribute to their reduced peak VO₂. However, it is unknown whether arterial stiffness is generalized in HFpEF and whether it contributes to exercise intolerance.

We hypothesized that peripheral arterial stiffness is increased in older HFpEF patients, beyond the extent that occurs with normal aging alone, similar to the changes in the thoracic aorta, and that these changes may contribute to their severe exercise intolerance. To test these hypotheses, we non-invasively measured indexes of stiffness of the carotid artery, a large vessel easily accessible by high resolution ultrasound, and exercise capacity in older patients with HFpEF in comparison to groups of young and old healthy normal volunteers.

Methods

Subjects

Data regarding flow mediated arterial dilation have been recently reported from a subset of these subjects.²² As previously described,^4,8,22,23 HFpEF was defined as HF with normal systolic function (LV ejection fraction ≥ 50% and no segmental wall motion abnormalities) and no evidence of significant coronary or valvular heart disease or pulmonary disease. The diagnosis of HF was based on clinical criteria as previously described,^4,8,23 that included a HF clinical score from National Health and Nutrition Examination Survey-I of ≥3,²⁴ and those utilized by Rich et al,²⁵ that included a history of acute pulmonary edema, or the occurrence of at least 2 of the following with no other identifiable cause and with improvement following diuresis: dyspnea on exertion, paroxysmal nocturnal dyspnea, orthopnea, bilateral lower extremity edema, or exertional fatigue. Final determination was made by a board-certified cardiologist following review of medical records, interview, examination, and rest and exercise echocardiography (the latter to exclude inducible ischemia as confounder). There were 69 patients with HFpEF.

As previously described, normal, healthy volunteers were screened and excluded if they had any chronic medical illness, were on any chronic medication, had current complaints or an abnormal physical examination (including blood pressure ≥ 140/90 mmHg), had abnormal results on the screening tests (electrocardiogram, rest and exercise echocardiogram, and spirometry), or were regularly exercising.^4,22,23 There were 24 young healthy volunteers (age < 30 years, YHC) and 38 older healthy participants (age > 60 years, OHC).

Because of the significant influence of atherosclerosis on vascular function,²⁶ in both patients and healthy subjects, the protocol excluded those at high risk (known hyperlipidemia, cigarette smoking) and those with known or suspected coronary, cerebrovascular, and peripheral arterial disease by record review, history, physical examination, exercise echocardiography, and carotid ultrasound.

Study Protocol

The study protocol was approved by the Institutional Review Board at Wake Forest University Health Sciences. All subjects were familiarized with the testing environment and procedures and informed consent was obtained during the screening visit. During a subsequent visit, patients reported in the morning following an overnight fast and prior to taking their morning medications, and in a single visit the outcome measures of carotid artery stiffness, LV function, and exercise capacity were obtained. All testing was performed by and all results were analyzed by individuals blinded to patient groups.

Echocardiography

As previously described,^4,8,23,27 resting echocardiography was performed by an experienced, registered echosonographer using a Philips Sonos 5500 (Andover, Massachusetts) ultrasound imaging system fitted with multifrequency transducer. Standard 2-dimensional images were obtained in the parasternal long-axis and short-axis views and apical 4- and 2-chamber views. Off-line analyses were performed using a digital analysis workstation according to ASE standards⁴. Doppler mitral filling patterns were categorized as normal, impaired relaxation, pseudonoramal, and restrictive.^28,29

Exercise Testing Protocol

As previously described,^{4,8,13,23,27,30} exercise testing was performed with participants in the upright position on an electronically braked cycle ergometer. A detailed description of the exercise testing protocol methods is available on the online supplement.

Carotid artery stiffness measurements

As previously described,³¹ standardized longitudinal B-mode images of the left common carotid artery were recorded with the subject in the supine position using a commercially available ultrasound instrument (Sequoia, Accuson, Inc.) fitted with a high frequency (10 MHz) linear probe and using vascular software and optimized settings. A detailed description of the carotid artery stiffness measurements methods is available on the online supplement.

Statistical Analysis

Values were expressed as means ± SD unless otherwise noted. Comparisons were performed using analysis of covariance. Intergroup comparisons of baseline characteristics and measures of exercise performance, and carotid artery stiffness were made using the independent t-test for continuous measures and Fisher’s exact test for categorical measures. Carotid arterial distensibility was selected as the primary outcome measure of arterial stiffness prior to study initiation. Because of non-normal distribution, carotid stiffness measures were log-transformed. Multiple linear regression analysis was performed to determine significant predictors of peak VO₂ and to determine the independent effects of these variables on peak VO₂ after adjustment for differences in sex, race and body mass index. For all analyses, a two-tailed p-value of <0.05 was required for significance.

Results

Carotid artery imaging and exercise testing were well tolerated in all individuals and there were no adverse events associated with either.

Participant Characteristics

Characteristics of the HFpEF, YHC and OHC are shown in Table 1. The OHC and HFpEF groups were well matched for age, however, body mass was higher for HFpEF than YHC or OHC. There was a higher percentage of women in the OHC and HFpEF groups than in YHC. The HFpEF patients had characteristics similar to those reported from population studies, and from previous reports from our laboratory.^4,8,23,29 Specifically, they had increased left atrial diameter, LV posterior and septal wall thickness, mass and mass to volume ratio compared to OHC (Table 1). HFpEF patients were stable, New York Heart Association (NYHA) class II (46%) and III (54%). They had a mean LV ejection fraction by echocardiography of 59 ± 8%, and most had abnormal Doppler mitral flow patterns.²⁹ Chronic systemic hypertension was present in 90% of HFpEF patients and diabetes was present in 28%. HFpEF patients were being clinically treated with the following medications: ACE-Inhibitors/angiotensin receptor antagonists (45%), digoxin (6%), diuretics (61%), nitrates (12%), beta blockers (21%) and calcium channel blockers (30%). All patients were in sinus rhythm.

Table 1.

Characteristics of the Study Population

Characteristic	YHC (n=24)	OHC (n=38)	HFpEF (n=69)	p-Value
Age (ys)	26 ± 3	69 ± 6	70 ± 7	0.65
Women	12 (50)	25 (66)	52 (77)	0.37
Caucasian	23 (96)	36 (95)	47 (68)	0.001
Body weight (kg)	73 ± 15	72 ± 14	87 ± 19	<0.001
Body surface area (m2)	1.86 ± 0.24	1.80 ± 0.20	1.94 ± 0.23	0.01
Body mass index (kg/m2)	24 ± 3	26 ± 3	32 ± 7	<0.001
Ejection fraction (%)	--	65 ± 8	59 ± 8	0.01
Septal wall thickness (cm)	--	1.0 ± 0.1	1.4 ± 0.3	<0.001
Posterior wall thickness (cm)	--	0.9 ± 0.1	1.2 ± 0.2	<0.001
Mass (g)	--	167 ± 46	261 ± 88	<0.001
Mass/volume ratio	--	2.52 ± 1.06	3.22 ± 1.60	0.07
Left atrial diameter (cm)	--	3.1 ± 0.5	3.5 ± 0.7	0.02
Mitral early velocity (cm/s)	--	68 ± 18	74 ± 20	0.21
Mitral atrial velocity (cm/s)	--	73 ± 13	84 ± 24	0.006
Early/atrial ratio	--	0.94 ± 0.19	1.01 ± 0.81	0.51
Deceleration time (ms)	--	217 ± 49	228 ± 71	0.41
Isovolumic relaxation time (ms)	--	74 ± 17	82 ± 23	0.08
Diastolic Filling
Normal	--	30 (79)	0 (0)	<0.001
Impaired relaxation	--	8 (21)	32 (50)	0.006
Pseudonormal	--	0 (0)	29 (45)	<0.001
Restrictive	--	0 (0)	3 (5)	0.29
History of hypertension	--	--	62 (90)	--
Diabetes mellitus	--	--	19 (28)	--
ACE	--	--	27 (39)	--
Angiotensin receptor blockers	--	--	4 (6)	--
Digoxin	--	--	4 (6)	--
Diuretics	--	--	42 (61)	--
Beta-blockers	--	--	15 (22)	--
Calcium channel blockers	--	--	21 (30)	--
Nitrates	--	--	8 (12)	--

Values are mean ± SD or count (%). P-value indicates comparison of HFpEF versus OHC. ACE, angiotensin converting enzyme inhibitor.

Exercise Performance

Participants gave an exhaustive exercise effort and mean peak respiratory exchange ratios were >1.13 for all 3 groups (Table 2). Peak VO₂ (L/min or ml/kg/min) was severely reduced in HFpEF patients compared to OHC subjects and was greater in YHC subjects than in both older groups (Table 2). Peak exercise workload, time, heart rate were also markedly reduced in HFpEF patients compared to OHC subjects and were greater in YHC subjects than in both older groups (all p<0.001). Peak exercise systolic blood pressure was similar in HFpEF patients and OHC subjects (p=0.42) and in both was higher than in YHC subjects (p<0.01 for both). No significant difference was found between YHC and OHC or OHC and HFpEF patients for the Ve/VCO₂ slope (Table 2). Six minute walk distance was also reduced in HFpEF patients compared to OHC subjects (p<0.001) and in both was reduced compared to YHC subjects (p<0.001 for both).

Table 2.

Peak Exercise Performance

Parameter	YHC	OHC	HFpEF	YHC vs OHC p-Value	OHC vs HFpEF p-Value
VO2 (ml/kg/min)	32.0 ± 7.2	19.7 ± 3.7	14.1 ± 2.9	<0.001	<0.001
VO2 (ml/min)	2310 ± 665	1418 ± 397	1218 ± 360	<0.001	0.010
Time (seconds)	1243 ± 394	737 ± 190	540 ± 197	<0.001	<0.001
Workload (Watts)	163 ± 55	89 ± 28	67 ± 29	<0.001	<0.001
Heart Rate (bpm)	176 ± 16	148 ± 14	128 ± 19	<0.001	<0.001
Systolic BP (mmHg)	176 ± 19	195 ± 23	191 ± 24	0.001	0.419
Diastolic BP (mmHg)	83 ± 12	88 ± 9	90 ± 13	0.056	0.458
Oxygen pulse (ml/beat)	13.3 ± 4.2	9.6 ± 2.7	9.7 ± 3.0	0.001	0.906
VE (l/min)	85 ± 20	59 ± 17	48 ± 16	<0.001	0.001
RER	1.16 ± 0.09	1.21 ± 0.09	1.13 ± 0.08	0.052	<0.001
6 minute walk (m)	665 ± 70	551 ± 59	425 ± 103	<0.001	<0.001
Ve/VCO2 Slope	28.6 ± 4.5	31.1 ± 3.6	32.4 ± 5.8	0.084	0.293

Values are mean ± SD. BP, blood pressure; RER, respiratory exchange ratio; VE, minute ventilation; VO₂, oxygen consumption; VCO_2, carbon dioxide production.

Carotid artery measurements

Arterial and lumen diameters were increased in HFpEF compared to OHC and YHC (p<0.001; Table 3). Compared to YHC, OHC had significantly increased carotid arterial stiffness indexes (decreased arterial compliance, increased PEM, YEM, and beta index, Table 3). Compared to OHC, patients with HFpEF had further reductions in arterial distensibility (p=0.008), and increased YEM (p=0.018). The decreased carotid arterial distensibility in HFpEF patients appeared primarily due to increased pulse pressure, since phasic arterial diameter change was similar to OHC. Carotid intimal media thickness was increased in OHC compared to YHC and also similar in HFpEF compared to OHC. These results were not significantly altered following adjustments for gender or medications.

Table 3.

Carotid Artery Stiffness Measurements

Parameter	YHC	OHC	HFpEF	YHC vs OHC p-Value	OHC vs HFpEF p-Value
Primary Carotid Stiffness Measure
Carotid distensibility (×10−3 mmHg−1)	1.96 ± 1.18	1.33 ± 0.55	0.97 ± 0.45	0.211	0.008
Secondary Carotid Stiffness Measures
Carotid compliance (×10−3 mm*mmHg−1)	97.7 ± 57.3	66.3 ± 34.8	58.6 ± 24.0	0.010	0.295
Peterson’s elastic modulus (kPa)	76 ± 37	194 ± 120	237 ± 129	<0.001	0.131
Young’s elastic modulus (kPa)	450 ± 229	925 ± 530	1320 ± 884	<0.001	0.018
Beta Index	6.46 ± 3.21	14.61 ± 8.86	16.54 ± 8.35	<0.001	0.315
Carotid Artery Dimensions
Intima-medial thickness (mm)	0.57 ± 0.06	0.75 ± 0.12	0.79 ± 0.14	<0.001	0.207
Systolic arterial diameter (mm)	7.12 ± 0.78	7.48 ± 0.94	8.34 ± 0.98	0.169	<0.001
Diastolic arterial diameter (mm)	6.53 ± 0.70	7.14 ± 0.85	7.95 ± 0.97	0.012	<0.001
Systolic luminal diameter (mm)	6.03 ± 0.83	6.02 ± 0.79	6.80 ± 1.06	0.986	0.001
Diastolic luminal diameter (mm)	5.59 ± 0.74	5.63 ± 0.71	6.34 ± 1.02	0.885	0.002
Arterial diameter change (mm)	0.59 ± 0.23	0.34 ± 0.17	0.39 ± 0.17	<0.001	0.183
Luminal diameter change (mm)	0.44 ± 0.20	0.39 ± 0.18	0.42 ± 0.18	0.493	0.509
Blood Pressure
Systolic blood pressure (mmHg)	112 ± 12	131 ± 15	146 ± 18	<0.001	<0.001
Diastolic blood pressure (mmHg)	69 ± 10	75 ± 9	76 ± 11	0.023	0.729
Pulse pressure (mmHg)	43 ± 7	56 ± 13	70 ± 16	<0.001	<0.001

Values are means ± SD.

Relationship of carotid arterial stiffness indexes with exercise performance

Indices of carotid arterial stiffness including PEM, YEM, β-index and distensibility, adjusted for sex, race and BMI, were significantly correlated with peak exercise VO₂ (Figure 1). Given that HFpEF had significantly lower maximal HR, the relationship between oxygen pulse (O₂P, equal to VO₂/HR) and carotid arterial stiffness indices was performed. The O₂P was significantly correlated with carotid arterial distensibility (r=0.26, p=0.04) but was not was related to PEM (r=−0.20, p=0.11), YEM (r=−0.20, p=0.10) or β-index(r=−0.16, p=0.18). No significant association was found between Ve/VCO₂ slope and carotid arterial distensibility (r=−0.02, p=0.88), YEM (r=−0.06, p=0.65), PEM (r=0.01, p=0.97) and Beta index (r=0.01, p=0.91). Carotid arterial distensibility was also correlated with 6-minute walk distance (r=0.25; p<0.03).

Figure 1.

Relationship of carotid arterial distensibility (A), Young’s elastic modulus (B), Peterson’s modulus (C), and Beta index (D) to peak exercise VO₂ for the study group. Young normals (circles); old normals (squares); HFpEF (triangles). Correlation coefficients and p-values shown are following log transformation and adjustment for sex, race and body mass index.

Discussion

This study demonstrates that although healthy, normal aging alone is accompanied by increased carotid arterial stiffness and reduced peak VO₂, older patients with HFpEF have severely reduced exercise capacity and increased carotid arterial stiffness beyond that which occurs with normal ‘non-hypertensive’ aging. Measures of carotid arterial stiffness performed at rest correlated significantly with peak VO₂ and 6-minute walk distance. These data support the hypothesis that increased arterial stiffness may play a role in the pathophysiology of HFpEF, the dominant form of HF in the older population. In addition, because exercise intolerance is the primary chronic symptom in HFpEF, these data suggest that increased arterial stiffness may be a potential therapeutic target in older patients with this disorder. To this end, endurance training may be an important therapy to improve arterial stiffness in older HFpEF patients. Finally, because the carotid artery is a large vessel easily assessable by high resolution ultrasound imaging, this technique may provide a practical means for serial evaluation of arterial stiffness during future clinical intervention trials in HFpEF.

These data significantly extend previous reports from our group and others suggesting that arterial stiffness is increased in older patients with HFpEF.^5,13,32,33 We have previously reported that stiffness of the proximal thoracic aorta is increased in older patients with both HFpEF and HFrEF and that in both types of HF it is a strong, independent predictor of the severity of exercise intolerance.^13,14 Melenovsky et al reported that carotid mean blood pressure and carotid pulse pressure were increased while total arterial compliance (measured as stroke volume divided by carotid pulse pressure) was significantly decreased in HFpEF compared to age-and sex-matched healthy control subjects.³⁴ Arterial sites other than the aorta, including the carotid and radial arteries, have been shown to have increased stiffness in patients with HFrEF.¹⁶ The present findings indicate that arterial stiffness extends beyond the thoracic aorta in HFpEF as well. We have previously reported other similarities in the pathophysiology of HFpEF and HFrEF, including severely reduced exercise capacity, exercise cardiac output, and quality of life and increased neurohormonal activation.^4,13,14,35

The present study utilized high resolution ultrasound to assess carotid arterial stiffness. While this technique can provide high quality data at rest, it is not feasible during upright maximal exercise. However, Tartiere-Kesri et al. recently measured carotid artery stiffness at rest and during low-intensity (30 watts, equal to 39% peak power output) sub-maximal cycling in older HFpEF patients (n=23) and age-matched healthy controls (n-15).³² They reported that rest and exercise carotid systolic blood pressure, carotid pulse pressure, and proximal arterial load (carotid Peterson modulus, aortic pulse wave velocity) were significantly increased while arterial compliance was significantly lower in HFpEF patients versus healthy controls.³² Also, the change in carotid Peterson’s modulus from rest to 30 watt cycling was significantly increased in older HFpEF compared controls (+155% vs. −5%, respectively), and was inversely related to peak power output or 6-minute walk distance. We extend these findings by studying a larger group of older HFpEF patients and by including both young and old healthy control subjects to demonstrate that carotid arterial distensibility is decreased in HFpEF beyond the changes due to normal aging alone, and by correlating these changes with peak exercise VO₂ as well as 6-minute walk distance.

The present study also extends prior findings by excluding patients with evidence of significant atherosclerotic plaque on carotid imaging, and patients with any history or evidence of cerebrovascular, peripheral vascular, or coronary artery disease. There was also no significant increase in intimal medial thickness in HFpEF compared to healthy age-matched volunteers, suggesting that the observed changes in arterial stiffness and their relationship with peak VO₂ were not necessarily due merely to atherosclerosis. The absence of differences in phasic arterial diameter change suggests that the differences in stiffness were due primarily to increased pulse pressure, a finding consistent with that found at rest or low-level cycle exercise by Tartiere-Kesri and associates.³²

There are a number of potential mechanisms that could be responsible for the altered arterial stiffness in HF patients.³⁶ First, neurohormonal changes in HF, including activation of the renin-angiotensin system and increased plasma norepinephrine, may cause vasoconstriction and sodium retention in the vascular wall.^37,38 We and others have shown that HFpEF patients have activation of both renin-angiotensin system and the adrenergic system.^4,39 Second, the hypertrophic effect of angiotensin II and aldosterone on vascular smooth muscle cells results in changes in vascular wall structure.^40-42 Endothelial dysfunction also affects vasodilatation properties of the artery and proliferation of smooth muscle cells.⁴⁰ Finally, atherosclerosis has been associated with impaired arterial elastic properties, and may result in decreased distensibility.^42,43 The above changes can be accelerated by chronic hypertension and diabetes. Notably, in population-based studies, similar to our patient group, hypertension is found in approximately 90% of older HFpEF patients and diabetes in approximately 30%.⁴⁴

Potential Limitations

The present study was designed prior to publication of the criteria proposed by Paulus et al.⁴⁵ However, the inclusion criteria used have been shown to identify patients who have severe abnormalities in key pathophysiological attributes similar to patients with established, severe systolic heart failure and to have significantly increased rates of death and heart failure rehospitalization.^4,24,25,46 The Paulus criteria require 3 obligatory features: signs or symptoms of congestive heart failure; preserved systolic function; and evidence of LV diastolic dysfunction. The first 2 criteria were automatically met by study design. The third criterion as stated by Paulus et al. is best fulfilled by either invasive measurements or tissue Doppler and pulmonary venous flow, which are not available in this study. However, Paulus et al. acknowledge the finding by Zile et al.²⁹ that in patients with the combination of a clear history of HF, normal EF, and concentric LV remodeling (all typical of the patients in the present study), 92% were found to have abnormal diastolic function by subsequent invasive measurements. The present study had 2 additional features supported by Paulus et al., including formal cardiopulmonary exercise testing with measurement of peak VO₂ to confirm the presence of severely reduced exercise capacity and pulmonary function testing to prevent misdiagnosis due to pulmonary disease.

Cardiac medications were withheld the evening before exercise testing and carotid artery imaging in HFpEF patients (approximately 12-24 hours). Participants also abstained from caffeine ingestion for 24 hours prior to testing. However, we cannot exclude the potential for residual effects of vasoactive drugs that may confound measures of carotid arterial stiffness. Despite this, most of the medications in the HFpEF patients would be expected to reduce arterial stiffness. By definition, subjects in the healthy older group were taking no chronic medications. Thus, the severity of arterial stiffness observed in the HFpEF patients would be more likely to be underestimated due to medication effects, rather than overestimated. Although current (< 2 years) smokers were excluded, some participants had been smokers in the past.

In the present study, we did not have an older control group with diabetes or hypertensive left ventricular hypertrophy without HF, therefore, it is possible that the increased carotid arterial stiffness observed in our elderly HFpEF patients may have been due to antecedent hypertension. Indeed, Melanovsky previously reported that carotid mean blood pressure, carotid augmentation index and arterial compliance were similar between HFpEF patients and individuals with hypertensive left ventricular hypertrophy without overt HF.³⁴

Measures of carotid distensibility were obtained during supine rest, and therefore the present data do not exclude additional, more severe abnormalities in vascular function, such as impaired vasodilation, that may occur during exercise and potentially contribute to exercise tolerance⁵. Indeed, our finding of a significant positive (but weak) correlation between peak VO₂ or O₂P (an indirect measure of stroke volume) and carotid distensibility suggests that increased arterial loading may result in the blunted peak exercise SV found in some studies of clinically stable older HFpEF patients³. Although these data, taken together with previous reports from our group and other investigators, suggest that there is a generalized increase in systemic arterial stiffness in patients with HFpEF, there can be substantial regional and segmental variations in arterial function.^13,22 While the carotid artery is relatively proximal to the left ventricle, there are relatively few data examining its role in determining impedance to ventricular ejection and overall systemic vascular resistance, unlike the case with the aorta.^13,14

The finding of abnormal arterial stiffness and significant correlations with exercise tolerance in a cross-sectional study cannot prove a causal relationship. Furthermore, peak VO₂ is determined by a complex interaction of multiple organ systems and physiological responses. Thus, it is not certain that modification of arterial stiffness, if feasible, would lead to improved exercise capacity.

The present study utilized a variety of indexes of arterial stiffness, each of which has somewhat different determinants and implications, and there is lack of consensus in the literature regarding which of the indexes is optimal for clinical studies. Carotid arterial distensibility was the pre-selected primary outcome, however, most of the indexes of arterial stiffness were in agreement regarding the key findings of the study.

Perspectives

Carotid arterial distensibility is decreased in older patients with HFpEF beyond the changes which occur with normal aging alone, and is correlated with peak exercise VO₂ and 6 minute walk distance. This suggests that a generalized increase in systemic arterial stiffness may contribute to the pathophysiology of exercise intolerance in older patients with HFpEF. Assessment of carotid stiffness by high resolution ultrasound may provide a practical means for serial assessment of arterial stiffness during clinical studies of therapeutic agents aimed at improving exercise intolerance, the primary chronic symptom in HFPEF.

Novelty and significance.

What is new?

• • Carotid arterial distensibility is decreased in older patients with heart failure with preserved ejection fraction (HFpEF) beyond the changes which occur with normal aging alone, and is correlated with exercise capacity.

What is relevant?

• • Increased arterial stiffness may contribute to the pathophysiology of exercise intolerance, the primary symptom in chronic HFpEF, which is the dominant form of heart failure in the community.