Cardiorespiratory Fitness Benefits of Long-Term Maintenance-Phase Cardiac Rehabilitation in Males and Females: A Retrospective Cohort Study

Abstract

Purpose:

This study investigated if associations exist between enrolment delay and VO₂peak over five years of maintenance-phase cardiac rehabilitation (CR) in males and females.

Method:

Data were extracted from the records of participants who had enrolled for ≥ 1 year in CR and completed ≥ 2 cardiopulmonary exercise tests. Mixed model analyses examined VO₂peak trajectories for up to five years of enrolment. Interactions between enrolment delay × enrolment duration, baseline age × enrolment duration, and baseline VO₂peak × enrolment duration were explored for inclusion in the model.

Results:

The charts of 151 males (aged 63.9 ± 9.4 y) and 32 females (aged 65.3 ± 9.0 y) were included in the analyses. The enrolment delay following a cardiovascular event was 1.8 ± 3.0 years for males and 1.3 ± 1.7 years for females. No associations were found between enrolment delay × enrolment duration on VO₂peak in males (β[SEj, 0.07[0.05]; 95% CI −0.02, 0.16, p = 0.12) or in females (β[SE], 0.07[0.13j; 95% CI −0.18, 0.33, p = 0.57), but predicted trajectories suggest clinically significantly improvements in VO₂ peak (range, 1.3 to 1.6 mL/kg/min).

Conclusions:

Early enrolment in CR is recommended and encouraged, but the benefits of long-term CR are possible despite delays.

Cardiac rehabilitation (CR) is a critical component in the continuum of care for the management and secondary prevention of cardiovascular disease (CVD).^1,2 There are up to four phases of CR in the Canadian context: acute care (phase 1) and outpatient rehabilitation (phases 2–3), and the maintenance-phase CR (phase 4).³ Although each phase may differ slightly regarding timelines and treatment goals, CR generally consists of multidisciplinary, comprehensive programming geared toward risk factor modification, exercise prescription, psychosocial support, education on diet, and the promotion of lifelong physical activity to foster optimal recovery and slow the trajectory of CVD.^1–3 Importantly, CR programmes are cost-effective management strategies^4–6 to improve cardiorespiratory fitness (CRF)^7,8 and lower the risk of CVD, recurrent myocardial-related hospitalizations, and cardiovascular mortality.⁹

The timely access to and enrolment in early-phase CR programmes (phases 1–3) are important for the clinical management of CVD in both males and females.^10,11 It is recommended that individuals with CVD enrol in early-phase CR within 21 days after a cardiac event to reverse the pathological remodelling.^12,13 Yet, on average, individuals face delays of up to 150 days from hospital discharge to CR commencement.^14,15 Delays have been associated with attenuated gains in CRF and fewer improvements in cardiovascular risk factors (e.g., blood pressure, lipid levels).^10,16

Lack of access to programmes and resources contributes to low referral,¹⁷ under-utilization, lack of adherence, and delayed enrolment in early-phase CR,^10,18 particularly among females.^19,20 The literature surrounding long-term maintenance-phase CR (phase 4) is limited; only one study has explored the association between delayed enrolment and CRF after 18 months of long-term CR.²¹ Of 48 males and 14 females, early enrollers demonstrated greater improvements in CRF compared to late enrollers, although results were not disaggregated by sex.²¹ Given the known sex differences in cardiovascular aging and CVD care,^22,23 there is a need to explore the association disaggregated by sex of delayed enrolment after several years of long-term CR.

The purpose of this study was to determine if associations exist between enrolment delay (defined as the elapsed time from the cardiac event to initiation of maintenance-phase CR) and the CRF (VO₂peak) trajectories over enrolment duration in long-term maintenance-phase CR in both males and females. Based on previous literature,²¹ it was hypothesized that earlier enrolment would be associated with greater improvements in CRF (VO₂peak) over time. The null hypothesis was that earlier enrolment would not be associated with greater improvements in CRF over time.

Methods

This study was a retrospective chart review of data from a cohort of participants in a community-based, maintenance -phase CR programme in Hamilton, Ontario, Canada. Between January and April 2017, we extracted all of the data used for this study from participant charts dated between January 1985 and December 2016.

This study extends our earlier published work²¹ and includes a larger, more recent cohort of individuals with CVD (n = 183). The Hamilton Integrated Research Ethics Board approved the study (2017-1248). The participants in this article are referred to as male and female rather than men and women because this study focuses on the physiological sex differences and mechanisms driving CRF trajectories throughout enrolment in CR.

Participant eligibility

In total, 599 participants who had enrolled in the maintenance-phase CR programme at McMaster Physical Activity Centre of Excellence were considered for this study. To be included in this retrospective mixed-model analysis, participants had to have: (1) been 18 years of age or older; (2) been enrolled in long-term CR for at least 12 months; (3) had documented information to determine time from cardiac event to programme entry; and (4) completed a minimum of at least two cardiopulmonary exercise tests (CPETs) with available VO₂peak data.

Maintenance-phase CR programme

A description of the maintenance-phase CR programme has been published previously.²⁴ The programme was offered to community-dwelling adults ≥18 years old with CVD. A cardiologist or primary health care provider referred the participants to the programme. Prior to enrolment, participants underwent a baseline incremental cardiopulmonary exercise testing (CPET) protocol and initial physical assessment, which included anthro-pometric measurements (e.g., height, weight, BMI), a risk-factor evaluation, and a medication review. A comprehensive, individualized aerobic and resistance exercise training programme was then prescribed based on the assessment results.

The aerobic exercise programme consisted of moderate-intensity exercise at 60–65% of heart rate reserve for 30 minutes, two times per week under staff supervision. For the resistance training programme, participants were encouraged to perform one to three sets of 12 repetitions in all major muscle groups two times per week under staff supervision. Resistance training loads were initially prescribed at 30–40% and 50–60% of 1-repetition maximum for upper and lower extremities, respectively. Participants were also encouraged to exercise independently three times per week; however, this activity was not monitored or recorded throughout the programme. Progressions to the intensity and duration of exercise prescriptions were made, according to published CR guidelines, as participants improved in CRF and strength.³

Education and self-management strategies, including ongoing heart-health education, were provided informally via brochures and knowledge-translation seminars led by the CR programme staff. Participants were required to pay a monthly membership fee for the CR maintenance programme.

Primary outcome

The outcome of interest was CRF, defined as the peak oxygen uptake (VO₂peak, mL/kg/min) achieved during CPET. Each data point for VO₂ peak was considered one observation. CPETs were conducted on approximately an annual basis or as requested by a medical professional; therefore, the time between each CPET was not standardized. CPETs were performed at two sites using standardized testing equipment and protocols. VO₂peak was measured at both sites using indirect calorimetry (VMAX CareFusion; Vyaire Medical, Mettawa, IL) during incremental CPET protocols on a cycle ergometer or treadmill. Prior to each CPET, standard calibration procedures were performed on the metabolic cart according to manufacturer protocols. A cardiovascular technologist conducted the CPETs with physician supervision. Exercise testing protocols included a two-minute warm-up and two-minute cool-down. The cycle CPET followed a ramp protocol, which started at 100 kiloponds per minute and increased by increments of 100 kiloponds per minute every minute. The treadmill CPET workload started at 0% grade and 2.7 kilometers per hour and increased in speed and grade every two minutes. The tests were continued until exhaustion or until the participant could not maintain the appropriate cadence. There were no reported issues or documented protocol deviations during exercise testing.

Data extraction and variables used in mixed model analyses

Demographic information included age (y), height (cm), weight (kg), the date of cardiovascular event or surgical procedure, the date of enrolment, the reason for enrolment, and the dates of the CPETs. CPET data – including VO₂peak (mL/kg/min), resting and peak heart rate (beats/ min), blood pressure (mmHg), and test modality (treadmill or cycle) – were extracted for all available time points. Enrolment duration (y) was calculated as the difference between the dates of the first and last CPETs. Enrolment delay (y) was calculated as the time between the dates of the cardiovascular event or surgical procedure and the first CPET.

Statistical analysis

We performed descriptive statistics to describe demographic information and baseline characteristics as means ± standard deviation or medians (interquartile [IQR] range) for normally and non-normally distributed data, respectively, and frequencies (n, %) for categorical data. Differences in baseline characteristics between males and females were determined using independent t-tests or Wil-coxon rank-sum tests for parametric and non-parametric data, respectively. We used two-proportion Z-tests to identify differences between males and females for discrete variables. According to sex and gender equity in research guidelines,²⁵ baseline characteristics, and mixed model analyses were disaggregated by sex.

Given the study’s uneven cell sizes between males (n = 151) and females (n = 32), we decided a priori to conduct mixed model analyses independently for both males and females to describe sex-specific longitudinal trajectories of CRF (VO2peak, continuous dependent variable) over CR enrolment duration (enrolment duration, continuous independent variable). Enrolment delay (y) was included as a secondary continuous independent variable. Since age²⁶ and initial fitness levels²⁷ are known determinants of CRF, we controlled for baseline age and baseline VO₂peak in our analyses.

To build our models, we first established the relationship between VO₂peak with enrolment duration via lowess curves and mixed model analyses (e.g., testing for polynomial terms). An enrolment delay X enrolment duration interaction was maintained in our models regardless of statistical significance, as previous literature has shown attenuated benefits associated with late enrolment in CR for CRF.^10,21,28

Additional exploratory interaction terms were tested, and non-significant terms were removed from the models to preserve degrees of freedom. We then identified random intercepts and slopes and the most appropriate covariance structure. Residual plots were used to identify any potential highly influencing residuals. Any residual outliers that were in excess of ± 3 and influenced our beta-coefficients of interest by ≥ 10% were deemed influential and subsequently removed from the models.²⁹

Lastly, Bayesian information criteria and log-likelihood ratio tests were used to identify the best-fitting nested and non-nested mixed models. Since enrolment delays in early-phase CR have been reported for up to 150 days (i.e., ~5 mo)^14,15 after the cardiac event and ranging between three and 12 months,³⁰ we modelled the predicted trajectories at six months to represent “early” enrolment and 1.5 years to represent “late” enrolment in long-term CR. We considered an effect to be statistically significant at p < 0.05. All analyses were performed using STATA, version 16.1 (StataCorp LLC, College Station, TX).

Results

We reviewed 599 participant charts and completed data extraction between January and April 2017. In total, 183 participants (n = 151 males, n = 32 females) met the study eligibility criteria. Males ineligible for the study were significantly older (mean ± SD, 66.9 ± 10.4 vs. 63.9 ± 9.4 y, t[443] = 2.94, p = 0.004), had lower VO₂peak (20.1 ± 5.3 vs. 22.9 ± 7.0 mL/kg/min, t[274] = −4.23, p < 0.001), had a greater BMI (29.4 ± 11.4 vs. 27.4 ± 4.0 kg/m², t[225] = 2.18, p = 0.029), and were prescribed more cholesterol medication (86% vs. 75%, Z = 3.23, p = 0.001). Also, they were more likely to have never smoked (17% vs. 32%, Z = −2.20, p = 0.027 but had a greater proportion of individuals with a positive smoking history (83% vs. 68%, Z = 2.22, p = 0.026) compared to the males included in the study. There were no significant differences between baseline demographic variables among females who were included or were ineligible for the study. The study flow chart is presented in Figure 1.

Figure 1.

Flow of Data Extracted and Included in the Analysis.

Table 1 summarizes the baseline characteristics of the entire sample of 183 participants included in the final analysis, disaggregated by sex. Males had greater VO₂peak values at baseline compared to females (22.9 ± 7.0 vs. 16.0 ± 4.1 mL/kg/min, t[74] = 7.50, p < 0.001), which were both lower than sex-based, non-CVD reference values (males 28.4 ± 6.6 mL/kg/min, females 18.5 ± 4.7 mL/kg/ min).²⁶ In total, n = 148/151 males (98%) and all females were tested on a cycle ergometer protocol. On average, participants enrolled in the CR programme 1.7 ± 2.8 years following their cardiovascular event or surgical procedure (males 1.8 ± 3.0 y, females 1.3 ± 1.7 y, t[80] = 1.11, p = 0.27). The time between each CPET was not significantly different between males and females (1.4 ± 0.9 vs. 1.3 ± 0.9 y, t[865] = 0.66, p = 0.51). The time delay for enrolment in the maintenance-phase CR programme was not significantly different between males and females (median [IQR ], 0.75 (8.2) vs. 0.71 (2.1) y, Z = -0.22, p = 0.82). Among the 151 males included in the study, the average enrolment duration was 6.6 years but on closer inspection, there were only 37 participants (25%) with durations exceeding 10 years and fewer observations for VO₂peak (n = 127/864 observations, 15%, 3.4 observations per person) beyond 10 years of enrolment. Similarly, there were only nine of the 32 female participants (28%) with durations exceeding 10 years, and there were fewer observations (n = 31/184 observations, 17%, 3.4 observations per person) beyond 10 years of enrolment. Therefore, to maximize the non-missing observations and improve the generalizability of the mixed models, VO₂peak data were truncated at five years to preserve 70% available data in both the male (n = 524/737 observations, 71%) and female (n = 107/153, 70%) models.

Table 1.

Baseline Characteristics of the 183 Participants Enrolled in the CR Programme

	Total		Males		Females
Variable	n	mean ± SD*	n	mean ± SD*	n	mean ± SD*	p-value
Age, y	183	64.2 ± 9.3	151	63.9 ± 9.4	32	65.3 ± 9.0	0.48
Weight, kg	154	81.7 ± 14.8	128	83.5 ±13.1	26	73.1 ±19.4	0.014
Height, cm	155	172.2 ± 9.1	129	174.7 ± 7.3	26	159.9 ± 6.8	<0.001
BMI,kg/m2	154	27.6 ± 4.8	128	27.4 ± 4.0	26	28.7 ± 7.6	0.40
Smoking history, n (%)	82		69		13
Never smoked, median (IQR)		29 (35.4)		22 (31.9)		7 (53.8)	0.13
Ever smoked, median (IQR)		53 (64.6)		47 (68.1)		6 (46.2)	0.13
Medications, n (%)	179		148		31
Blood pressure		159 (88.8)		129 (87.2)		30 (96.7)	0.12
Cholesterol		135 (75.4)		111 (75.0)		24 (77.4)	0.78
Diabetes		26 (14.5)		22 (14.9)		4 (12.9)	0.77
Reason for enrolment, n (%)	183		151		32
CABG		74 (40.4)		62 (41.1)		12 (37.5)	0.71
Coronary angioplasty		33 (18.0)		30 (19.9)		3(9.4)	0.16
Myocardial infarction		41 (22.4)		33 (21.9)		8 (25.0)	0.70
Other heart surgery		20 (10.9)		14 (9.3)		6 (18.8)	0.12
Other conditions		15 (8.2)		12 (7.9)		3(9.4)	0.78
Enrolment duration, y	183	6.6±5.3	151	6.6±5.3	32	6.5 ± 5.2	0.85
Enrolment delay, y median (IQR)	183	0.75(8.16)	151	0.75 (8.2)	32	0.71 (2.1)	0.82
HRrest, beats/min	151	69.8 ± 12.0	121	69.5 ± 12.1	30	71.2 ± 11.8	0.46
SBPrest, mmHg	177	128.3 ± 19.2	145	127.3 ± 18.5	32	132.9 ± 21.8	0.13
DBPrestmmHg	177	77.1 ± 10.4	145	77.3 ± 10.8	32	76.1 ± 8.2	0.55
HRpeak, beats/min	183	131.1 ± 23.6	151	132.1 ± 23.3	32	126.4 ± 25.0	0.22
SBPpeak, mmHg	134	176.2 ± 30.7	107	177.4 ± 32.5	27	171.5 ± 21.7	0.26
DBPpeakmmHg	133	80.7 ± 14.6	107	79.8 ± 10.7	27	8419 ± 24.6	0.39
VO2peak, mL/kg/min	183	21.8 ± 7.0	151	22.9 ± 7.0	32	16.0 ± 4.1	<0.001

^* Unless otherwise stated.

CABG = coronary artery bypass grafting; HR = heart rate; SBP = systolic blood pressure; DBP = diastolic blood pressure; VO 2 peak = peak oxygen consumption

Table 2 shows the non-linear changes in VO₂peak in males and females over the five-year truncated enrolment duration. In the male model, there was a non-linear trajectory of VO₂peak over time. The random-effects variance components in this model included a random intercept and random slope. Baseline VO₂peak values varied between male participants; therefore, we included a random intercept term (variance estimate [SE] [standard error (SE)], 0.70 [0.60]; 95% confidence interval [CI], 1.30, 2.65). Since the rate of change in VO₂peak varied between participants, we also included a random slope to the model (SE, 1.85 [0.34]; 95% CI 1.30, 2.65). There were no influencing residual observations. An independent covariance structure was identified because there was no correlation between the random intercept and random slope in this model. We found an interaction between baseline age × enrolment duration (β [SE], −0.05 [0.02]; 95% CI -0.09, −0.02, p = 0.004) and baseline VO₂peak × enrolment duration (β [SE], −0.08 [0.02]; 95% CI −0.12, −0.03, p = 0.002), but no significant interaction between enrolment delay × enrolment duration (β [SE], 0.07 [0.05]; 95% CI −0.02, 0.16, p = 0.12).

Table 2.

Mixed Model Analyses on Changes in VO2 Max over Five Years after Controlling for Baseline Age, Baseline VO2 Max, and Enrolment Delay in Males and Females

Males (n = 151, 524 observations)
Fixed effects variables	β (SE)	95% CI	P
Enrolment duration	6.45 (1.51)	3.49, 9.41	< 0.001
Enrolment duration2	−0.32 (0.06)	−0.44, -0.19	< 0.001
Enrolment delay	−0.09 (0.07)	−0.23, 0.04	0.16
Covariate: baseline age	−0.03 (0.02)	−0.08, 0.01	0.15
Covariate: baseline VO2peak	0.93 (0.03)	0.87, 0.99	< 0.001
Enrolment delay × enrolment Duration	0.07 (0.05)	−0.02, 0.16	0.12
Baseline age × enrolment duration	−0.05 (0.02)	−0.09, −0.02	0.004
Baseline VO2peak x enrolment duration	−0.08 (0.02)	−0.12, −0.03	0.002
Constant	3.99 (1.79)	0.49, 7.49	0.026
Random effects	Variance (SE)	95% CI
Slope	1.85 (0.34)	1.30, 2.65
Intercept	0.70 (0.60)	0.13,3.69
Residual	6.70 (0.53)	5.74, 7.82
Model fit statistics	Statistic
Log likelihood	−1371.7
Bayesian information criteria	2818.5
Females (n = 32,107 observations)
Fixed effects variables	β (SE)	95% CI	P
Enrolment duration	0.21 (0.20)	−0.19,0.61	0.30
Enrolment delay	−0.01 (0.30)	−0.59, 0.58	0.98
Covariate: baseline age	−0.05 (0.05)	−0.14, 0.05	0.32
Covariate: baseline VO2peak	0.81 (0.10)	0.60, 1.01	< 0.001
Enrolment delay x enrolment duration	0.07 (0.13)	−0.18,0.33	0.57
Constant	6.60(4.10)	−1.44, 14.63	0.11
Random effects	Variance (SE)	95% CI
Intercept	3.05 (1.11)	1.49, 6.23
Residual	5.08(0.81)	3.72, 6.93
Model fit statistics	Statistic
Log likelihood	−255.8
Bayesian information criteria	549.0

VO₂peak = peak oxygen consumption; p = Beta coefficient; CI = confidence interval; SE = standard error.

In contrast to the trajectories observed for male participants, changes in VO₂peak in the female model were deemed linear. The random-effects variance components in this model included a random intercept for baseline VO₂peak ([SE], 3.05 [1.11]; 95% CI, 1.49, 6.23). The rate of change in VO₂peak did not vary between participants, thus a random slope was not included. There were no influencing residual observations. No interaction was found between enrolment delay x enrolment duration (β [SE], 0.07 [0.13]; 95% CI −0.18, 0.33, p = 0.57).

Figure 2 depicts the predicted changes in VO₂peak over the truncated five years of enrolment duration, considering baseline age, baseline VO₂peak, and enrolment delay in males and females. In the male model “A,” VO₂peak increases non-linearly for the first two years of enrolment for early (i.e., 6 mo) and late (i.e., 1.5 y) enrollers, subsequently followed by a non-linear decline. This model predicts that the greatest improvements in VO₂peak occur between Year 1 and 2 and represent changes of 1.3 and 1.5 mL/kg/min in early and late male enrollers, respectively. In the female model “B,” VO₂ peak increases linearly throughout the entire enrolment duration for early (i.e., 6 mo) and late (i.e., 1.5 y) enrollers, with predicted improvements in VO₂peak of 1.3 and 1.6 mL/kg/min in early and late female enrollers, respectively.

Figure 2.

Mixed model graph of predicted changes in peak oxygen uptake (VO₂ peak, mL/kg/min) in males (n = 151, 524 observations) and females (n = 32, 107 observations) over five years of enrolment controlling for baseline age, baseline VO₂ peak, and enrolment delay among early enrollers (6 mo, closed circles) and late enrollers (1.5 y, open diamonds). The vertical bars indicate standard error.

Discussion

Findings from this study suggest that improvements in CRF from long-term CR are possible for up to two years in males and up to five years in females, regardless of the magnitude of the delay between the cardiac event and the initiation of CR. This contrasts with the large body of literature that shows the importance of early enrolment for cardiovascular function and health following early-phase CR programmes. Indeed, early enrolment in early-phase CR programmes is undeniably critical for promoting optimal recovery, managing a new onset of CVD, and slowing the progression of secondary CVD events. Several reports have demonstrated that early enrolment is associated with increased CR participation and uptake;³⁰ reduced cardiovascular events and mortality;³¹ improved cardiovascular health indices such as body weight, blood pressure, and lipid profiles;²⁸ improved exercise capacity;³² mobility; higher quality of life; and self-reported physical activity participation.¹⁶

One previous study examined the effect of enrolment delay on CRF with long-term (18 mo) CR²¹ and corroborated the findings of early-phase CR studies. However, this study had a smaller sample size (n = 62) and did not disaggregate by sex; also, the pre-post design did not allow for the identification of potentially non-linear changes in CRF over enrolment time. Our study extends these previous findings by including a larger sample size with more CRF observations over a longer period of enrolment duration (n = 183, 631 observations, 5 y). This allowed us to use mixed model analyses to account for random effect estimates and to model linear and non-linear sex-based trajectories over time using enrolment duration and delay as continuous variables. Moreover, we were able to explore additional interactions in the larger sample of males and found that baseline age and baseline VO₂peak were associated with improvements in CRF in long-term CR, rather than enrolment delay.

It has been proposed that there is a window for exercise-induced improvements in cardiac remodelling early after an ischemic event,¹³ as the largest changes in end-systolic volume and left-ventricular ejection fraction have been reported when CR programmes are initiated one week post-event and are at least six months in dura-tion.¹³ Moreover, delaying exercise training by as little as one week after a cardiac event may require an additional month of CR to achieve comparable improvements in cardiac remodelling and CRF.¹³ However, the lack of associations between enrolment delay and CRF observed in this study contrast the literature supporting the early window for cardiac remodelling. There may be additional physiological factors in addition to cardiac remodelling driving the changes in VO₂ peak following longer-term CR, such as improvements in skeletal muscle strength²⁴ and improved skeletal muscle peripheral oxygen extraction (i.e., arterial-venous oxygen difference).³³ Specifically, Ades and colleagues found that gains in VO₂ peak following 12 months of CR were driven by peripheral skeletal muscle adaptations, such as improved arterial-venous oxygen difference and skeletal muscle fibre area, independent of central changes in cardiac function (e.g., cardiac output) among individuals with coronary artery disease.³³ Thus, our findings support the promotion of long-term aerobic and resistance exercise among individuals with CVD regardless of possible delays in enrolment. Predicted trajectories of both early and late enrolment in males and females suggest clinically significant improvements in VO₂ peak, as changes as low as 1 mL/kg/min in males³⁴ and females³⁵ are associated with a 10% reduction in cardiovascular mortality.

A novel aspect of this study is that we disaggregated our results by sex, providing insight and potential implications²³ into sex-specific trajectories in VO₂peak during long-term CR. It was not surprising, and was consistent with previous research,³⁶ that females had lower VO₂peak compared to males at all time points. There are well-documented physiological differences that underlie this finding, such as reduced stroke volume and cardiac output observed among females when compared to males.³⁷ Interestingly, we also found that females have linear improvements of CRF for up to five years, while males in our cohort began to experience declines in CRF after two years. These sex differences may be attributed to various age-associated changes in cardiovascular structure and function, and the decline in sex hormone production in males and females.²²

In males, testosterone production declines with age and is associated with a progressive loss of muscle mass and strength.³⁸ Males typically have greater declines in CRF,^39,40 endothelial dysfunction, and arterial stiffening with aging; compared to females, they experience CVD earlier in adulthood and middle age.^22,41 Therefore, these age-associated cardiovascular changes and accumulation of CVD risk factors among males earlier in the life course may play a role in the observed attenuated cardiovascular adaptations and CRF during long-term CR. Nonetheless, the rates of non-linear decline in our sample of males are comparable to reported rates of age-related decline of VO₂peak in healthy older males²⁶ and males with congenital heart disease.⁴² In contrast, females experience a withdrawal of endogenous estrogen during menopause that may augment the changes in cardiovascular aging seen in postmenopausal females.²² However, there are many potential reasons why we observed linear improvements in CRF over time in females. Specifically, post-menopausal females with CVD appear to achieve similar improvements in exercise capacity with males.⁴³ Compared to males, females may experience greater changes in vascular function after exercise⁴⁴ and participate in greater physical activity after early-phase CR.⁴⁵ Further, as a result of the protective effects of estrogen on the cardiovascular system,⁴⁶ females may experience more preservation and less age-related decline in cardiac output, VO2 max, and arterial-venous oxygen difference.⁴⁰ Females may also encounter a later onset of endothelial dysfunction and arterial stiffening throughout aging in comparison to males.^22,47 Taken together, the longitudinal linear improvements in CRF over five years observed in our sample is highly novel and clinically relevant given the paucity of research on females in CR.

Our findings need to be interpreted with caution. Our sample size did not have the statistical power to explore additional interactions, such as baseline age or baseline VO₂peak with enrolment time on the CRF trajectory in females. We also did not have data regarding socio-economic status or educational level, important gender-related factors that are known facilitators to enrolment in and adherence to CR.^18,48 It is possible that our sample may have been biased toward females with greater baseline fitness at programme entry, which may have encouraged adherence to and enrolment in long-term CR. Indeed, we found that females tended to enrol slightly earlier (1.3 ± 1.7 y) than males (1.8 ± 3.0 y). This finding suggests a potential positive trend of increased enrolment and utilization of CR in females. Future prospective research with larger sample sizes is required to confirm our results and explore the sex- and gender-related factors associated with enrolment and improvements among females in long-term CR.

We also acknowledge the limitations of the retrospective design and potential sources of bias (e.g., selection and survival bias) of this study. We found that males who were ineligible were older, had lower VO₂peak, higher BMI, were prescribed more cholesterol medications, and were more likely to have a previous smoking history compared to the males who were included, thus limiting the generalizability and interpretability of our findings. We also did not have information regarding disease severity or mortality throughout the programme, potential comorbidities of relevance (e.g., diabetes, depression, cognitive impairment), menopausal status, individual-specific measures of acute length of stay in acute cardiac care, or complications during care. Nor did we have data on programme adherence and attendance, or physical activity levels outside of the programme. In addition, we did not have documented information regarding earlier courses in cardiac care (e.g., phase 1–3 short-term CR) or reasons for delayed enrolment in the maintenance-phase CR programme, which could have helped explain why some participants had extensive delays. We also did not have access to other CPET variables, such as the respiratory exchange ratio, which is a valuable indicator of relative effort during exercise. As well, we did not have the statistical power to include additional variables (e.g., BMI, cardiovascular comorbidities, medications) in our models; therefore, we were not able to control or account for these potential variables or time-varying covariates in our sex-specific mixed-model analyses. Nonetheless, we accounted for baseline age and baseline VO₂peak as they are the strongest predictors of changes in CRF after CR.^26,27

Conclusion

This is the first study to report improvements in CRF over time in long-term CR, for individuals with early and late enrolment. Our findings suggest that benefits in CRF are still possible with long-term CR in both males and females regardless of delays in CR enrolment. Nonetheless, early enrolment in all phases of CR is recommended and should still be highly encouraged. Future prospective research is required to confirm our findings and explore the effects of late enrolment in long-term CR on additional clinical outcomes.

Key Messages

What is already known on this topic

The timely access to and enrolment in early-phase cardiac rehabilitation programmes are important for the clinical management of cardiovascular disease in both males and females. However, less is known on the associations between enrolment delay and changes in cardiorespiratory fitness (VO₂peak) over five years of maintenance-phase cardiac rehabilitation in males and females

What this study adds

Despite delays in enrollment, we found clinically significant and non-linear improvements in VO₂peak up to 2 years in cardiac rehabilitation among males (range: 1.3 to 1.5 mL/kg/min) and 5-year linear improvements in VO₂peak in females (range 1.3 to 1.6 mL/kg/min). Our findings suggest that benefits in cardiac rehabilitation are still conferred despite delayed enrolment.