Cardiovascular Aging and Exercise: Implications for Heart Failure Prevention and Management

Measuring biological age is critical to studying the link between accelerated aging and CVD at a population level. Numerous biological age estimation models incorporating biomarkers, epigenetics, anthropometric, and physiological inputs to measure biological age have been developed and validated. The Phenotypic Age Acceleration model is one such model that utilizes chronologic age and a combination of blood-based chemistry and hematology parameters to estimate biological age.²¹ A similar score can also be created using the Klemera-Doubal method, which uses all available biomarkers to estimate biological age using mathematical optimization.²² A higher phenotypic age acceleration is associated with multimorbidity and increased mortality risk, and partially mediates the association between unhealthy lifestyles and incident CVD and mortality.^21,23 Multiple studies have also demonstrated an association between biological age and abnormal cardiovascular structure and function, including vascular stiffness, adverse cardiac remodeling (lower left ventricular [LV] mass and stroke volume), and increased risk of heart failure (HF).^24–26
测量生物学年龄对于在人群水平上研究加速衰老与心血管疾病之间的联系至关重要。已经开发并验证了许多生物学年龄评估模型，这些模型结合了生物标志物、表观遗传学、人体测量学和生理学输入来测量生物学年龄。“表型年龄加速”模型就是其中一种，它利用实际年龄以及基于血液的化学和血液学参数的组合来估计生物学年龄。 ²¹ 也可以使用 Klemera-Doubal 方法创建类似的分数，该方法使用所有可用的生物标志物，通过数学优化来估计生物学年龄。 ²² 表型年龄加速升高与多病共存和死亡风险增加相关，并部分介导不健康的生活方式与新发 CVD 和死亡率之间的关联。 多项研究还表明，生物学年龄与异常心血管结构和功能之间存在关联，包括血管僵硬、不良心脏重塑（左心室[LV]质量和卒中容量降低）以及心力衰竭（HF）风险增加。

Biological aging scores have also been developed to assess epigenetic age using specific DNA methylation patterns. For instance, the GrimAge acceleration model estimates epigenetic age by using 1030 CpG islands, blood-based biomarkers, and clinical risk factors. In the CARDIA (Coronary Artery Disease in Young Adults) cohort, an increase in GrimAge acceleration was associated with an increased risk for incident diabetes²⁷ and risk of CVD and mortality.²⁸ Similarly, in the Atherosclerosis Risk in Communities study, the Horvath and Hannum models (epigenetic scores using DNA methylation patterns) were associated with a higher risk of subclinical atherosclerosis and incident CVD independent of traditional cardiovascular risk factors.²⁹ Similar findings have been noted using other biological age estimation models across different community-dwelling cohorts.^28,30,31 Together, these observations support the notion of accelerated aging being a key driver of abnormalities in cardiovascular structure and function, and increased risk of CVD and may be a target for therapeutic interventions.
人们还开发了生物衰老评分，旨在使用特定的 DNA 甲基化模式来评估表观遗传年龄。例如，GrimAge 加速模型通过使用 1030 个 CpG 岛、基于血液的生物标志物和临床危险因素来估计表观遗传年龄。在 CARDIA（年轻人冠状动脉疾病）队列中，GrimAge 加速的增加与新发糖尿病 ²⁷ 以及 CVD 和死亡风险的增加相关。 ²⁸ 同样，在社区动脉粥样硬化风险研究中，Horvath 和 Hannum 模型（使用 DNA 甲基化模式的表观遗传评分）与亚临床动脉粥样硬化和独立于传统心血管危险因素的心血管疾病事件的较高风险相关。 ²⁹ 在不同的社区居住人群队列中使用其他生物年龄估计模型也发现了类似的结果。 ^28,30,31 总之，这些观察结果支持了加速衰老是心血管结构和功能异常以及心血管疾病风险增加的关键驱动因素的观点，并可能成为治疗干预的靶点。

Accelerated biological aging translates to the accumulation of subclinical disease and deficits across nearly all organ systems. This results in a diminished reserve capacity and increased disease severity that manifests clinically as the frailty syndrome.³² The frailty syndrome is characterized by the loss of reserve across multiple physiological systems, impairing the homeostatic capacity to tolerate external stressors.³² Frailty develops through dysregulation of immune, hormonal, and endocrine systems with upregulation of inflammatory cytokines, which contribute to inflammaging³³ and predispose to a catabolic state resulting in sarcopenia. Clinically, these changes appear as impaired functional status and loss of physiological reserve.^14,34,35 Genome-wide association studies have implicated multiple genes that are associated with both accelerated aging and CVD in frailty.³⁶ The prevalence of frailty among community-dwelling adults without CVD is ≈15%.³⁷ However, the prevalence of frailty is much higher in older adults with prevalent CVD (reported up to 75%) and differs substantially across CVD subtypes.³⁸
加速的生物衰老转化为亚临床疾病的积累，以及几乎所有器官系统的功能缺陷。这导致储备能力下降和疾病严重程度增加，并在临床上表现为虚弱综合征。 ³² 虚弱综合征的特征是多个生理系统的储备丧失，从而损害了耐受外部压力的稳态能力。 ³² 虚弱的发生是由于免疫、激素和内分泌系统失调，以及炎症细胞因子上调，这会导致炎症衰老 ³³ 并易于发生分解代谢状态，从而导致肌少症。临床上，这些变化表现为功能状态受损和生理储备丧失。 ^14,34,35 全基因组关联研究表明，有多个基因与虚弱相关的加速衰老和心血管疾病有关。 ³⁶ 在没有 CVD 的社区居住成年人中，虚弱的患病率约为 15%。 ³⁷ 然而，在患有 CVD 的老年人中，虚弱的患病率要高得多（据报道高达 75%），并且在不同的 CVD 亚型中差异很大。 ³⁸

Among age-related CVD, a higher frailty burden has been associated with a greater risk of valvular heart disease, such as aortic stenosis, atrial fibrillation, and HF, particularly HFpEF.^39–43 Higher frailty burden is also associated with greater abnormalities in cardiac structure and function among older adults without CVD.^43–46 HFpEF is particularly intertwined with frailty and represents a downstream clinical manifestation of accelerated biological aging and the associated decline in physiological reserve.⁴ HFpEF occurs almost exclusively in older adults, is preceded by an accelerated decline in cardiorespiratory fitness and functional status, and is characterized by severe exercise intolerance.⁴⁷ Patients with HFpEF also have multiple comorbidities, which contribute to the development of frailty and sarcopenia that potentiates disease severity.⁴ Indeed, HFpEF is increasingly recognized as a true geriatric syndrome, with accelerated aging, sarcopenia, and frailty as key pathophysiologic determinants (Figure 1).⁹
在与年龄相关的 CVD 中，较高的衰弱负担与更高的瓣膜性心脏病风险相关，例如主动脉瓣狭窄、房颤和 HF，尤其是 HFpEF。 ^39–43 较高的衰弱负担也与无 CVD 的老年人的心脏结构和功能异常程度增加有关。 ^43–46 射血分数保留型心力衰竭（HFpEF）与体弱尤其密切相关，代表着加速生物衰老以及相关的生理储备下降的下游临床表现。 ⁴ 射血分数保留型心力衰竭几乎只发生在老年人身上，其发生之前存在心肺适能和功能状态的加速下降，并以严重的运动不耐受为特征。 ⁴⁷ 射血分数保留型心力衰竭（HFpEF）患者也常伴有多种合并症，这些合并症会导致虚弱和肌少症，从而加剧疾病的严重程度。 ⁴ 事实上，HFpEF 越来越被认为是一种真正的老年综合征，其关键病理生理决定因素是加速衰老、肌少症和虚弱（图 1）。 ⁹

Age-related increase in left atrial (LA) size has been shown in multiple studies.^67–70 However, the dilation of the LA in the absence of a pathological process occurs only after the seventh decade of life.⁷¹ The mechanisms of age-related dilation of the LA are not entirely understood but may be in response to chronically elevated LV end-diastolic pressures.⁷² Aging results in electromechanical changes in the LA, with a decline in LA compliance and function.^73–77 LA size is also a significant risk factor for multiple age-related CVDs, such as atrial fibrillation and stroke.^78,79 LA strain imaging by echocardiography offers a sensitive assessment of LA function. The reservoir and contraction strain remain unchanged with age, but the conduit function deteriorates, suggesting reduced compliance.⁷⁶
多项研究表明，左心房 (LA) 大小随年龄增长而增加。 ^67–70 然而，在没有病理过程的情况下，LA 的扩张仅在七十岁之后发生。 ⁷¹ 与年龄相关的 LA 扩张的机制尚未完全清楚，但可能是对慢性升高的左心室舒张末期压力的反应。 ⁷² 衰老会导致 LA 发生机电变化，LA 顺应性和功能下降。 ^73–77 左心房大小也是多种年龄相关性心血管疾病（如心房颤动和卒中）的重要危险因素。 ^78,79 通过超声心动图进行左心房应变成像可以灵敏地评估左心房功能。储器和收缩应变随年龄增长保持不变，但导管功能会恶化，表明顺应性降低。 ⁷⁶

In the absence of coronary artery disease and hypertension, normal aging does not increase LV mass. Studies of carefully selected normotensive healthy adults using echocardiography and magnetic resonance imaging–based assessment of LV mass have consistently found no increase in LV mass with aging.^80–82 In a cross-sectional study of 336 healthy, normotensive adults across a wide age range, Hees et al⁸⁰ demonstrated distinct sex associations between age and LV morphology. Specifically, among women, they observed an increase in LV wall thickness and a concurrent decrease in LV length with aging such that the mean LV mass remained constant. In contrast, men had a modest decline in LV mass related to decreased LV length without a change in LV wall thickness. In contrast, in an autopsy study of 765 normal hearts from people aged 20 to 99 years, Kitzman et al⁸³ observed an increase in heart weight indexed to body size with aging in women but not men. Specifically, myocardial thickness increases predominantly in the interventricular septum with relatively little LV and right ventricular free wall thickness change. The differences in the methodology of cardiac mass measurements (assessment of LV mass by cardiac magnetic resonance imaging versus crude heart weight using autopsy hearts) may account for the differences noted between these studies. Regarding LV cavity size, evidence from cross-sectional and longitudinal epidemiological cohorts has shown that the LV internal diameter at systole and diastole reduces with normal age, resulting in a smaller LV cavity size.^84,85 In addition, there is a decline in LV length, which results in increased sphericity of the heart.^71,80 Age-related reduction in LV cavity size and increased wall thickness is reflected in a higher mass/volume ratio (relative wall thickness), corresponding to concentric LV remodeling with normal aging noted in multiple studies.^86–89 Accelerated biological aging results in pathological LV hypertrophy characterized by concentric hypertrophy with cardiomyocyte thickening and fibrosis, which results in a marked reduction in the LV cavity size disproportionate to age.⁹⁰ This is often related to long-term exposure to cardiovascular risk factors such as hypertension and obesity, which accelerates biological aging. In contrast, physical activity and endurance training-related activities, which are lifestyle traits associated with healthy aging, lead to physiological LV hypertrophy with increased LV size and LV mass but not relative wall thickness.⁹¹
在没有冠状动脉疾病和高血压的情况下，正常衰老不会增加左心室质量。对精心挑选的血压正常健康成人进行的研究，使用基于超声心动图和磁共振成像的左心室质量评估，一直发现左心室质量不随年龄增长而增加。 ^80–82 在一项针对 336 名健康、血压正常成人的横断面研究中，Hees 等人 ⁸⁰ 证明了年龄与左心室形态之间存在明显的性别关联。 具体而言，在女性中，他们观察到随着年龄的增长，LV 壁厚增加，同时 LV 长度减少，因此平均 LV 质量保持不变。相比之下，男性 LV 质量略有下降，这与 LV 长度的减少有关，而 LV 壁厚度没有变化。相比之下，在 Kitzman 等人 ⁸³ 对 765 颗年龄在 20 至 99 岁之间的正常心脏进行的尸检研究中，观察到女性的心脏重量指数随年龄增长而增加，而男性则没有。 具体而言，心肌厚度增加主要发生在室间隔，而左心室和右心室游离壁厚度的变化相对较小。心脏质量测量方法（通过心脏磁共振成像评估左心室质量与使用尸检心脏的粗略心脏重量）的差异可能是导致这些研究之间差异的原因。 关于左心室腔大小，横断面和纵向流行病学队列研究的证据表明，随着正常衰老，左心室收缩末期和舒张末期内径减小，导致左心室腔变小。 ^84,85 此外，左心室长度也会下降，从而导致心脏球形度增加。 ^71,80 与年龄相关的左心室腔大小缩小和壁厚增加反映在较高的质量/体积比（相对壁厚）中，这与多项研究中发现的正常衰老时发生的心室向心性重塑相对应。 ^86–89 加速的生物衰老会导致病理性左心室肥厚，其特征为向心性肥厚伴心肌细胞增厚和纤维化，导致左心室腔大小显著缩小，与年龄不成比例。 ⁹⁰ 这通常与长期暴露于高血压和肥胖等心血管风险因素有关，这些因素会加速生物衰老。相反，体力活动和耐力训练相关的活动是与健康衰老相关的生活方式特征，可导致生理性左心室肥厚，左心室大小和左心室质量增加，但相对壁厚度没有增加。 ⁹¹

Age-related changes are also notable in the cardiac valves. Particularly, the aortic and mitral leaflet thickness is noted to increase along the closure margins with aging.⁹² In the cardiovascular health study, aortic valve sclerosis was present in 26% of participants. Valvular calcification is often regarded as a finding associated with accelerated aging and predisposes to an increased risk of valvular stenosis. In the cardiovascular health study, 2% of the cohort had hemodynamically significant aortic stenosis.⁹³ Mitral annular calcification is also common among older adults and was noted in 10.3% of men and 15.8% of women participants of the Framingham Heart Study.⁹⁴ While the prevalence of valvular calcification increases with age, the rate of calcification is influenced by genetic, environmental, and immune factors.⁹⁵ Calcification of the aortic and mitral valves is initially triggered by inflammation, which results in maladaptive ultrastructural changes that result in valvular thickening and apoptosis of valvular interstitial cells and upregulation of disease-related markers such as alkaline phosphatase and osteocalcin.^96,97 As such, valvular calcification can occur at an accelerated pace and result in calcific aortic valve disease the most common valvular disease in older adults.⁹⁸ Furthermore, the presence of mitral annular calcification is associated with a significantly higher risk for adverse cardiovascular outcomes.⁹⁴
与年龄相关的心脏瓣膜变化也值得关注。特别是，主动脉和二尖瓣叶的厚度随着年龄的增长，在闭合边缘处会明显增加。 ⁹² 在一项心血管健康研究中，26%的参与者存在主动脉瓣硬化。瓣膜钙化通常被认为是与加速衰老相关的发现，并增加了瓣膜狭窄的风险。 在心血管健康研究中，2%的队列有血流动力学意义上的主动脉瓣狭窄。 ⁹³ 二尖瓣环钙化在老年人中也很常见，在 Framingham 心脏研究的参与者中，男性占 10.3%，女性占 15.8%。 ⁹⁴ 虽然瓣膜钙化的患病率随着年龄的增长而增加，但钙化的速度受遗传、环境和免疫因素的影响。 ⁹⁵ 主动脉和二尖瓣的钙化最初由炎症引发，导致适应不良的超微结构变化，从而导致瓣膜增厚以及瓣膜间质细胞凋亡，并上调疾病相关标志物，如碱性磷酸酶和骨钙素。 ^96,97 因此，瓣膜钙化可能以更快的速度发生，并导致钙化性主动脉瓣疾病，这是老年人最常见的瓣膜疾病。 ⁹⁸ 此外，二尖瓣环钙化的存在与不良心血管事件风险显著升高相关。 ⁹⁴

Functional changes accompany changes in cardiac structure with aging. A reduction in LV stroke volume with age is noted as the LV cavity size reduces, and the wall thickness increases. In a study of carefully selected volunteers free of CVD, the LV stroke volume index was reduced significantly with normal aging.⁹⁹ Similarly, the Multiethnic Study of Atherosclerosis and the Framingham Heart Study have demonstrated a cross-sectional association between older age and lower LV stroke volume.^84,100 Similarly, LV contractility may also decline with aging. In a study of volunteers free of CVD, LV end-systolic volume, a measure of LV contractility, declined with normal aging.⁹⁹ Global longitudinal strain is a sensitive marker of myocardial contractility and is also noted to be lower, reflecting diminished contractility of the LV, with age, which is more evident in men than in women.^101–105 The extent to which decline in LV contractility is related to healthy aging versus a consequence of underlying subclinical disease has been a matter of debate. In one study of carefully selected volunteers, LV strain was not associated with age alone but also with levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide), implicating neurohormonal stress and subclinical CVD.¹⁰⁵ However, increases in NT-ProBNP levels may also be related to the aging process with worsening diastolic function as discussed below. Together, aging results in a decline in stroke volume and reduced contractility but results in normal resting cardiac function, and these changes in LV systolic function are more pronounced and occur earlier with accelerated aging and the presence of underlying subclinical CVD. It is noteworthy that in contrast with SV and contractility measures, LV ejection fraction increases slightly with age and is higher among women than men.^101–104 This may be related more to decreases in LV end-diastolic volume than increases in LV stroke volume.
随着年龄增长，心脏结构的变化伴随着功能上的改变。随着左心室腔变小，壁厚增加，左心室射血量随年龄增长而降低。在一项针对精心挑选的、无心血管疾病志愿者的研究中，左心室射血量指数随着正常衰老而显著降低。 ⁹⁹ 同样，多种族动脉粥样硬化研究和弗雷明汉心脏研究也证实了老年与较低的左心室射血量之间的横断面关联。 ^84,100 同样，左心室收缩力也可能随着年龄的增长而下降。在一项针对无心血管疾病 (CVD) 志愿者的研究中，左心室收缩末期容积（一种衡量左心室收缩力的指标）随着正常衰老而下降。 ⁹⁹ 全局纵向应变是心肌收缩力的一个敏感标志物，并且也观察到其随着年龄的增长而降低，反映出左心室收缩力减弱，这在男性中比在女性中更为明显。 ^101–105 左室收缩功能的下降在多大程度上与健康衰老有关，以及在多大程度上是潜在亚临床疾病的后果，一直是争论的问题。在一项精心挑选的志愿者研究中，左室应变与年龄本身无关，而且还与 NT-proBNP（N-末端 B 型脑钠肽前体）水平有关，表明存在神经激素应激和亚临床 CVD。 ¹⁰⁵ 然而，如下文所述，NT-ProBNP 水平的升高也可能与伴随舒张功能恶化的衰老过程有关。总而言之，衰老会导致每搏输出量下降和收缩力降低，但会导致正常的静息心脏功能，并且这些左室收缩功能的变化在加速衰老和存在潜在的亚临床心血管疾病的情况下更为明显且发生更早。 值得注意的是，与 SV 和收缩力指标相比，LV 射血分数随年龄略有增加，并且女性高于男性。 ^101–104 这可能更多与 LV 舒张末期容积的减少有关，而不是 LV 搏出量的增加。

Alteration in diastolic function with age has been consistently reported across various studies.^106–109 Impairment in diastolic filling with a decline in early LA emptying, prolonged late diastolic filling, and longer isovolumic relaxation time are characteristic findings in older adults without overt cardiovascular pathology.^107,109 Concurrently, the peak A-wave velocity, representing atrial contraction and late LV filling, increases. The early diastolic peak-filling rate declines by 30% to 50% between the second and eighth decades of life.¹¹⁰ Tissue Doppler imaging–based relaxation velocities measured at the mitral annulus are frequently used to characterize diastolic function and cardiac filling pressures in contemporary clinical practice.¹¹¹ In the Atherosclerosis Risk in Communities study, older adults without evidence of CVD had lower values for Doppler relaxation velocities without increased risk of adverse cardiovascular events, suggesting that the impairment in relaxation is part of the normal aging process.¹⁰⁷ This finding has been recapitulated in multiple cohorts of individuals free of CVD.^110,112,113 An analysis from the Baltimore Longitudinal Study of Aging that included participants without CVD who underwent cardiac magnetic resonance imaging demonstrated that the age-related impairment in LV diastolic filling may be driven by changes in left atrial characteristics. Specifically, the investigators found that the association between age and relaxation velocities was entirely attenuated after adjustment for LA pressure.¹¹⁰ This observation suggests that changes in diastolic function with age may be related to changes in LA compliance and contractile properties. Moreover, in a study of volunteers without CVD who underwent hemodynamic assessment, age was associated with slightly higher resting pulmonary capillary wedge pressure (r=0.17; P<0.05).⁹⁹ In patients with accelerated biological aging, diastolic dysfunction develops at an earlier age and is associated with reduced exercise capacity and future risk of HF.¹¹⁴
在多项研究中，年龄相关的舒张功能改变一直有报道。 ^106–109 舒张充盈受损，伴随早期左心房排空减少、晚期舒张充盈延长和等容舒张时间延长，是无明显心血管病理的老年人的特征性表现。 ^107,109 同时，代表心房收缩和晚期左心室充盈的 A 波峰值速度增加。 在 20 岁到 80 岁之间，早期舒张期峰值充盈率下降 30% 到 50%。 ¹¹⁰ 基于组织多普勒成像的、在二尖瓣环处测量的舒张期松弛速度，常用于描述当代临床实践中的舒张功能和心脏充盈压。 ¹¹¹ 在动脉粥样硬化社区风险研究中，无心血管疾病证据的老年人多普勒舒张速度值较低，但不良心血管事件风险并未增加，提示舒张功能受损是正常衰老过程的一部分。 ¹⁰⁷ 这一发现在多个无心血管疾病的个体队列中得到了重复证实。 ^110,112,113 来自巴尔的摩衰老纵向研究的一项分析，纳入了未患有 CVD 且接受过心脏磁共振成像的参与者，结果表明，与年龄相关的 LV 舒张充盈受损可能由左心房特征的变化驱动。具体而言，研究人员发现，在调整 LA 压力后，年龄与松弛速度之间的关联完全减弱。 ¹¹⁰ 这一观察结果表明，随着年龄增长，舒张功能的变化可能与左心房顺应性和收缩特性的变化有关。 此外，在一项对未患 CVD 并接受血流动力学评估的志愿者进行的研究中，年龄与略高的静息肺毛细血管楔压相关（r=0.17；P<0.05）。 ⁹⁹ 在生物衰老加速的患者中，舒张功能障碍发生年龄较早，并与运动能力下降和未来发生 HF 的风险相关。 ¹¹⁴

Aging results in structural and functional changes to the large- and medium-sized arteries, even without atherosclerotic disease.¹¹⁵ The walls of arteries thicken due to hypertrophy of smooth muscle cells and expansion of the extracellular matrix with collagen content, which can irreversibly cross-link with advanced glycation end products.^116,117 In addition, calcium deposition occurs in the arteries, and Mönckeberg arteriosclerosis develops.^118,119 Together, these changes result in loss of elasticity and increased stiffness of the arterial structures.¹²⁰ The capacity for endothelium-dependent vasodilation through nitric oxide signaling diminishes at the endothelium level.^121–123 Concomitantly, the angiotensin-II production in the arterial wall increases, resulting in constrictive remodeling.^117,124 Aging results in an increase in reactive oxidative species and low-grade chronic inflammation that worsens endothelial and microvascular dysfunction.¹²⁵ Clinically, these changes manifest as mild increases in systolic blood pressure and a decline in diastolic blood pressure due to loss of elasticity and increased vascular stiffness. With age, the coronary arteries become dilated and have increased tortuosity, likely due to increased shear forces.¹²⁶ In addition, the number of collateral vessels increases in response to the development of atherosclerosis. The development of lipid-rich plaques characteristic of atherosclerosis is not part of normal aging and is a result of accelerated biological aging.
即使没有动脉粥样硬化性疾病，衰老也会导致大中动脉的结构和功能发生变化。 ¹¹⁵ 由于平滑肌细胞肥大和细胞外基质随胶原含量扩张，动脉壁增厚，这可能会与晚期糖基化终产物发生不可逆的交联。 ^116,117 此外，钙沉积发生在动脉中，并发生门克贝格动脉硬化。 ^118,119 共同作用下，这些改变导致动脉结构失去弹性并增加硬度。 ¹²⁰ 内皮依赖性血管舒张通过一氧化氮信号传导的能力在内皮水平下降。 ^121–123 同时，动脉壁中血管紧张素 II 的产生增加，导致血管收缩性重塑。 ^117,124 衰老导致活性氧增加和低度慢性炎症，从而加剧内皮和微血管功能障碍。 ¹²⁵ 临床上，这些变化表现为收缩压轻度升高和舒张压下降，这是由于弹性丧失和血管僵硬度增加所致。随着年龄的增长，冠状动脉扩张并增加弯曲度，这可能是由于剪切力增加所致。 ¹²⁶ 此外，侧支血管的数量会随着动脉粥样硬化的发展而增加。富含脂质的斑块是动脉粥样硬化的特征，它的发展并非正常衰老的一部分，而是生物衰老加速的结果。

The influence of lifestyle and environment on aging-related vascular changes is evident from recent studies of individuals from the indigenous Tsimane population in the Bolivian Amazon, who live a preindustrial lifestyle of hunting, gathering, fishing, and farming along the Maniqui River. In a seminal study of Tsimane individuals who underwent coronary artery calcium screening, investigators found a low prevalence of atherosclerosis, with 65% of octogenarians being free of coronary atherosclerosis.¹²⁷ Similarly, the Yanomami and Ye’kwana peoples from a remote area of the Venezuelan rainforest have low blood pressure. The Yanomami, free entirely of Western influence, did not have an increase in blood pressure with age. In contrast, the Ye’kwena people are exposed to a Western lifestyle, including intermittent exposure to processed foods and salt, and were noted to have an age-related increase in blood pressure in early childhood (age, 1–20 years).¹²⁸ These findings suggest that age-related changes to the vasculature, which are near universal in the industrialized world, are strongly influenced by lifestyle, diet, behaviors, and the environment and are related to accelerated aging.
生活方式和环境对衰老相关血管变化的影响，在近期对玻利维亚亚马逊地区奇曼人（Tsimane）的研究中可见一斑。奇曼人沿马尼基河（Maniqui River）生活，以狩猎、采集、捕鱼和农耕为生的前工业时代生活方式。 在一项对奇马内人（Tsimane）进行冠状动脉钙化筛查的开创性研究中，研究人员发现动脉粥样硬化的患病率很低，65%的八旬老人没有冠状动脉粥样硬化。 ¹²⁷ 同样，来自委内瑞拉热带雨林偏远地区的亚诺玛米人和耶瓜纳人（Yanomami and Ye’kwana）的血压也很低。完全没有西方影响的亚诺玛米人，其血压没有随年龄增长而升高。 相比之下，耶库安纳人接触到西方生活方式，包括偶尔接触加工食品和盐，并注意到他们在儿童早期（1-20 岁）的血压出现与年龄相关的升高。[1] 这些发现表明，血管系统与年龄相关的变化在工业化世界几乎是普遍存在的，它受到生活方式、饮食、行为和环境的强烈影响，并且与加速衰老有关。

Aerobic exercise capacity, the gold-standard measure of cardiovascular performance and reserve, is objectively measured by peak exercise oxygen consumption (VO_2peak). Aerobic capacity declines with age.^129–131 Studies in healthy volunteers have demonstrated that VO_2peak declines by 3% to 8% per decade of life between the ages of 20 and 70 years. However, the rate of decline may vary considerably based on physical activity levels, exercise training, and comorbidities.¹³² The decline in aerobic capacity accelerates considerably (>20% per 10 years) after the seventh decade of life.¹³³ VO_2peak is governed by the Fick principle and is defined as the product of peak exercise cardiac output and peak exercise peripheral arteriovenous oxygen difference (A-VO_2diff; Figure 3). Changes in either the cardiac or peripheral reserve or both may account for the decline in VO_2peak with aging, as discussed in more detail in the following sections.
有氧运动能力是心血管功能和储备的金标准测量方法，可通过峰值运动耗氧量（VO _2peak ）进行客观测量。有氧运动能力随年龄增长而下降。 ^129–131 对健康志愿者的研究表明，在 20 至 70 岁之间，VO _2peak 每十年下降 3% 至 8%。然而，下降速度可能因体力活动水平、运动训练和合并症而异。 ¹³² 在七十岁之后，有氧能力下降明显加速（>10 年内下降 20%）。 ¹³³ VO _2peak 受 Fick 原理支配，定义为峰值运动心输出量和峰值运动外周动静脉氧含量差（A-VO _2diff ）的乘积（图 3）。心脏或外周储备或两者兼有的变化可能导致 VO _2peak 随年龄增长而下降，这将在以下章节中更详细地讨论。

Underlying structural changes in the myocardium and vasculature result in alterations in the pressure-volume relationships, reducing stroke volume through the Frank-Starling mechanism. The inability to augment stroke volume in response to stress/exercise is characteristic of the aging process. In a cross-sectional study of volunteers free of CVD who underwent resting and exercise hemodynamic assessments, Pandey et al⁹⁹ demonstrated that age was associated with a decline in VO_2peak (40% decline over 5.5 decades) that was primarily driven by reductions in exercise cardiac output due to concurrent reductions in peak exercise stroke volume and heart rate. Aging is associated with a decline in peak heart rate, reduced heart rate responsiveness to autonomic nervous system input, and a decrease in heart rate variability.^134–136 The age-related decline in exercise stroke volume is likely driven by a reduced inotropic reserve (reduced contractility with lower ejection fraction and lower end-systolic volume).⁹⁹ Notably, the decline in peak exercise stroke volume is more prominent in older age (>60 years) than in middle age.^99,137,138 In the seminal Dallas Bed Rest Study, no decline in stroke volume at peak exercise was noted on the 30-year follow-up visit (from ages of 20 to 50 years) but a prominent decline was observed at the subsequent 40-year follow-up (by the age of 60 years).^138,139 This is particularly relevant considering the accelerated rate of decline in VO_2peak that occurs after the sixth decade of life.¹³³ Together, a decline in stroke volume reserve may have an important role in the age-related decline in VO_2peak, particularly in the later decades of life.
心肌和血管的潜在结构性改变导致压力-容量关系发生变化，通过 Frank-Starling 机制减少了卒中容量。在应激/运动时无法增加卒中容量是衰老过程的特征。 在一项针对未患心血管疾病的志愿者的横断面研究中，这些志愿者接受了静息和运动血流动力学评估，Pandey 等人 ⁹⁹ 证实，年龄与 VO _2peak 的下降有关（在 5.5 个十年中下降了 40%），这主要是由于运动时心输出量的减少所致，而心输出量的减少又是由于峰值运动量时每搏输出量和心率的同步下降所致。 衰老与峰值心率下降、对自主神经系统输入的反应性降低以及心率变异性降低有关 ^134–136 。与年龄相关的运动性每搏输出量下降可能是由变力储备降低（收缩力降低，射血分数和收缩末期容积降低）驱动的 ⁹⁹ 。值得注意的是，峰值运动性每搏输出量的下降在老年（>60 岁）比在中年更明显。 ^99,137,138 在具有开创性的达拉斯卧床休息研究中，在 30 年随访时（从 20 岁到 50 岁），未观察到峰值运动时的每搏输出量下降，但在随后的 40 年随访时（到 60 岁时）观察到显著下降。 ^138,139 考虑到 60 岁之后 VO _2peak 的下降速度加快，这一点尤为重要。 ¹³³ 总之，每搏输出量储备的下降可能在与年龄相关的 VO _2peak 下降中发挥重要作用，尤其是在生命后期。

The effect of aging on LV compliance and relaxation may also contribute to reduced stroke volume reserve.^140,141 Some studies using invasive exercise hemodynamic assessments have shown a significant increase in submaximal and near-maximal exercise LV filling pressure and a reduction in the exercise cardiac output to LV filling pressure ratio with aging.¹⁴¹ However, the exaggerated filling pressure response to exercise in older adults is more evident in supine exercise hemodynamic assessment studies^140,142 and less so with upright assessment.⁹⁹ Among individuals with accelerated aging-related CVD, such as HFpEF, the disproportionate rise of filling pressure with exercise is pronounced and often considered pathognomic.¹⁴³ These observations suggest that progressive decline in LV compliance may be a more consistent feature of accelerated cardiac aging.¹⁴⁴
衰老对左心室顺应性和舒张功能的影响也可能导致每搏输出量储备减少。 ^140,141 一些使用有创运动血流动力学评估的研究表明，随着年龄的增长，次极量和接近极量运动时左心室充盈压显著增加，运动时心输出量与左心室充盈压的比率降低。 ¹⁴¹ 然而，老年人对运动时充盈压反应的过度增加在卧位运动血流动力学评估研究中更为明显 ^140,142 ，而在直立评估中则不那么明显 ⁹⁹ 。在患有加速衰老相关 CVD 的个体中，如 HFpEF，运动时充盈压不成比例的升高非常明显，通常被认为是病理性的。 ¹⁴³ 这些观察结果表明，左心室顺应性的进行性下降可能是加速心脏衰老的一个更一致的特征。 ¹⁴⁴

Most studies,^{139,145–150} though not all,^99,137,141 indicate that peak exercise A-VO_2diff declines with aging. Several peripheral factors may contribute to reductions in peak exercise A-VO_2diff in older adults, including changes in skeletal muscle mass and quality, skeletal muscle blood flow and capillary density, and mitochondrial function. Reductions in skeletal muscle mass and quality are associated with lower VO_2peak and physical function performance in older adults.^151–153 Reduced muscle mass lowers the amount of metabolically active tissue available to extract and use oxygen during exercise, contributing to reduced peak exercise A-VO_2diff observed in older adults. However, the relative contribution of reduced muscle mass to decreased peak exercise A-VO_2diff is likely small.¹⁵⁴ In contrast, abnormal skeletal muscle qualities are believed to play a larger role. In particular, increased accumulation of intermuscular adipose tissue (termed myosteatosis) is associated with reduced aerobic exercise tolerance,^155–158 muscular strength,^157,159,160 and physical function.^{155,156,160,161} Excess adiposity within skeletal muscle likely redirects blood flow away from active skeletal muscle during exercise, reducing muscle blood flow and diminishing functional capacity.¹⁶²
多数研究（ ^{139,145–150} 尽管并非全部 ^99,137,141 ）表明，峰值运动 A-VO _2diff 随年龄增长而下降。若干外周因素可能导致老年人峰值运动 A-VO _2diff 降低，包括骨骼肌质量和质量的变化、骨骼肌血流和毛细血管密度以及线粒体功能。骨骼肌质量和质量的降低与老年人较低的 VO _2peak 和身体功能表现相关。 ^151–153 肌肉量减少会降低代谢活跃组织的量，而这些组织原本可以在运动过程中提取和利用氧气，从而导致老年人观察到的峰值运动 A-VO _2diff 降低。然而，肌肉量减少对峰值运动 A-VO _2diff 降低的相对贡献可能很小。 ¹⁵⁴ 相比之下，异常的骨骼肌质量被认为起着更大的作用。 特别是，肌间脂肪组织（称为肌脂过多症）的积累增加与有氧运动耐量 ^155–158 、肌力 ^157,159,160 和身体功能 ^{155,156,160,161} 的降低有关。骨骼肌内过多的脂肪可能在运动期间将血流从活跃的骨骼肌转移，从而减少肌肉血流量并降低功能能力。 ¹⁶²

Skeletal muscle blood flow is lower during submaximal^163–166 and maximal exercises¹⁶⁷ and is a major contributor to reduced VO_2peak in older adults.^167,168 While impairments in skeletal muscle blood flow may be due to declines in maximal cardiac output with age, studies have shown that muscle blood flow is reduced during both small muscle mass (single knee extensor and forearm exercise) and large muscle mass (cycling) exercise in older adults. These observations suggest that reduced limb blood flow during exercise may be secondary to peripheral limitations including lower vascular conductance (blood flow/mean arterial pressure).¹⁶⁹ The impairment in vascular conductance with aging is the result of lowered nitric oxide and prostaglandin availability,¹⁷⁰ coupled with increased endothelium-derived vasoconstrictor (ET-1),¹⁷¹ which together promote endothelial dysfunction and attenuated vasodilatory responses to exercise in older adults. In addition, aging impairs the ability to contract skeletal muscle to blunt sympathetic vasoconstriction (a process known as functional sympatholysis), which is critical for proper regulation of blood flow distribution and oxygen delivery within skeletal muscle during dynamic exercise.^169,172,173 Finally, studies have shown that capillary density within skeletal muscle is up to 25% lower in older versus younger adults.^174–176 Decreased skeletal muscle capillary density leads to reduced muscle perfusion and red blood cell transit time, which diminishes convective oxygen delivery and extraction during exercise.^176,177 As such, skeletal muscle capillary density is an important determinant of peak exercise A-VO_2diff.^145,178 Together, decreases in skeletal muscle blood flow and capillary density may be major contributors to reduced peak exercise A-VO_2diff observed in older adults, as both significantly impact oxygen delivery and uptake within skeletal muscle.^155,179
老年人在次极量 ^163–166 和极量运动 ¹⁶⁷ 期间，骨骼肌血流量较低， _2peak 这是导致 VO 降低的主要原因。 ^167,168 虽然骨骼肌血流量的下降可能是由于年龄增长导致的最大心输出量下降，但研究表明，老年人在小肌肉群（单膝伸展和前臂运动）和大肌肉群（自行车）运动期间，肌肉血流量都会减少。 这些观察结果表明，运动期间肢体血流量的减少可能是周围限制（包括较低的血管传导性（血流量/平均动脉压））的继发结果。 ¹⁶⁹ 血管传导性随年龄增长而降低是由于一氧化氮和前列腺素的可用性降低， ¹⁷⁰ 加上内皮衍生血管收缩剂（ET-1）的增加， ¹⁷¹ 共同促进内皮功能障碍和老年人运动时血管舒张反应减弱。 此外，衰老会损害收缩骨骼肌以减轻交感神经血管收缩的能力（这一过程被称为功能性交感神经溶解），这对于动态运动期间骨骼肌内血流分布和氧气输送的适当调节至关重要。 ^169,172,173 最后，研究表明，老年人骨骼肌内的毛细血管密度比年轻人低 25%。 ^174–176 骨骼肌毛细血管密度降低会导致肌肉灌注减少和红细胞通过时间延长，从而减少运动期间的对流氧气输送和提取。 ^176,177 因此，骨骼肌毛细血管密度是峰值运动 A-VO _2diff 的一个重要决定因素。 ^145,178 总之，骨骼肌血流和毛细血管密度的降低可能是导致老年人观察到的峰值运动 A-VO _2diff 降低的主要因素，因为两者都显着影响骨骼肌内的氧气输送和摄取。 ^155,179

Physical activity levels over the life course are an important prognostic indicator of adverse outcomes.¹⁸⁰ Physical activity is defined as energy utilized beyond basal metabolic rate, can include all activities of daily life, and is measured as kilocalories or metabolic equivalents. Historically, it was assessed by self-report but recently has been measured objectively using wearable accelerometers. Higher levels of physical activity have been associated with reduced biological age, as assessed by the Phenotypic Age Acceleration model in the National Health and Nutrition Examination Survey cohort.¹⁸¹ Across multiple cohort studies, higher physical activity levels are a strong predictor of healthy aging, as defined by different metrics including functional independence and less decline in functional status,^182,183 lower frailty burden,¹⁸⁴ and the composite of absence of chronic disease, functional, and cognitive impairments.¹⁸⁵ The association of higher physical activity levels with healthy aging is consistent in middle age and older age¹⁸⁵ and independent of baseline functional status.¹⁸³
生命历程中的体力活动水平是预测不良结局的重要指标。 ¹⁸⁰ 体力活动被定义为超出基础代谢率所消耗的能量，可以包括所有的日常生活活动，并以千卡或代谢当量来衡量。过去，体力活动通常通过自我报告进行评估，但最近开始使用可穿戴加速度计进行客观测量。 在全国健康和营养调查队列中，通过表型年龄加速模型评估，较高水平的体力活动与生物学年龄的降低有关。 ¹⁸¹ 在多项队列研究中，较高的体力活动水平是健康老龄化的有力预测指标，健康老龄化由不同的指标定义，包括功能独立性和功能状态下降较少， ^182,183 较低的虚弱负担， ¹⁸⁴ 以及没有慢性疾病、功能和认知障碍的综合指标。 ¹⁸⁵ 较高的体力活动水平与健康老龄化之间的关联在中年和老年均一致， ¹⁸⁵ 并且与基线功能状态无关。 ¹⁸³

Higher self-reported physical activity levels have been consistently associated with reduced risk of mortality and CVD in several epidemiological cohort studies.^186–188 These observations are consistent with self-reported and objectively measured physical activity levels (Table 3). A large individual-level meta-analysis of 8 cohort studies that included 36 383 individuals with objectively measured physical activity levels demonstrated that higher overall physical activity levels were associated with lower mortality risk.¹⁸⁹ However, a nonlinear dose-response relationship was noted between total physical activity volume and all-cause mortality, with the most significant risk reduction noted in moving from the lowest quartile to the next quartile of physical activity (52% risk reduction) and modest marginal improvements with subsequent increments in physical activity levels. These observations are consistent with the current guidelines recommend 150 to 300 min/wk of moderate to vigorous aerobic physical activity¹⁹⁰
在多项流行病学队列研究中，较高的自我报告体力活动水平与死亡率和心血管疾病风险降低持续相关。 ^186–188 这些观察结果与自我报告和客观测量的体力活动水平相符（表 3）。 一项对 8 个队列研究进行的大型个体水平荟萃分析（纳入了 36 383 名具有客观测量的体力活动水平的个体）表明，较高的总体体力活动水平与较低的死亡风险相关。 ¹⁸⁹ 然而，总的体力活动量与全因死亡率之间存在非线性剂量-反应关系，其中最显著的风险降低出现在从最低四分位数到下一个四分位数的体力活动（风险降低 52%），而随后的体力活动水平增加带来的边际改善较为适度。 这些观察结果与目前的指南相符，指南建议每周进行 150 至 300 分钟的中等至高强度有氧体力活动 ¹⁹⁰

In contrast, recent studies have observed a more graded and linear dose-response relationship for objectively measured physical activity levels and risk of nonfatal incident CVD. A contemporary analysis from the UK Biobank cohort, which included 103 687 participants with objective measures of physical activity by accelerometers, demonstrated a 27% to 53% risk reduction in incident CVD in the second and fourth (most active) quartiles, respectively, compared with the referent (least active) group.¹⁹¹ These findings suggest that the cardiovascular benefit of physical activity may be more consistent and graded across the spectrum of the dose-response curve. The cardiovascular benefits of light-intensity physical activity in reducing the risk of adverse CV events at moderate doses seem to be more exaggerated among older adults. A recent analysis of 8 prospective studies, which included 20 152 individuals with objectively measured physical activity in the form of daily step counts, found that 6000 to 9000 steps per day were associated with a 40% to 50% lower risk of incident CVD among older adults over the age of 60 years.¹⁹² In contrast, no association was noted among younger adults. Similar findings were reported in the Women’s Health Initiative cohort, where higher levels of light physical activity were associated with a graded reduction in incident CVD independent of cardiovascular risk factors among older women (mean age, 78.5 years).¹⁹³
相比之下，近期的研究观察到，客观测量的体力活动水平与非致命性突发心血管疾病风险之间存在更均衡和线性的剂量-反应关系。一项来自英国生物样本库队列的当代分析，纳入了 103687 名通过加速计客观测量体力活动的参与者，结果表明，与参考组（活动量最少组）相比，第二和第四（活动量最大）四分位数中，突发心血管疾病的风险分别降低了 27%至 53%。 ¹⁹¹ 这些发现表明，体力活动对心血管的益处可能在剂量-反应曲线的整个范围内更加一致和分级。对于老年人而言，适度剂量的轻度体力活动在降低不良心血管事件风险方面的心血管益处似乎更为显著。 最近一项对 8 项前瞻性研究的分析，纳入了 20152 名通过每日步数客观测量体力活动的人，发现每天 6000 至 9000 步与 60 岁以上老年人新发 CVD 风险降低 40%至 50%相关 ¹⁹² 。相比之下，在年轻人中未观察到这种关联。 在“妇女健康倡议”队列中也报告了类似的结果，其中较高的轻度体力活动水平与老年妇女（平均年龄 78.5 岁）心血管疾病事件的逐步减少相关，且与心血管危险因素无关。 ¹⁹³

A linear dose-dependent relationship has been reported between physical activity levels and the risk of HF.^194–198 This is consistent with self-reported and objectively measured physical activity levels. In a pooled analysis of 12 prospective cohort studies with over 370 460 participants, participants engaging in guideline-recommended levels of physical activity (500 metabolic equivalents-min/wk) had modest reductions in HF risk (10% lower risk). In contrast, large reductions in HF risk were noted among those reporting physical activity at twice (19% lower risk) and 4× (35% lower risk) the guideline-recommended levels.¹⁹⁶ Similar observations were also reported in the UK Biobank cohort using objectively measured physical activity, where higher levels of moderate physical activity were associated with a lower risk of incident HF in a graded fashion up to high levels much beyond the current guideline-recommended levels of 300 min/wk (66% lower risk).¹⁹⁹ It is noteworthy that the association between physical activity and HF risk differs for HF subtypes, HFpEF and HF with reduced ejection fraction (HFrEF), such that higher physical activity levels are more strongly associated with a lower risk of HFpEF but not HFrEF. In a pooled analysis, leisure-time physical activity level above 1000 metabolic equivalents-min/wk was associated with a 19% risk reduction for HFpEF. In contrast, physical activity levels were not associated with HFrEF risk.²⁰⁰ Similar findings of a stronger association between physical activity levels and risk of HFpEF but not HFrEF were confirmed in the Objective Physical Activity and Cardiovascular Health in Older Women study using objective measures of physical activity levels.¹⁹⁷
一项研究报告指出，体力活动水平与心力衰竭风险之间存在线性剂量依赖关系。 ^194–198 这与自我报告和客观测量的体力活动水平相符。在一项对超过 370460 名参与者的 12 项前瞻性队列研究的汇总分析中，参与符合指南推荐水平体力活动（500 代谢当量-分钟/周）的参与者，其心力衰竭风险略有降低（风险降低 10%）。 相比之下，报告身体活动量达到指南推荐量 2 倍（风险降低 19%）和 4 倍（风险降低 35%）的人群，心力衰竭风险显著降低。 ¹⁹⁶ 英国生物样本库队列也报告了类似的观察结果，该研究使用了客观测量的体力活动，结果显示，较高水平的适度体力活动与较低的心力衰竭发生风险相关，并且呈梯度关系，直至远高于当前指南推荐的每周 300 分钟的水平（风险降低 66%）。 ¹⁹⁹ 值得注意的是，体力活动与心力衰竭（HF）风险之间的关联因心力衰竭亚型而异，表现为射血分数保留型心力衰竭（HFpEF）和射血分数降低型心力衰竭（HFrEF），较高的体力活动水平与较低的 HFpEF 风险更密切相关，但与 HFrEF 则不然。在一项汇总分析中，高于 1000 代谢当量-分钟/周的休闲时间体力活动水平与 HFpEF 风险降低 19%相关。相比之下，体力活动水平与 HFrEF 风险无关。 ²⁰⁰ 在老年妇女客观体力活动与心血管健康研究中，使用体力活动水平的客观测量也证实了类似的发现，即体力活动水平与 HFpEF 风险之间存在更强的关联，但与 HFrEF 的关联则不然。 ¹⁹⁷

In addition to physical activity levels, higher levels of cardiorespiratory fitness, a gold-standard integrative measure of exercise capacity affected by aging as discussed previously, have also been associated with lower risk of adverse CV outcomes, particularly HFpEF. There is a monotonic decline in VO_2peak with aging in middle age, with an accelerated decline noted in older adults (>60 years).¹³³ Seminal studies from the Cooper Center for Longitudinal Study have demonstrated that lower levels of cardiorespiratory fitness in mid-life and greater decline in cardiorespiratory fitness with aging are strongly associated with higher risk of HF in older age.^194,201 Furthermore, the association of baseline and decline in cardiorespiratory fitness with the risk of HF is stronger for HFpEF than HFrEF.⁴⁷ The stronger association of physical activity and cardiorespiratory fitness levels with the risk of HFpEF but not HFrEF is particularly relevant in the context of HFpEF representing an accelerated cardiac aging phenotype. It highlights the potential role of physical activity and exercise interventions in mitigating accelerated aging-related CVD.
除了体力活动水平，较高的心肺适能水平（这是衡量运动能力的金标准综合指标，并会受到衰老的影响，如前所述）也与较低的不良心血管事件风险相关，尤其是射血分数保留型心力衰竭 (HFpEF)。随着年龄增长，中年人的 VO _2peak 呈单调下降趋势，老年人（>60 岁）则出现加速下降。 ¹³³ 库珀纵向研究中心的重要研究表明，中年时期较低的心肺适能水平以及随着年龄增长心肺适能的更大程度下降与老年时期较高的心力衰竭风险密切相关。 ^194,201 此外，基线心肺适能和心肺适能下降与心力衰竭风险的关联对于射血分数保留型心力衰竭 (HFpEF) 比射血分数降低型心力衰竭 (HFrEF) 更强。 ⁴⁷ 身体活动和心肺适能水平与 HFpEF 风险的关联更强，但与 HFrEF 的关联不强，这在 HFpEF 代表加速心脏衰老表型的情况下尤为重要。这突出了身体活动和运动干预在减轻与加速衰老相关的 CVD 方面的潜在作用。

Several observational cohort studies have demonstrated a strong, graded association between higher physical activity and cardiorespiratory fitness, and lower prevalence of CVD risk factors, including diabetes, hypertension, hyperlipidemia, and obesity.^202–206 However, differences in antecedent development of CVD risk factors do not fully mediate the high physical activity and cardiorespiratory fitness–associated reduction in the risk of HF, implicating a more direct effect on the cardiovascular structure and function.²⁰¹ Development of HF with aging is characterized by intermediate development of subclinical abnormalities in cardiac structure and function. Numerous observational studies have demonstrated a predictable and consistent association between physical activity, cardiorespiratory fitness, and subclinical HF phenotypes. In the CARDIA study, lower cardiorespiratory fitness in young adulthood was associated with measures of abnormal LV systolic and diastolic function in middle age, and the association between low cardiorespiratory fitness and adverse diastolic function was independent of traditional cardiovascular risk factor burden.²⁰⁷ Moreover, in the Dallas Heart Study, low cardiorespiratory fitness and objectively measured physical activity levels among middle-aged adults were associated with higher peak systolic circumferential strain (worse cardiac contractility), irrespective of risk factor burden, demonstrating an independent association between low fitness levels and adverse cardiac remodeling.^208,209 Notably, higher levels of cardiorespiratory fitness among participants of the Cooper Center for Longitudinal Study were associated with better diastolic function and less concentric remodeling.²¹⁰ Together, these observations suggest that higher levels of physical activity and cardiorespiratory fitness may contribute to better cardiometabolic health and attenuate the development of accelerated cardiac aging phenotype.
多项观察性队列研究表明，较高的体力活动和心肺功能与较低的 CVD 风险因素（包括糖尿病、高血压、高脂血症和肥胖）患病率之间存在显著且分级的关联。 ^202–206 然而，心血管疾病风险因素先前发展的差异并不能完全解释高体力活动和心肺适能相关的心力衰竭风险降低，这意味着对心血管结构和功能有更直接的影响。 ²⁰¹ 随着年龄增长而发生的心力衰竭的特征是心脏结构和功能亚临床异常的中间发展阶段。 大量观察性研究已证实，体力活动、心肺适能和亚临床 HF 表型之间存在可预测且一致的关联。在 CARDIA 研究中，青年时期较低的心肺适能与中年时期异常的左心室收缩和舒张功能相关，并且低心肺适能与不良舒张功能之间的关联独立于传统心血管风险因素负担。 ²⁰⁷ 此外，在达拉斯心脏研究中，中年人的低心肺适能和客观测量的体力活动水平与较高的峰值收缩环向应变（较差的心脏收缩力）相关，而与风险因素负担无关，这表明低适能水平与不良心脏重塑之间存在独立的关联。 ^208,209 值得注意的是，在库珀纵向研究中心参与者中，较高的心肺适能水平与更好的舒张功能和更少的心脏向心性重构相关联。 ²¹⁰ 总之，这些观察结果表明，较高水平的体力活动和心肺适能可能有助于更好的心血管代谢健康，并减轻加速心脏衰老表型的发生。

Small randomized controlled trials (RCTs) have evaluated the effects of different exercise training interventions on biological aging. In a single-center RCT of 30 middle-aged participants, a 4-week high-intensity exercise training significantly reduced biological age as assessed by a transcriptomic clock model.²¹¹ Benefits of exercise on reversing accelerated biological aging are augmented by add-on dietary and nutritional interventions. To this end, in a secondary analysis of an RCT of 107 participants who underwent different diet and exercise interventions, diet and combination of diet with exercise significantly reduced biological age as assessed by different models (the Klemera-Doubal method biological age, the homeostatic dysregulation score, and the health aging index).²¹² In a larger Vitamin D3 - Omega-3 - Home Exercise - Healthy Aging and Longevity Trial that enrolled 777 participants, a combination of exercise with nutritional supplementation of omega-III fatty acids significantly reduced biological age as assessed by DNA methylation-based models (Phenotypic Age Acceleration, GrimAge, and GrimAge2).²¹³ Together, these observations highlight the effectiveness of exercise, alone or combined with dietary interventions, in reversing accelerated aging phenotypes.
一些小型随机对照试验 (RCT) 已经评估了不同运动训练干预对生物衰老的影响。在一项针对 30 名中年参与者的单中心 RCT 中，为期 4 周的高强度运动训练显著降低了生物年龄，这是通过转录组时钟模型评估的。 ²¹¹ 运动在逆转加速生物衰老方面的益处可以通过附加的饮食和营养干预来增强。 为此，在一项针对 107 名受试者进行不同饮食和运动干预的 RCT 的二次分析中，饮食以及饮食与运动的结合显著降低了通过不同模型评估的生物学年龄（Klemera-Doubal 法生物学年龄、稳态失调评分和健康老龄化指数）。 ²¹² 在一项纳入了 777 名参与者的大型维生素 D3 - Omega-3 - 居家运动 - 健康衰老与长寿试验中，运动与 omega-III 脂肪酸营养补充剂的结合显著降低了通过基于 DNA 甲基化的模型（表型年龄加速、GrimAge 和 GrimAge2）评估的生物学年龄。 ²¹³ 总之，这些观察结果突出了运动（单独或与饮食干预相结合）在逆转加速衰老表型方面的有效性。

Several trials and associated meta-analyses have demonstrated improvements in cardiometabolic parameters with exercise training. A significant increase in VO_2peak with exercise training has been shown in older individuals without CVD (including sedentary^214,215 and overweight/obese²¹⁶ cohorts) and among those with CAD,^217,218 HFrEF²¹⁹ (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training,²²⁰ Study of Myocardial Recovery After Exercise Training in Heart Failure²²¹ and the Exercise Rehabilitation Trial²²²), and HFpEF.^223–228 Direct comparisons of outcomes between studies of different populations should be interpreted with caution, but, on average, exercise training appears to provide higher increases in VO_2peak in older sedentary or overweight/obese populations (>3.5 mL/kg per min)^214–216 compared with patients with CAD (>2.5 mL/kg per min)²¹⁸ and those with HF (0.4–2.7 mL/kg per min).^{220,223,229–233}
多项试验和相关的荟萃分析表明，运动训练可以改善心脏代谢参数。 在没有 CVD 的老年人（包括久坐 ^214,215 和超重/肥胖 ²¹⁶ 人群）以及 CAD ^217,218 、HFrEF ²¹⁹ 患者（心力衰竭：一项调查运动训练结果的对照试验， ²²⁰ 心力衰竭运动训练后心肌恢复研究 ²²¹ 和运动康复试验 ²²² ）和 HFpEF 患者中，运动训练可显著提高 VO _2peak 。 ^223–228 不同人群研究结果的直接比较应谨慎解读，但平均而言，运动训练似乎能使老年久坐或超重/肥胖人群的 VO_2max增加幅度更高（>3.5 mL/kg/min）， ^214–216 而冠心病（CAD）患者（>2.5 mL/kg/min） ²¹⁸ 和心力衰竭（HF）患者（0.4–2.7 mL/kg/min）的增加幅度相对较低。 ^{220,223,229–233}

In addition to cardiorespiratory fitness, exercise training studies have demonstrated benefits for various cardiovascular and metabolic health parameters.^234,235 Across various primary and secondary prevention populations, exercise training has improved blood pressure,²³⁶ hemoglobin A1c in diabetes^237,238 and prediabetes,²³⁹ lipid profile,^240,241 and combined CVD risk profiles.²⁴² Exercise training also typically reduces body weight/waist circumference (in many studies of different populations),²⁴³ but may even more reliably reduce pathogenic metrics such as adipose tissue or visceral fat with associated stable or decreased body weight.^238,244,245 Individual studies and associated populations/outcomes are too numerous and diverse to highlight each individually. Among this array of studies, select notable trials contributing to the findings above include the Comparison of the Cardiovascular Benefits of Resistance, Aerobic, and Combined Exercise trial²⁴² (n=406 adults with overweight/obesity), the Sapporo Fitness Club Trial²⁴⁶ (n=561 adults with overweight/obesity and 2 additional CVD risk factors), and Studies of Targeted Risk Reduction Interventions through Defined Exercise trials (n=111 and n=137, respectively; sedentary, overweight/obese adults with dyslipidemia) programs.^240,247
除了心肺适能外，运动训练研究也证实了其对多种心血管和代谢健康参数的益处。 ^234,235 在各种一级和二级预防人群中，运动训练改善了血压， ²³⁶ 糖尿病 ^237,238 和糖尿病前期患者的糖化血红蛋白（hemoglobin A1c）， ²³⁹ 血脂谱， ^240,241 以及综合心血管疾病（CVD）风险状况。 ²⁴² 运动训练通常也能减轻体重/腰围（在许多不同人群的研究中）， ²⁴³ 但可能更可靠地减少致病指标，如脂肪组织或内脏脂肪，同时体重保持稳定或下降。 ^238,244,245 由于各个研究及其相关人群/结局数量众多且各不相同，因此无法在此逐一强调。 在这些研究中，对上述发现做出贡献的著名试验包括：阻力、有氧和联合运动对心血管益处的比较试验 ²⁴² （n=406，超重/肥胖成人）、札幌健身俱乐部试验 ²⁴⁶ （n=561，超重/肥胖且具有 2 项额外 CVD 风险因素的成人）以及通过定义的运动试验进行靶向风险降低干预研究（分别为 n=111 和 n=137；久坐、超重/肥胖且患有血脂异常的成人）项目。 ^240,247

Mechanistic studies from athletes and those individuals who participate in a high volume of lifelong exercise provide mechanistic and phenomenological insight into how exercise alters cardiac structure and function to improve exercise cardiac performance favorably. The cardiac hypertrophy in athletes, athlete’s heart, has been well described in the literature.^248–250 This adaptive hypertrophy of the heart occurs in response to the exercise training stimuli, resulting in larger cardiac size, stroke volume, higher VO_2peak, and cardiac output.²⁵¹ A major contribution to our understanding of the physiological effects of exercise training on cardiac performance across the age spectrum has been made by a series of studies done by Levine et al⁶⁵ over the last 2 decades.^{139,146,252–255} In a seminal study from his group, Arbab-Zadeh et al⁶⁵ demonstrated that athletes with prolonged and sustained endurance training over the life course have higher stroke volume and better LV compliance than sedentary but healthy older adults. Moreover, LV compliance in older endurance athletes did not differ from that of younger controls. These findings suggest that exercise training may prevent age-related LV stiffness and diastolic impairment. A subsequent study by the group characterized the relationship between lifelong exercise dose and cardiac compliance in older age.²⁵² Older lifelong competitive exercisers (>3 days of exercise per week) had better LV compliance than their sedentary counterparts. In addition, LV compliance and VO_2peak increased with higher doses of lifelong exercise, suggesting that exercise volume over the lifetime directly results in positive adaptations on diastolic function. Furthermore, prolonged, high-intensity exercise training can reverse some adverse cardiac remodeling noted in sedentary middle-aged adults. Specifically, Howden et al²⁵⁵ demonstrated that 2 years of high-intensity training improved cardiorespiratory fitness and LV stiffness among healthy, middle-aged, sedentary adults. Heida et al observed similar improvements in LV stiffness with 1-year of high-intensity training among those with LV hypertrophy and elevated cardiac biomarkers (stage B HF).²⁵⁶ It is noteworthy that the favorable effects of high intensity, prolonged exercise training on LV stiffness have been noted in middle-aged adults but not older adults or those with established HFpEF. Specifically, 1 year of vigorous exercise training in older adults did not reverse LV stiffness or improve exercise cardiac output or stroke volume reserve.²⁵³ Still, it did increase arterial elastance and improved cardiorespiratory fitness. Similarly, among patients with established HFpEF, a 1-year progressive endurance exercise training program did not improve LV compliance, arterial stiffness, or exercise capacity.²⁵⁴ These observations suggest that among older sedentary adults or those with established HFpEF, the myocardial stiffness may be less amenable to improvement with exercise, and the favorable effects of exercise on VO_2peak may be more related to its effects on peripheral oxygen extraction as discussed in the following.
来自运动员和终身参与大量运动的个体的机制研究，为我们提供了关于运动如何改变心脏结构和功能，从而有利地改善运动时心脏功能的机制性和现象学方面的深入见解。运动员的心脏肥大，即“运动员心脏”，在文献中已有充分描述。 ^248–250 这种心脏的适应性肥大是对运动训练刺激的反应，导致心脏尺寸增大、卒中量增加、VO _2peak 值升高以及心输出量增加。 ²⁵¹ Levine 等人 ⁶⁵ 在过去 20 年中所做的一系列研究，对我们理解运动训练对不同年龄段人群心脏功能的生理影响做出了重要贡献。 ^{139,146,252–255} 在他所在研究小组的一项具有开创性的研究中，Arbab-Zadeh 等人 ⁶⁵ 证明，与久坐但健康的年长者相比，一生中接受长期和持续耐力训练的运动员具有更高的卒中量和更好的左心室顺应性。此外，年长耐力运动员的左心室顺应性与年轻对照组没有差异。这些发现表明，运动训练可能预防与年龄相关的左心室僵硬和舒张功能障碍。 该小组随后的研究描述了终生运动剂量与老年人心脏顺应性之间的关系。 ²⁵² 年长的终生竞技运动者（每周运动 >3 天）比久坐的同龄人具有更好的左心室顺应性。此外，左心室顺应性和 VO _2peak 随着终生运动剂量的增加而增加，表明终生运动量直接导致舒张功能的积极适应。 此外，长时间、高强度的运动训练可以逆转久坐不动的中年人出现的一些不良心脏重塑。具体而言，Howden 等人 ²⁵⁵ 证实，在健康、中年、久坐不动的成年人中，为期 2 年的高强度训练改善了心肺功能和左心室（LV）僵硬度。Heida 等人观察到，在患有 LV 肥厚和心脏生物标志物升高（B 期心力衰竭，HF）的患者中，为期 1 年的高强度训练也观察到类似的 LV 僵硬度改善。 值得注意的是，高强度、长时间的运动训练对左心室僵硬度的有利影响已在中年人中得到证实，但在老年人或已确诊的射血分数保留型心力衰竭（HFpEF）患者中未见报道。具体而言，老年人进行为期 1 年的剧烈运动训练并未逆转左心室僵硬度，也未改善运动时的心输出量或每搏输出量储备 ²⁵³ 。尽管如此，它确实增加了动脉弹性，并改善了心肺功能。 同样，在已确诊为 HFpEF 的患者中，为期 1 年的渐进式耐力运动训练计划并未改善 LV 顺应性、动脉僵硬度或运动能力。 ²⁵⁴ 这些观察结果表明，在老年久坐的成年人或已确诊为 HFpEF 的患者中，心肌僵硬度可能不太容易通过运动得到改善，而运动对 VO _2peak 的有利影响可能更多地与其对外周氧气提取的影响有关，如下文所述。

Skeletal muscle is remarkably adaptive in its structure and function to physiological stimuli such as exercise, even in older sedentary adults.²⁵⁷ Indeed, 3 months of aerobic exercise training in sedentary older adults have been shown to improve VO_2peak by ≈18% secondary to increases in peak exercise A-VO_2diff, with no changes in peak cardiac output.¹⁴⁵ Contrary to effects on LV stiffness, which vary by age, exercise training elicits similar skeletal muscle adaptations in older and younger sedentary individuals.^145,258 These include modulation of functional sympatholysis,^259,260 increase in skeletal muscle mitochondrial content^261–264 and function,^263,264 capillarizations,^262,265 and capillary-to-fiber ratio.^265,266 Increases in capillary density increase red blood cell mean transit time and the area for diffusion while decreasing the diffusion distance from the red blood cell to the muscle fiber.¹⁷⁷ Furthermore, increases in skeletal muscle mitochondrial content and function improve oxygen utilization and ATP production. These exercise training–induced favorable changes in skeletal muscle are similar to those observed in athletes and contribute to increased peak exercise A-VO_2dif.^{169,258,259,261}
即使在老年久坐的成年人中，骨骼肌在结构和功能上对运动等生理刺激也具有显著的适应性。 ²⁵⁷ 事实上，研究表明，久坐的老年人经过 3 个月的有氧运动训练后，由于峰值运动 A-VO _2diff 增加，VO _2peak 改善了约 18%，而峰值心输出量没有变化。 ¹⁴⁵ 与对左心室僵硬度的影响（随年龄而异）相反，运动训练在老年和年轻的久坐个体中引起类似的骨骼肌适应。 ^145,258 这些包括功能性交感神经溶解的调节， ^259,260 骨骼肌线粒体含量 ^261–264 和功能的增加， ^263,264 毛细血管化， ^262,265 以及毛细血管与纤维比率。 ^265,266 毛细血管密度增加会延长红细胞的平均通过时间和扩散面积，同时缩短红细胞到肌纤维的扩散距离。 ¹⁷⁷ 此外，骨骼肌线粒体含量和功能的增加可改善氧气利用率和 ATP 的产生。这些运动训练引起的骨骼肌的有利变化与在运动员中观察到的相似，并有助于增加峰值运动 A-VO _2dif 。 ^{169,258,259,261}

Among older patients with HFpEF, supervised exercise training improves exercise capacity mainly through favorable effects on peripheral mechanisms.^267,268 Haykowsky et al²⁶⁷ demonstrated that among older adults with HFpEF, the favorable effect of exercise training on cardiac output was only responsible for 16% of the improvement in VO_2peak, and the increase in peripheral oxygen extraction was responsible for most of the aerobic capacity improvement. A subanalysis from the Optimising Exercise Training in Prevention and Treatment of Diastolic Heart Failure trial (OptimEX-Clin) with patients with chronic stable HFpEF demonstrated that aerobic exercise training improved skeletal muscle energy metabolism and reduced markers of muscle atrophy after 3 months of exercise training.²⁶⁹ Together, these findings suggest a more pronounced role of exercise training on skeletal muscle function in exerting its beneficial effects in patients with HFpEF.
在患有 HFpEF 的老年患者中，监督下的运动训练主要通过对周围机制的有利影响来提高运动能力。 ^267,268 Haykowsky 等人 ²⁶⁷ 证明，在患有 HFpEF 的老年人中，运动训练对心输出量的有利影响仅占 VO _2peak 改善的 16%，而周围氧气提取的增加是大部分有氧能力改善的原因。 一项对慢性稳定型射血分数保留型心力衰竭（HFpEF）患者进行的“优化运动训练预防和治疗舒张性心力衰竭试验（OptimEX-Clin）”的子分析表明，有氧运动训练改善了骨骼肌能量代谢，并在运动训练 3 个月后减少了肌肉萎缩的标志物。 ²⁶⁹ 总之，这些发现表明，运动训练在骨骼肌功能方面发挥了更显著的作用，从而在 HFpEF 患者中发挥其有益作用。

As such, the response to exercise training in different organ systems remains heterogeneous and an area of extensive investigation.²⁷⁰ The ongoing multicenter Molecular Transducers of Physical Activity Consortium study has identified thousands of exercise training–induced changes across a wide variety of target tissues, highlighting that exercise leads to a pleiotropic, whole-organism-wide stimulus that interacts with genetic, cellular, and subcellular functions.^271–273 In this way, the biological effects of exercise seem to mirror the aging process, where aging occurs across multiple organ systems and results in cellular and subcellular changes, the cumulative effects of which emerge as biological aging.
因此，不同器官系统对运动训练的反应仍然是异质性的，并且是一个广泛的研究领域。 ²⁷⁰ 正在进行的多中心“体力活动分子转导器联盟”研究已经确定了运动训练在多种目标组织中引起的数千种变化，强调运动会导致多效性的、全身性的刺激，并与遗传、细胞和亚细胞功能相互作用。 ^271–273 这样看来，运动的生物学效应似乎与衰老过程相似，衰老发生在多个器官系统中，并导致细胞和亚细胞的变化，这些变化的累积效应表现为生物学衰老。

Adequately powering and executing RCTs evaluating the effects of structured exercise training and physical activity interventions on the risk of HF in otherwise healthy, community-dwelling adults remain challenging. As a result, few individual trials have been successfully performed to assess the effects of exercise training on HF incidence as a secondary or exploratory outcome. The Generation-100 RCT²⁷⁴ remains one of the largest and longest exercise training studies in healthy participants (n=1567), assessing 5 years of exercise training (moderate-intensity, continuous exercise training [MICT] versus high-intensity interval training [HIIT] versus activity recommendation) in a specific population: healthy and fit older patients (aged 70–77 years) in Norway. In this study, exercise training resulted in an improvement in cardiovascular risk factors but did not accrue enough HF events to assess its effect on the same.²⁷⁵ In the LIFE study (n=1635),²⁷⁶ structured physical activity intervention reduced major mobility disability but did show a significant effect on the risk of HF, again limited by fewer events and lack of power.²⁷⁷ In the Action for Health in Diabetes trial (n=5145) that enrolled individuals with type 2 diabetes and overweight or obesity, an intensive lifestyle intervention targeting improved physical activity and weight loss did not lead to significant reductions in risk of HF despite relatively longer follow-up and a higher number of HF hospitalization events than prior studies.²⁷⁸ However, in exploratory analyses, greater improvement in cardiorespiratory fitness on follow-up was associated with a lower risk of HF, particularly HFpEF.⁴⁷ Together, while RCT data for the prevention of HF with exercise and physical activity intervention are lacking owing to the lack of adequately powered RCTs with long-term follow-up, the convergence of epidemiological, mechanistic, and guideline-based evidence provides a compelling rationale for exercise and physical activity intervention as a key strategy in the primary prevention of HF.
充分支持并执行 RCT，以评估结构化运动训练和体力活动干预对原本健康的社区居住成年人发生心力衰竭风险的影响，仍然具有挑战性。因此，很少有单独的试验能够成功评估运动训练对心力衰竭发生率的影响，作为次要或探索性结局。 Generation-100 RCT ²⁷⁴ 仍然是针对健康参与者（n=1567）进行的最大型、历时最长的运动训练研究之一，该研究在特定人群中评估了 5 年的运动训练效果（中等强度持续运动训练 [MICT] 与高强度间歇训练 [HIIT] 与活动推荐）：挪威健康且身体健康的年长患者（年龄 70-77 岁）。 在本研究中，运动训练改善了心血管危险因素，但没有积累足够的心力衰竭（HF）事件来评估其对心力衰竭的影响。 ²⁷⁵ 在 LIFE 研究（n=1635） ²⁷⁶ 中，有组织的体育活动干预减少了主要的行动障碍，但没有显示出对 HF 风险的显著影响，同样也受到事件较少和缺乏统计功效的限制。 ²⁷⁷ 在糖尿病健康行动试验(Action for Health in Diabetes trial, n=5145)中，该试验纳入了 2 型糖尿病和超重或肥胖的个体，一项旨在改善身体活动和减轻体重的强化生活方式干预措施，尽管随访时间相对较长，且心力衰竭(HF)住院事件的数量多于之前的研究，但并未显著降低 HF 风险。 ²⁷⁸ 然而，在探索性分析中，随访时心肺适能的更大改善与较低的 HF 风险相关，尤其是 HFpEF。 ⁴⁷ 总而言之，虽然由于缺乏具有长期随访的、充分赋能的 RCT，因此缺乏通过运动和体育活动干预预防 HF 的 RCT 数据，但流行病学、机制和基于指南的证据的融合为将运动和体育活动干预作为 HF 一级预防的关键策略提供了令人信服的理由。

Several studies have examined the utility of exercise training in patients with prevalent HFrEF. Specifically, Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) was one of the seminal exercise training trials with a sufficient sample size (n=2331) to evaluate mortality and hospitalization outcomes in patients with chronic stable HFrEF.²²⁰ Although the protocol-specified primary analysis demonstrated no reduction in hospitalization/mortality with the exercise training intervention, the prespecified analysis adjusting for risk factors found a significant reduction in all-cause mortality or hospitalization (Hazard Ratio, 0.89 [95% CI, 0.81–0.99]; P=0.03).²⁷⁹ Similarly, a small (n=123) study subsequently evaluated supervised exercise training for 10 years (2x/wk) and found a significant reduction in hospitalization and cardiac mortality.²⁸⁰ Comprehensive study-level pooled analyses have demonstrated up to 30% reduction in the risk of all-cause hospitalization with exercise-based cardiac rehabilitation (versus control) in adults with HF with no difference in the risk of mortality.²⁸¹ Among HF subtypes, multiple meta-analyses of RCTs of exercise training in participants with HFpEF have demonstrated consistent improvement in exercise capacity and quality of life with exercise training.^233,268 Furthermore, there have been signals that patients with HFpEF may benefit more in exercise capacity gains with exercise training than patients with HFrEF. In the HF-ACTION trial, participants gained only 0.4 to 0.6 mL/kg per min in VO_2peak although this may have been impacted by intervention adherence.²²⁰ Multiple trials in HFpEF, on the other hand, have demonstrated a median effect of ≈2 mL/kg per min in VO_2peak.²³³ Furthermore, the only direct, head-to-head comparison of exercise training across HF subtypes found significantly greater improvement in VO_2peak in patients with HFpEF compared with those with HFrEF.²⁸² More recently, in the Rehabilitation Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial, a multidomain rehabilitation intervention was associated with greater improvement in physical function, quality of life, and exercise capacity among participants hospitalized with acute decompensated HFpEF versus HFrEF.²⁸³ For clinical outcomes, study-level pooled analysis has demonstrated greater risk reduction in risk of hospitalization with exercise training (versus control) in patients with HFpEF versus HFrEF (HFpEF: odds ratio, 0.43 [95% CI, 0.30–0.62]; P<0.001 versus HFrEF: odds ratio, 0.71 [95% CI, 0.54–0.94]; P=0.02).²⁸⁴ The ongoing Physical Rehabilitation for Older Patients with Acute HFpEF (Unique identifier: NCT05525663) trial is an adequately powered RCT that is evaluating the effects of a multidomain rehabilitation intervention on clinical outcomes of mortality of HF hospitalization in older adults with acute decompensated HFpEF.
多项研究检验了运动训练在患有 HFrEF 患者中的效用。具体来说，Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) 是一项具有足够样本量 (n=2331) 的重要运动训练试验，旨在评估慢性稳定 HFrEF 患者的死亡率和住院结局。 ²²⁰ 尽管方案规定的主要分析表明，运动训练干预并未降低住院/死亡率，但对风险因素进行调整的预先指定分析发现，全因死亡率或住院率显著降低（风险比，0.89 [95% CI，0.81–0.99]；P=0.03）。 ²⁷⁹ 同样，一项小型研究（n=123）随后评估了为期 10 年（2 次/周）的监督运动训练，发现住院率和心脏死亡率显著降低。 ²⁸⁰ 综合性研究层面的汇总分析表明，在心力衰竭成人患者中，以运动为基础的心脏康复（相对于对照组）可降低高达 30%的全因住院风险，而死亡风险无差异。 ²⁸¹ 在心力衰竭亚型中，针对射血分数保留型心力衰竭（HFpEF）患者进行运动训练的多个 RCTs 的荟萃分析表明，运动训练可始终如一地提高运动能力和生活质量。 ^233,268 此外，有迹象表明，与 HFrEF 患者相比，HFpEF 患者可能从运动训练中获得更大的运动能力提升。在 HF-ACTION 试验中，参与者的 VO₂峰值仅增加了 0.4 至 0.6 mL/kg/min _^2peak ，但这可能受到了干预依从性的影响。 ²²⁰ 另一方面，多项 HFpEF 试验表明，VO₂峰值的中位数效应约为 2 mL/kg/min _^2peak 。 ²³³ 此外，唯一一项针对不同 HF 亚型进行运动训练的直接、头对头比较研究发现，HFpEF 患者的 VO _2peak 改善程度明显高于 HFrEF 患者。 ²⁸² 最近，在老年急性心力衰竭患者康复治疗（REHAB-HF）试验中，多领域康复干预与急性失代偿性射血分数保留型心力衰竭（HFpEF）患者相比，射血分数降低型心力衰竭（HFrEF）住院患者在身体功能、生活质量和运动能力方面的改善更大。 ²⁸³ 对于临床结局，研究层面的汇总分析表明，在 HFpEF 患者中，运动训练（相对于对照组）在降低住院风险方面比 HFrEF 患者效果更佳（HFpEF：优势比，0.43 [95% CI，0.30–0.62]；P<0.001，而 HFrEF：优势比，0.71 [95% CI，0.54–0.94]；P=0.02）。 ²⁸⁴ 正在进行的针对急性 HFpEF 老年患者的身体康复（Unique identifier：NCT05525663）试验是一项充分赋能的 RCT，正在评估多领域康复干预对急性失代偿性 HFpEF 老年患者死亡率或 HF 住院等临床结局的影响。

The design of early exercise training and cardiac rehabilitation programs primarily relied on aerobic, MICT regimens; these included a graduated increase in effort/exercise time over the training period and were typically enacted through walking or biking exertion. In the past decade, alternative and adjunct modalities, including HIIT and resistance training, have been studied in primary and secondary prevention populations. In general, results have either been neutral between MICT and HIIT^221,285,286 or slightly favored HIIT in a subset of studies in healthy or overweight/obese populations.^216,275,276 Several meta-analyses have suggested that HIIT may be superior to MICT in HFpEF,^233,287,288 but these should be interpreted with extreme caution, given that (1) the largest direct comparison study (OptimEx-Clin; n=180) was neutral; 2) other contributing studies were small (n=24 and n=15)^289,290; (3) 1 of the 3 included studies demonstrated no improvement in VO_2peak with MICT versus control,²⁹⁰ in contrast to many other studies that have found significant improvement with MICT in HFpEF; and (4) several of these meta-analyses^233,288 utilized a secondary outcome point estimate from OptimEx-Clin (12-month change in VO_2peak, trending to favor HIIT) compared with the primary outcome of 3-month change in VO_2peak (which trended to favor MICT without statistical significance), which would have been more consistent for comparison to the other included studies. It should be noted that the evidence base for MICT is much larger (ie, the number of trials and total participants studied) and may be implementable in a broader range of patients (ie, frail and musculoskeletal limitations). However, this remains an area of active research. From existing data, it appears that the clinical focus should be on implementing proven exercise training regimens (MICT or HIIT) based on patients’ preferences and logistical feasibility and increasing the frequency/duration of training, as tolerated.^240,286 Furthermore, resistance training can improve body composition/lean mass, strength, and cardiometabolic metrics and, therefore, has increasingly become of interest for exercise training regimens. In aggregate, resistance training in isolation has demonstrated less reliable cardiometabolic results,^{234,239,242,245} but it improves VO_2peak^216,247,291 and has been shown to have supportive/additive effects alongside aerobic training for leg strength and muscle quality.²²⁷
早期运动训练和心脏康复计划的设计主要依赖于有氧、中等强度持续训练(MICT)方案；这些方案包括在训练期间逐步增加运动强度/运动时间，并且通常通过步行或自行车运动来实现。在过去的十年中，包括高强度间歇训练(HIIT)和阻力训练在内的替代和辅助方式已在 primary 和 secondary 预防人群中进行了研究。 一般来说，在健康或超重/肥胖人群的部分研究中，MICT 和 HIIT 的结果要么是中性的 ^221,285,286 ，要么略微偏向 HIIT。 ^216,275,276 几项荟萃分析表明，在高射血分数心力衰竭 (HFpEF) 患者中，高强度间歇训练 (HIIT) 可能优于中等强度持续训练 (MICT)， ^233,287,288 但鉴于以下原因，应极其谨慎地解读这些分析：(1) 最大的直接比较研究（OptimEx-Clin；n=180）结果为中性；2) 其他有贡献的研究规模较小（n=24 和 n=15） ^289,290 ；(3) 在纳入的 3 项研究中，有 1 项研究显示，与对照组相比，MICT 对 VO _2peak 没有改善， ²⁹⁰ 这与其他许多研究发现 MICT 可显著改善 HFpEF 的结果相反；(4) 这些荟萃分析中，有几项 ^233,288 使用了 OptimEx-Clin 的次要终点估计值（12 个月 VO _2peak 变化，趋势偏向 HIIT），而不是 3 个月 VO _2peak 变化的主要终点（趋势偏向 MICT，但无统计学意义），而与纳入的其他研究相比，主要终点更具一致性。 应该指出的是，关于中等强度持续训练(MICT)的证据基础要大得多（即，试验次数和研究的总参与者人数），并且可能适用于更广泛的患者（即，体弱者和肌肉骨骼受限者）。然而，这仍然是一个活跃的研究领域。 根据现有数据，临床重点似乎应该放在根据患者的偏好和后勤可行性实施已证实有效的运动训练方案（MICT 或 HIIT），并在可耐受的情况下增加训练的频率/持续时间。 ^240,286 此外，阻力训练可以改善身体成分/瘦体重、力量和心脏代谢指标，因此，越来越受到运动训练方案的关注。 总的来说，孤立的阻力训练显示出不太可靠的心脏代谢结果， ^{234,239,242,245} 但它改善了 VO _2peak ^216,247,291 ，并且已被证明在腿部力量和肌肉质量方面与有氧训练一起具有支持/累加效果。 ²²⁷

In contrast to data for immediate response outcomes (assessed at intervention completion), the evidence base for the intermediate and long-term functional effects of exercise training is limited. Definitions for the timeline of longer-term effects are not standardized, but durable effects may be generally defined as between 6 and 24 months after the completion of the intervention. In contrast, legacy effects are typically described as years after completion of the intervention, long after cessation of the treatment.^292–294 In the few existing studies, legacy effects have often been studied ≈10 years after the intervention^293–295 but may be reasonably defined as early as 2 years after intervention completion and up to 20 years.^296,297
与即时反应结果（在干预结束时评估）的数据相比，运动训练对中期和长期功能影响的证据基础有限。长期影响的时间线定义尚未标准化，但持久影响通常可定义为干预完成后 6 至 24 个月之间。 相比之下，后效通常被描述为干预完成后数年，即治疗停止很久之后出现的效应。 ^292–294 在为数不多的现有研究中，后效通常在干预后约 10 年进行研究 ^293–295 ，但可以合理地定义为干预完成后最早 2 年到最长 20 年的时间范围内。 ^296,297

Regarding the durable effects of exercise training, several studies have evaluated effects in the months to 1 year after the initial, supervised regimen was completed. Often, a home prescription or recommendation for continued exercise training, with variable adherence monitoring, is utilized between immediate evaluation (ie, 3–6 months) and durable evaluation (ie, 6–24 months after completion of supervised regimen). The largest studies to evaluate the question of durability include HF-ACTION (HFrEF)²²⁰ and OptimEx-Clin (HFpEF).²⁸⁵ In addition to the primary mortality/hospitalization outcomes, HF-ACTION demonstrated some degree of maintenance of benefits for exercise capacity (VO_2peak and exercise time, not six minute walk distance, which attenuated to nonsignificance), depression, and quality-of-life metrics at 12 months^220,298,299 and up to 26 months for quality of life.²⁹⁹ In contrast, the OptimEx-Clin evaluation at 12 months suggested that exercise benefits (primary outcome and VO_2peak) regressed markedly in the months following exercise training. However, the intensity of monitoring and guidance in the 3- to 12-month home phase may have differed between the 2 programs.
关于运动训练的持久效果，有多项研究评估了在最初的监督方案完成后几个月到 1 年内的效果。通常，在即时评估（即 3-6 个月）和持久评估（即完成监督方案后 6-24 个月）之间，会采用家庭处方或持续运动训练的建议，并进行不同程度的依从性监测。 关于持久性的最大型研究包括 HF-ACTION（HFrEF） ²²⁰ 和 OptimEx-Clin（HFpEF）。 ²⁸⁵ 除了主要死亡率/住院结局外，HF-ACTION 还证明了运动能力（VO _2peak 和运动时间，而非六分钟步行距离，后者减弱至无统计学意义）、抑郁症和生活质量指标在 12 个月时 ^220,298,299 以及长达 26 个月的生活质量方面，均在一定程度上保持了益处。 ²⁹⁹ 相比之下，OptimEx-Clin 研究在 12 个月时的评估表明，运动带来的益处（主要结局和 VO _2peak ）在运动训练后的几个月里明显消退。然而，在这两个项目中，3 至 12 个月家庭阶段的监测和指导强度可能有所不同。

Data regarding the legacy effects of exercise training are even more limited. The STRRIDE program remains one of the few trials to re-evaluate participants in the legacy phase, through a 10-year Reunion study.²⁹³ Participants from the exercise training groups were found to have an attenuated decline in VO_2peak and smaller increases in waist circumference. Furthermore, legacy exercise training participants were found to have improved fasting insulin and mean arterial blood pressure compared with controls. These encouraging findings have limitations, including a tightly defined trial cohort, the opportunity at randomization for control arm participants to pursue the exercise training arm (including potential bias), and the lack of inclusion of dropout participants in the Reunion study. Future investigation of both the durable and legacy effects of exercise training across population cohorts is needed to define current results and to support the development of strategies to improve long-term effects.
关于运动训练的遗留效应的数据甚至更加有限。STRRIDE 计划仍然是为数不多的在遗留阶段重新评估参与者的试验之一，通过一项为期 10 年的重聚研究。 ²⁹³ 结果发现，运动训练组的参与者 VO _2peak 的下降幅度有所减缓，腰围的增加幅度也有所减小。 此外，与对照组相比，既往运动训练参与者的空腹胰岛素和平均动脉血压均有所改善。这些令人鼓舞的发现也存在局限性，包括定义严格的试验队列、随机分组时对照组参与者有机会参加运动训练组（包括潜在的偏倚），以及 Reunion 研究中未纳入退出研究的参与者。 未来需要对不同人群队列中运动训练的持久效应和长期效应进行进一步研究，以明确目前的结果，并支持制定改善长期效果的策略。