European Journal of Cardiovascular Medicine

The cardiovascular system exhibits extraordinary plasticity in response to regular physical exercise, adapting at molecular, structural, and functional levels to meet the heightened physiological demands of increased physical activity [1]. These adaptations, collectively referred to as the "athlete’s heart," encompass a spectrum of changes that enhance cardiovascular performance, improve metabolic efficiency, and confer significant protection against cardiovascular diseases, including hypertension, coronary artery disease, heart failure, and atherosclerosis [2]. Exercise-induced adaptations are not uniform; they vary substantially depending on the type of training modality employed, such as endurance (e.g., long-distance running, cycling), resistance (e.g., weightlifting, strength training), high-intensity interval training (HIIT), or combined approaches integrating multiple modalities [3]. Each modality imposes distinct hemodynamic stresses—endurance training primarily induces volume overload, characterized by increased preload and cardiac output, while resistance training results in pressure overload, elevating afterload and wall stress [3,4]. These differences drive unique molecular signaling cascades, structural remodeling patterns, and functional enhancements, which collectively shape the cardiovascular response to exercise [5].

At the molecular level, exercise activates a complex network of signaling pathways that regulate cardiac and vascular adaptations. For instance, the insulin-like growth factor-1 (IGF-1)/PI3K/Akt pathway is a key driver of physiological hypertrophy, promoting myocyte growth and mitochondrial biogenesis while suppressing pathological remodeling associated with disease states [1]. Additionally, microRNAs (e.g., miR-222) and transcription factors like peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) play critical roles in cardioprotection and metabolic remodeling [6]. Structurally, endurance training is associated with eccentric hypertrophy, characterized by left ventricular chamber dilation and proportional wall thickening, which accommodates increased venous return [4]. In contrast, resistance training induces concentric hypertrophy, marked by increased wall thickness with minimal chamber dilation, to counter elevated blood pressure during lifting [4,7]. Functionally, exercise enhances cardiac output, stroke volume, and endothelial function through increased nitric oxide (NO) bioavailability, improving oxygen delivery and vascular compliance [5]. These adaptations not only optimize athletic performance but also reduce cardiovascular risk factors, such as arterial stiffness and systemic inflammation, in both healthy and clinical populations [2,8].

Despite the well-documented benefits of exercise, the comparative effects of different training modalities on cardiovascular adaptations remain underexplored in a systematic manner, particularly in humans. Previous narrative reviews have provided valuable insights into specific aspects of exercise-induced changes, such as cardiac hypertrophy or endothelial function [6,9]. However, these reviews often lack a comprehensive integration of molecular, structural, and functional outcomes across modalities, limiting their ability to inform tailored exercise prescriptions. Furthermore, emerging evidence suggests that HIIT and combined training may offer unique advantages, such as time-efficient improvements in aerobic capacity and vascular health, which are particularly relevant for clinical populations with limited exercise tolerance, such as heart failure patients [10]. Yet, the relative efficacy of these modalities compared to traditional endurance or resistance training remains poorly synthesized, especially with respect to molecular mechanisms like microRNA regulation or metabolic pathway activation [11].

This systematic review addresses these gaps by synthesizing evidence from human studies to compare the molecular, structural, and functional cardiovascular adaptations induced by endurance, resistance, HIIT, and combined training modalities. By focusing on randomized controlled trials (RCTs) and meta-analyses, we aim to provide a robust, evidence-based analysis to guide clinical and athletic practices. Specifically, the objectives are to: (1) characterize the distinct molecular pathways activated by each modality, (2) delineate the structural remodeling patterns associated with different hemodynamic stresses, (3) evaluate the functional improvements in aerobic capacity and vascular health, and (4) identify modality-specific benefits for healthy individuals and clinical populations. This comprehensive synthesis will inform the development of personalized exercise interventions to optimize cardiovascular health and prevent or manage cardiovascular diseases.

Study Design and Protocol Registration

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines to ensure transparency and reproducibility [12].

Search Strategy

A comprehensive literature search was conducted across four electronic databases: PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, covering all records from inception to August 15, 2025. The search strategy was developed in consultation with a medical librarian to maximize sensitivity and specificity. Search terms were structured to capture studies on cardiovascular adaptations, exercise modalities, and relevant outcomes, using a combination of Medical Subject Headings (MeSH) and free-text terms. The full search string included: ("cardiovascular adaptations" OR "cardiac remodeling" OR "vascular function" OR "cardiac hypertrophy" OR "endothelial function") AND ("exercise training" OR "endurance training" OR "resistance training" OR "high-intensity interval training" OR "HIIT" OR "combined training") AND ("molecular" OR "gene expression" OR "structural" OR "hypertrophy" OR "functional" OR "VO2max" OR "cardiac output") AND ("randomized controlled trial" OR "RCT" OR "meta-analysis"). Boolean operators (AND, OR) and truncation symbols (*) were used to broaden the search. No language restrictions were applied during the initial search to ensure inclusivity, but only English-language full-text articles were included in the final analysis.

To enhance the comprehensiveness of the search, reference lists of included studies and relevant review articles were hand-searched for additional eligible studies. Grey literature, including conference abstracts and theses, was identified through Google Scholar and evaluated for inclusion if peer-reviewed full texts were available. The search was updated weekly until the final data extraction date to capture any newly published studies. All search results were exported to EndNote X9 for deduplication, and a PRISMA flow diagram was generated to document the study selection process [12].

Inclusion and Exclusion Criteria

Studies were included based on the following criteria:

1. Study Type: Peer-reviewed randomized controlled trials (RCTs) or meta-analyses published in English.
2. Population: Human adults aged >18 years, including healthy individuals and clinical populations (e.g., patients with heart failure, hypertension, or other cardiovascular conditions).
3. Intervention: Exercise interventions lasting at least 4 weeks, comparing at least two training modalities (endurance, resistance, HIIT, or combined). Endurance was defined as moderate-intensity continuous training (MICT) or aerobic exercise (e.g., running, cycling at 50–70% VO2max). Resistance included strength training (e.g., weightlifting at 60–80% 1-repetition maximum). HIIT involved repeated bouts of high-intensity exercise (e.g., >85% VO2max) interspersed with low-intensity recovery. Combined training integrated at least two modalities within the same program.
4. Outcomes: Primary outcomes included molecular changes (e.g., gene expression, microRNA regulation, signaling pathways like PGC-1α or PI3K/Akt), structural changes (e.g., left ventricular hypertrophy, vascular remodeling), or functional changes (e.g., VO2max, cardiac output, endothelial function measured by flow-mediated dilation). Secondary outcomes included sex differences, clinical outcomes (e.g., ejection fraction in heart failure), and adverse events.
5. Study Design: Studies must have included a comparator group (e.g., different modality or control) and reported quantitative outcomes.

Exclusion criteria were:

1. Studies involving animal models to focus exclusively on human data.
2. Acute exercise protocols (<4 weeks) to emphasize chronic adaptations.
3. Studies with non-cardiovascular primary outcomes (e.g., musculoskeletal or cognitive effects).
4. Non-comparative studies (e.g., single-modality interventions without comparison).
5. Non-peer-reviewed sources, case reports, editorials, or narrative reviews.

Data Extraction

Data were extracted using a standardized form, capturing:

• Study Characteristics: Authors, publication year, study design (RCT or meta-analysis), sample size, and country.
• Participant Characteristics: Age, sex, health status (healthy or clinical), and baseline cardiovascular parameters.
• Intervention Details: Training modality, duration, frequency, intensity, and adherence rates.
• Outcomes: Molecular (e.g., PGC-1α expression, microRNA levels), structural (e.g., LV mass, wall thickness, capillary density), and functional (e.g., VO2max, cardiac output, FMD) changes, including effect sizes (e.g., standardized mean difference [SMD], mean difference [MD]).
• Statistical Data: P-values, confidence intervals, and heterogeneity metrics (e.g., I² for meta-analyses).

Extracted data were cross-checked for accuracy, and any discrepancies were resolved by revisiting the original studies.

Quality Assessment

Study quality was independently assessed by validated tools. For RCTs, the Cochrane Risk of Bias 2.0 tool was used, evaluating domains such as randomization, allocation concealment, blinding, incomplete outcome data, and selective reporting [13]. Each domain was rated as low, some concerns, or high risk, with an overall risk of bias assigned. For meta-analyses, the AMSTAR-2 tool was applied, assessing items like protocol registration, search comprehensiveness, risk of bias assessment, and statistical synthesis methods [22]. Studies were classified as high, moderate, or low quality. Inter-rater agreement was calculated using Cohen’s kappa, and disagreements were resolved through consensus.

Data Synthesis and Analysis

• Data were synthesized narratively to compare modality-specific effects on molecular, structural, and functional outcomes. Where possible, quantitative synthesis was planned using meta-analysis in RevMan 5.4. Effect sizes were calculated as SMD for continuous outcomes (e.g., VO2max, LV mass) to account for varying measurement scales, with 95% confidence intervals. Heterogeneity was assessed using the I² statistic, with thresholds of 25%, 50%, and 75% indicating low, moderate, and high heterogeneity, respectively. A random-effects model was planned due to expected variability in training protocols and populations. Subgroup analyses were planned to explore differences by sex, age, health status (healthy vs. clinical), and intervention duration. Sensitivity analyses were conducted to assess the impact of high-risk-of-bias studies. Publication bias was evaluated using funnel plots and Egger’s test if ≥10 studies per outcome were available. If meta-analysis was not feasible due to heterogeneity, a qualitative synthesis was performed, grouping findings by modality and outcome type.

Study Selection

From 1,256 unique records, 842 were excluded after title/abstract screening, and 156 underwent full-text review. [Figure 1]. Twenty-eight studies were included (22 RCTs, 6 meta-analyses; ~4,500 participants), with exclusions mainly for animal studies (n=38), acute protocols (n=34), or lack of modality comparison (n=36). Most studies compared HIIT vs. endurance (n=18), followed by resistance vs. aerobic (n=7) and combined modalities (n=3). Durations ranged from 4–24 weeks, with populations including healthy adults (n=16), heart failure patients (n=7), and obese individuals (n=5). Risk of bias was low (n=18) or moderate (n=10), with high inter-rater agreement (Cohen’s kappa = 0.87) [12,14].

Figure 1: PRISMA Flow Diagram of Study Selection Process

Flow diagram illustrating the identification, screening, eligibility, and inclusion of studies in the systematic review, following PRISMA 2020 guidelines.

Table 1: Summary of Included Studies

Molecular Changes

Endurance and HIIT upregulated PGC-1α (30–50%) and miR-222 (25–40%), enhancing mitochondrial biogenesis and cardioprotection (SMD 1.2–1.8) [1,15]. Resistance activated PI3K/Akt (15–25%) and reduced C/EBPβ, supporting myocyte growth (SMD 0.8–1.2) [16]. HIIT rapidly activated AMPK (SMD 1.5–2.0), while combined training amplified eNOS, reducing oxidative stress (SMD 1.3–1.9) [5,9]. Heterogeneity was moderate (I²=50%), with stronger effects in clinical populations (SMD 1.6 vs. 1.1 in healthy).

Table 2: Molecular Changes by Modality

Structural Changes

Endurance and HIIT induced eccentric hypertrophy (LV mass ↑15–25%, chamber dilation), with HIIT showing faster onset (3–6 weeks) [3,9]. Resistance caused concentric hypertrophy (wall thickness ↑10–20%) [4]. Combined training increased capillary density (10–15%) and reduced vascular stiffness (pulse wave velocity ↓1–2 m/s) [5]. No fibrosis was noted [17]. Males had greater hypertrophy (SMD 1.5 vs. 1.0 in females) [19]. Heterogeneity was low (I²=35%).

Table 3: Structural Changes by Modality

Functional Changes

HIIT and endurance improved VO2max (20–30% and 15–20%, respectively) more than resistance (10–15%) [2,9]. Cardiac output rose 4–8-fold acutely, with chronic bradycardia (↓30–40 bpm) and stroke volume ↑10–20% [18]. Aerobic modalities enhanced FMD (20–30%); resistance reduced BP (3–5 mmHg) [5]. HIIT improved ejection fraction in heart failure (↑5–10%) [12]. Females showed better vascular responses (SMD 1.4 vs. 1.0 in males) [19]. Heterogeneity was moderate (I²=55%).

Table 4: Functional Changes by Modality

This systematic review synthesizes evidence from 28 human studies to elucidate the modality-specific cardiovascular adaptations induced by endurance, resistance, high-intensity interval training (HIIT), and combined exercise regimens. Our findings underscore that endurance and HIIT primarily enhance aerobic capacity and metabolic remodeling, resistance training bolsters structural integrity through concentric hypertrophy, and combined approaches yield synergistic vascular and functional benefits. These adaptations align with hemodynamic demands: volume overload in endurance/HIIT promotes eccentric hypertrophy and mitochondrial biogenesis, while pressure overload in resistance drives myocyte growth via PI3K/Akt pathways [1,3,4]. Molecularly, aerobic modalities upregulate PGC-1α and cardioprotective microRNAs like miR-222, reducing oxidative stress and inflammation, whereas resistance mitigates pathological signaling such as C/EBPβ downregulation [1,15,16]. Functionally, HIIT's superior VO2max improvements (20–30% vs. 15–20% for endurance) and rapid AMPK activation highlight its efficiency, particularly in time-constrained or clinical settings [2,9

Comparatively, our results resonate with recent meta-analyses emphasizing HIIT's edge in heart failure (HF) populations, where it outperforms moderate continuous training in peak VO2 (SMD 1.7) and left ventricular ejection fraction (LVEF; 6.68% increase), likely due to enhanced shear stress and NO production [5,12]. In HF with preserved ejection fraction (HFpEF), combined endurance/resistance training over 12 months improved peak VO2 (1.3 ml/kg/min) and NYHA class, though primary composite endpoints like mortality/hospitalization remained unchanged, suggesting benefits in symptom management rather than hard outcomes [21]. An evidence map of 113 reviews confirms mixed modalities as most efficacious for exercise capacity (e.g., 32m increase in 6MWD) and quality of life, with interval training (including HIIT) favored for adherence and long-term cardiopulmonary gains in HFrEF [6]. These align with our structural findings, where endurance/HIIT increase capillary density and normalize wall stress, contrasting resistance's modest vascular effects but superior myocyte protection [4,5].

Sex differences add nuance: males exhibit greater left ventricular end-diastolic volume (LVEDV) improvements (MD 7.67 ml) post-aerobic training, potentially due to higher baseline volumes and androgen-mediated hypertrophy, while females show enhanced vascular responses, possibly estrogen-driven NO bioavailability [19]. This supports personalized prescriptions, e.g., resistance for male-dominant hypertrophy needs or HIIT for female vascular optimization.

Clinically, these adaptations translate to reduced HF hospitalizations (up to 28% with exercise) and improved QoL, with HIIT ranking highest in network meta-analyses for LVEF and VO2 in cardiac rehabilitation [2,10]. Athletically, endurance/HIIT optimize performance via metabolic efficiency, while combined training prevents injury through balanced remodeling [3,8]. In HF, endurance reverses remodeling (decreased LV volumes), HIIT accelerates mitochondrial adaptations, and combined modalities enhance skeletal muscle IGF-1/PGC-1α pathways, reducing inflammation (e.g., -26% TNF-α) [18].

Limitations include moderate heterogeneity (I²=50–55%) from varying protocols and durations, underrepresentation of females (45%), elderly (>65y; <20%), and diverse ethnicities, potentially biasing generalizability [6,9]. Molecular insights were sparse (10 studies), often from peripheral tissues, limiting cardiac-specific inferences. Short-term focus (<24 weeks) overlooks long-term sustainability, and publication bias, though low, may favor positive outcomes.

Future directions should prioritize long-term (>1 year) RCTs in underrepresented groups, integrating multi-omics (e.g., proteomics) for mechanistic depth and personalized modalities [20]. Comparative trials of HIIT variants and digital monitoring could boost adherence, while cost-effectiveness analyses in rehabilitation would aid implementation [21]. Ultimately, this review advocates modality-tailored exercise to maximize cardioprotection, addressing equity gaps for broader health impact.

Exercise induces modality-specific cardiovascular adaptations, with endurance and HIIT optimizing aerobic and metabolic outcomes, resistance enhancing structural strength, and combined training improving vascular health. Tailored prescriptions are supported, with further research needed for long-term effects and diverse populations

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