Table 3 Summary of assessed outcomes and main results of the reviewed studies

Bayer et al. [106]

Cognitive functions

Dementia detection test (DemTect)

Clock drawing test (CDT)

Physical functions

Six-minute Walk Test (6MWT)

Cardiovascular hemodynamic parameters

Resting heart rate

Resting systolic and diastolic blood pressure

Resting oxygen saturation

Within-group comparisons (pre-test vs. post-test)

↑ DemTect in IHHE (11.2 ± 3.5 points vs. 14.2 ± 3.7 points)

↑ CDT in IHHE (7.8 ± 2.9 points vs. 8.4 ± 3.0 points)

↑ 6MWT in IHHE and sham IHHE (234.3 ± 94.7 m vs. 290.7 ± 83.1 m; 250.6 ± 94.3 m vs. 277.7 ± 96.3 m)

Between-group comparisons

↑ DemTect in IHHE compared to sham IHHE (post-test: 14.2 ± 3.7 points vs. 11.3 ± 3.6 points)

↑ CDT in IHHE compared to sham IHHE (post-test: 8.4 ± 3.0 points vs. 6.8 ± 2.6 points)

↑ 6MWT in IHHE compared to sham IHHE (post-test: 290.7 ± 83.1 m vs. 277.7 ± 96.3 m)

Correlations

Δ-DemTect ↔ Δ-6MWT (r = + 0.57)

Δ-CDT ↔ Δ-6MWT (r = + 0.42)

Glazachev et al. [107]

Physical functions

Cardiopulmonary exercise test

Cardiovascular hemodynamic parameters

Resting heart rate

Resting systolic and diastolic blood pressure

Resting left ventricular ejection fraction

Blood markers

Haemoglobin concentration, reticulocytes, total cholesterol, high- and low-density lipoprotein, and glucose

Atherogenic index ((total cholesterol − high-density lipoprotein) ÷ high-density lipoprotein)

Quality of life 

Seattle Angina Questionnaire (SAQ)

Within-group comparisons (pre-test vs. post-test vs. 1-month follow-up)

↓ Angina as a reason to stop cardiopulmonary exercise test in IHHE (12 vs. 6 vs. 3^b, ^c)

↑ Time to exhaustion in cardiopulmonary exercise test (modified Bruce protocol) in IHHE (354 ± 194 s vs. 383 ± 141 s vs. 395 ± 130 s^b)

↑ Time to exhaustion in cardiopulmonary exercise (Bruce protocol) in IHHE (280 ± 126 s vs. 295 ± 79 s vs. 332 ± 113 s^b)

↑ VO_2peak in IHHE (14.3 ± 4.2 ml-O2/min/kg vs. 16.1 ± 4.2 ml-O2/min/kg^a vs. 15.4 ± 4.5 ml-O2/min/kg^a)

↓ Systolic blood pressure in IHHE (151 ± 19 mmHg vs. 130 ± 13 mmHg^a vs. 129 ± 11 mmHg^b)

↓ Diastolic blood pressure in IHHE (85 ± 11 mmHg vs. 73 ± 7 mmHg^a vs. 75 ± 9 mmHg^b)

↓ Resting heart rate in IHHE (71.5 ± 11.4 beats/min vs. 67.7 ± 8.3 beats/min^a vs. 66.6 ± 10.0 beats/min^b)

↓ Maximum heart rate in IHHE (122 ± 19 beats/min vs. 120 ± 14 beats/min^a vs. 116 ± 14 beats/min^b)

↑ Left ventricle ejection fraction in IHHE (14.3 ± 4.2% vs. 16.1 ± 4.2%^a vs. 15.4 ± 4.5%^b)

↑ Reticulocytes in IHHE (9.0 ± 4.5% vs. 11.3 ± 6.2%^a vs. 9.2 ± 4.8%^b)

↓ Total cholesterol in IHHE (5.6 ± 1.4 mmol/L vs. 5.1 ± 1.2 mmol/L^a vs. 5.5 ± 1.4 mmol/L^b)

↓ Low-density lipoprotein in IHHE (3.5 ± 1.2 mmol/L vs. 3.2 ± .9 mmol/L^a vs. 2.6 ± 1.3 mmol/L^b, ^c)

↓ Atherogenic index in IHHE (4.7 ± 1.8 vs. 3.4 ± 1.3^a vs. 3.5 ± 1.5^c)

↓ Glucose in IHHE (7.1 ± 2.3 mmol/L vs. 6.5 ± 1.7 mmol/L vs. 6.2 ± 1.7 mmol/L^c)

↑ SAQ physical limitation subscale in IHHE (43.3 ± 17.7 vs. 51.6 ± 13.1^a vs. 53.7 ± 17.8^b)

↑ SAQ angina stability subscale in IHHE (56.5 ± 27.4 vs. 78.3 ± 23.3^a vs. 79.6 ± 22.7^b)

↑ SAQ angina frequency subscale in IHHE (59.6 ± 27.6 vs. 81.1 ± 17.9^a vs.80.9 ± 18.2^b)

↑ SAQ treatment satisfaction subscale in IHHE (60.7 ± 16.2 vs. 77.4 ± 16.8^a vs. 80.5 ± 17.7^b)

↑ SAQ disease perception subscale in IHHE (47.2 ± 18.9 vs. 60.8 ± 17.8 vs. 63.4 ± 17.4^b)

Between-group comparisons

↓ Angina as a reason to stop cardiopulmonary exercise test in IHHE compared to sham IHHE (1-month follow-up: 3 vs. 6)

↑ Exercise time (modified Bruce protocol) in IHHE compared to sham IHHE (post-test: 383 ± 141 s vs. 280 ± 92)

↑ VO_2peak in IHHE compared to sham IHHE (1-month follow-up: 15.4 ± 4.5 ml-O₂/min/kg vs. 17.8 ± 4.9 ml-O₂/min/kg)

↑ Reticulocytes in IHHE compared to sham IHHE (post-test: 11.3 ± 6.2% vs. 6.4 ± 3.6%; 1-month follow-up: 9.2 ± 4.8% vs. 5.11 ± 3.13%)

↓ Total cholesterol in IHHE compared to sham IHHE (post-test 5.1 ± 1.2 mmol/L vs. 5.5 ± 0.9 mmol/L)

↓ Low-density lipoprotein in IHHE compared to sham IHHE (post-test: 3.2 ± .9 mmol/L vs. 3.6 ± 0.8 mmol/L; 1-month follow-up: 2.6 ± 1.3 mmol/L vs. 3.5 ± 0.8 mmol/L)

↓ Atherogenic index in IHHE compared to sham IHHE (post-test: 3.4 ± 1.3 vs. 3.6 ± 1.1)

↑ Atherogenic index in IHHE compared to sham IHHE (1-month follow-up: 3.5 ± 1.5 vs. 3.4 ± 1.0)

Susta et al. [108]

Physical functions

Cardiopulmonary exercise test

Cardiovascular hemodynamic parameters

 Inotropic reserve index (IRI, (maximal systolic blood pressure − resting systolic blood pressure) ÷ resting systolic blood pressure)

 Chronotropic reserve index (CRI, (maximal heart rate − resting heart rate) ÷ resting heart rate)

Resting heart rate and heart rate variability

Cardiovascular hemodynamic parameters

 Inotropic reserve index (IRI, (maximal systolic blood pressure − resting systolic blood pressure) ÷ resting systolic blood pressure)

 Chronotropic reserve index (CRI, (maximal heart rate − resting heart rate) ÷ resting heart rate)

Resting heart rate and heart rate variability

Blood markers

Red blood cell count, reticulocyte, haemoglobin concentration, and haematocrit

Hypoxia test (10 min at F_iO₂ = 0.10)

Oxygen saturation (S_pO₂) Maximal heart rate (HR_max)

Within-group comparisons (pre-test vs. post-test)

↑ PWC170 in IHHE (170.8 ± 44.8 W vs. 191.9 ± 26.9 W)

↓ IRI in IHHE (65.8 ± 3.6% vs. 54.8 ± 5.4%)

↓ CRI in IHHE (50.0 ± 5.3% vs. 38.0 ± 5.9%)

↑ S_pO₂ during hypoxic test in IHHE (77.9 ± 6.8% vs. 84.2 ± 5.7%)

↓ HR_max during hypoxic test in IHHE (82.2 ± 14.6 beats/min vs. 76.6 ± 11.0 beats/min)

↑ Standard deviation of R–R intervals in IHHE (54.0 ± 24.7 ms vs. 76.0.2 ± 26.8 ms)

↓ Low frequency power in IHHE (1300 ± 661 ms² vs. 801 ± 673 ms²)

↑ High frequency power in IHHE (277 ± 188 ms² vs. 624 ± 468 ms²)

↓ Low frequency to high frequency index in IHHE (8.01 ± 7.51 vs. 1.45 ± 1.71)

Between-group comparisons

↓ PWC170 in IHHE compared to control group (pre-test: 170.8 ± 44.8 W vs. 204.2 ± 13.8 W; post-test: 191.9 ± 26.9 W vs. 278.0 ± 19.3 W)

↑ IRI in IHHE compared to control group (pre-test: 65.8 ± 3.6% vs. 50.8 4.1%; post-test: 54.8 ± 5.4% vs. 49.6 3.8%)

↑ CRI in IHHE compared to control group (pre-test: 50.0 ± 5.3% vs. 37.5 ± 4.9%)

↓ S_pO₂ during hypoxic test in IHHE compared to control group (pre-test: 77.9 ± 6.8% vs. 83.7 ± 9.0%)

↑ HR_max during hypoxic test in IHHE compared to control group (pre-test: 82.2 ± 14.6 beats/min vs. 79.7 ± 13.1 beats/min)

↓ R–R intervals in IHHE compared to control group (post-test: 890 ± 160 ms vs. 990 ± 180 ms)

↓ Standard deviation of R–R intervals in IHHE (54.0 ± 24.7 ms vs. 82.0 ± 24.8 ms)

↑ HR_rest in IHHE compared to control group (post-test: 67.1 ± 13.7 beats/min vs. 60.4 ± 4.6 beats/min)

↓ High frequency in IHHE compared to control group (pre-test: 277 ± 188 ms vs. 1100 ± 344 ms²; post-test: 624 ± 468 ms² vs. 1167 ± 501 ms²)

↑ Low frequency to high frequency index in IHHE compared to control group (pre-test: 8.01 ± 7.51 vs. 2.2 ± 1.0)

Dudnik et al. [109]

Physical functions

Cardiopulmonary exercise test

Cardiovascular hemodynamic parameters

Resting heart rate

Resting systolic and diastolic blood pressure

Blood markers

Red blood cells count, white blood cell count, platelets, haemoglobin concentration, reticulocytes

Within-group comparisons (pre-test vs. post-test)

↑ VO_2peak in IHHE (13.9 ± 2.5 ml-O₂/min/kg vs. 19.9 ± 6.1 ml-O₂/min/kg)

Between-group comparisons

↑ Reticulocytes in IHHE compared to sham IHHE (post-test: 1.1 ± 0.5% vs. 0.6 ± 0.3%)

Interaction effects (group × time)

↓ Diastolic blood pressure in IHHE compared to sham IHHE (pre-test: 82.1 ± 11.1 mmHg vs. 77.9 ± 9.7 mmHg; post-test: 74.7 ± 8.9 mmHg vs. 82.0 ± 9.3 mmHg)

Glazachev et al. [110]

Physical functions

Cardiopulmonary exercise test

Blood markers

Total cholesterol, high and low-density lipoprotein, triglycerides, and glucose

Quality of life

Medical Outcome Study 36-item Short Form Health Survey (MOS SF-36)

Seattle Angina Questionnaire (SAQ)

Within-group comparisons (pre-test vs. post-test vs. 1-month follow-up)

↑ Time to exhaustion in cardiopulmonary exercise test (modified Bruce protocol) in IHHE (303 ± 147 s vs. 362 ± 124 s^a vs. 342 ± 113 s)

↑ Metabolic equivalent in IHHE (3.5 ± 1.2 vs. 39.1 ± 1.0 s vs. 4.2 ± 1.2 s)

↑ VO₂ at anaerobic threshold in IHHE (11.5 ± 1.3 ml-O₂/min/kg vs. 13.8 ± 2.0 ml-O₂/min/kg^a vs. 13.8 ± 0.3 ml-O₂/min/kg^b)

↑ MOS SF-36 physical functioning subscale in IHHE (84.2 ± 13.0 vs. 55.7 ± 12.0^a vs. 51.7 ± 14.0)

↑ MOS SF-36 role physical subscale in IHHE (47.0 ± 17.8 vs. 61.7 ± 18.8^a vs. 55.8 ± 19.0)

↑ MOS SF-36 body pain subscale in IHHE (22.0 ± 39.4 vs. 48.5 ± 43.7 vs. 58.8 ± 39.0^b)

↑ MOS SF-36 vitality subscale in IHHE

Between-group comparisons

↑ MOS SF-36 physical functioning subscale in IHHE compared to sham IHHE (post-test: 61.7 ± 18.8 vs. 47.5 ± 11.9)

↑ MOS SF-36 body pain subscale in IHHE compared to sham IHHE (post-test: 48.5 ± 43.7 vs. 27.3 ± 8.9)

↑ metabolic equivalent in IHHE compared to sham IHHE (post-test: 3.5 ± 0.9 vs. 3.8 ± 1.0)

↑ VO_2peak in IHHE compared to sham IHHE (post-test: 16.9 ± 1.4 ml-O₂/min/kg vs. 12.0 ± 6.3 ml-O₂/min/kg)

Serebrovska et al. [66]

Blood markers

Total cholesterol, high- and low-density lipoprotein, and triglycerides

Fasting glucose level and 2 h post-oral glucose tolerance test glucose level

Hypoxia test (20 min at F_iO₂ = 0.10)

Oxygen saturation (S_pO₂)

Maximal heart rate (HR_max)

Within-group comparisons (pre-test vs. post-test vs. 1-month follow-up)

↑ Minimum S_pO₂ during hypoxic test in IHHE (79.4 ± 3.8% vs. 81.5 ± 3.9^a % vs N.R.^b)

↓ Fasting glucose in IHHE and IHE (IHHE: 6.3 ± 0.5 mmol/L vs. 5.8 ± 0.7 mmol/L^a vs. 5.3 ± 0.8 mmol/L^b; IHE: 6.5 ± 0.4 mmol/L vs. 5.4 ± 0.5 mmol/L^a vs. 5.1 ± 0.6 mmol/L^b)

↓ 2-h post-oral glucose tolerance test glucose level in IHHE and IHE (IHHE: 7.9 ± 0.9 mmol/L vs. 6.8 ± 1.0 mmol/L^a vs. 6.4 ± 1.3 mmol/L^b; IHE: 8.3 ± 1.0 mmol/L vs. 7.0 ± 1.9 mmol/L^a vs. 6.4 ± 1.1 mmol/L^b)

↓ Total cholesterol in IHHE and IHE (IHHE: 6.3 ± 1.1 mmol/L vs. 5.7 ± 1.0 mmol/L^a vs. 6.1 ± 1.3 mmol/L; IHE: 6.2 ± 1.2 mmol/L vs. 5.3 ± 0.9 mmol/L^a vs. 5.8 ± 1.2 mmol/L)

↓ Low-density lipoprotein cholesteral in IHHE and IHE (IHHE: 4.2 ± 1.3 mmol/L vs. 3.5 ± 1.0 mmol/L^a vs. 3.5 ± 1.3 mmol/L^b; IHE: 4.0 ± 1.3 mmol/L vs. 3.3 ± 1.0 mmol/L^a vs. 3.4 ± 1.0 mmol/L)

Between-group comparisons

↓ Fasting glucose in IHHE compared to sham IHHE (1-month follow-up: 5.3 ± 0.8 mmol/L; vs 6.1 ± 0.8 mmol/L)

↓ Fasting glucose in IHE compared to sham IHHE (post-test: 5.4 ± 0.5 mmol/L vs. 6.12 ± 0.8 mmol/L; 1-month follow-up: 5.1 ± 0.6 mmol/L vs. 6.1 ± 0.8 mmol/L)

↓ 2-h post-oral glucose tolerance test glucose level in IHHE compared to sham IHHE (post-test: 6.8 ± 1.0 mmol/L vs. 8.3 ± 1.1 mmol/L; 1-month follow-up: 6.4 ± 1.3 mmol/L vs. 8.2 ± 1.2 mmol/L)

↓ 2-h post-oral glucose tolerance test glucose level in IHE compared to sham IHHE (post-test: 7.0 ± 1.9 mmol/L vs. 8.3 ± 1.1 mmol/L; 1-month follow-up: 6.4 ± 1.1 mmol/L vs. 8.2 ± 1.2 mmol/L)

↓ Total cholesterol in IHE compared to sham IHHE (1-month follow-up: 5.3 ± 0.9 mmol/L vs. 6.2 ± 0.9 mmol/L)

Serebrovska et al. [111]

Cognitive functions

Montreal Cognitive Assessment Test (MoCA)

Long latency cognitive event-related potential (P300, N200)

Blood markers

Amyloid-β and amyloid precursor protein (APP130, APP110, and APP110/APP130 ratio)

Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1)

Stimulated neutrophil extracellular traps formation in peripheral blood (NET_st)

Within-group comparisons (pre-test vs. post-test vs. 1-month follow-up)

↑ MoCA test score in IHHE (19.6 ± 1.6% vs. 22.1 ± 1.7%^a vs. 21.3 ± 1.6%)

↑ APP130 in IHHE (0.4 ± 0.1 r.U. vs. 0.7 ± 0.1 r.U.^a vs. 0.6 ± 0.1 r.U.^b)

↑ APP110 in IHHE (0.6 ± 0.1 r.U. vs. 0.7 ± 0.1 r.U.^a vs. 0.8 ± 0.1 r.U.^b)

↑ APP-ratio in IHHE (0.7 ± 0.1 vs. 0.9 ± 0.1^a vs. 0.8 ± 0.1)

↓ Amyloid-β in IHHE (2.6 ± 0.3 r.U. vs. 2.2 ± 0.4 r.U.^a vs. 2.1 ± 0.4 r.U.^b)

↓ NET_st in IHHE (12.7 ± 6.2% vs. 8.8 ± 3.3% vs. 6.1 ± 3.5%^b)

↓ NET_ns in IHHE (9.5 ± 2.1% vs. 4.5 ± 1.1%^a vs. 4.2 ± 1.3%^b)

↓ BACE1 in IHHE (85.3 ± 55.6 r.U. vs. 36.8 ± 34.6 r.U.^a vs. 45.6 ± 32.8 r.U.)

Between-group comparisons

↑ APP130 in IHHE compared to sham IHHE (post-test: 0.7 ± 0.1 r.U. vs. 0.4 ± 0.1 r.U.; 1-month follow-up: 0.6 ± 0.1 r.U. vs. 0.4 ± 0.1 r.U.)

↑ APP110 in IHHE compared to sham IHHE (post-test: 0.7 ± 0.1 r.U. vs. 0.5 ± 0.1 r.U.; 1-month follow-up: 0.8 ± 0.1 r.U. vs. 0.5 ± 0.1 r.U.)

↑ APP-ratio in IHHE compared to sham IHHE (post-test: 0.9 ± 0.1 vs. 0.8 ± 0.1)

↑ Amyloid-β in IHHE compared to sham IHHE (post-test: 2.2 ± 0.4 r.U. vs. 2.8 ± 0.4 r.U.; 1-month follow-up: 2.1 ± 0.4 r.U. vs. 2.8 ± 0.2 r.U.)

↓ NET_st in IHHE (1-month follow-up: 6.1 ± 3.5% vs. 11.2 ± 3.6%)

↓ NET_ns in IHHE (post-test: 4.5 ± 1.1% vs. 9.22 ± 3.9%; 1-month follow-up: 4.2 ± 1.3% vs. 8.25 ± 2.0%)

↓ BACE1 in IHHE (85.3 ± 55.6 r.U. vs. 36.8 ± 34.6 r.U.^a vs. 45.6 ± 32.8 r.U.)

Bestavashvili et al. [112]

Anthropometric parameters

Body mass index (BMI)

Waist circumference

Hip circumference

Blood markers

Total cholesterol, high- and low-density lipoprotein, and triglycerides

Alanine aminotransferase (ALT)

Aspartate aminotransferase (AST)

Galectin-3

Nitric oxide synthase 2 (NOS2)

Heat shock proteins (Hsp70)

Transforming growth factor beta-1 (TGF beta-1)

Heart-type fatty acid binding protein (H-FABP)

High-sensitive C-reactive protein (CRP-hs)

N-Terminal pro-hormone of brain natriuretic peptide (NTproBNP)

Within-group comparisons (pre-test vs. post-test)

↓ BMI in IHHE (34.2 ± 5.2 kg/m² vs. 33.3 ± 5.2 kg/m²)

↓ Waist circumference in IHHE (116.2 ± 11.2 cm vs. 111.0 ± 10.6 cm)

↓ Hip circumference in IHHE (114.1 ± 9.4 cm vs. 110.3 ± 9.4 cm)

↑ Total cholesterol in sham IHHE (4.8 ± 1.2 mmol/L vs. 5.1 ± 1.1 mmol/L)

↓ ALT in IHHE (37.3 ± 26.1 u/L vs. 29.0 ± 15.3 u/L)

↓ HSP70 in IHHE (0.963 ± 0.316 ng/mL vs. 0.865 ± 0.334 ng/mL)

↓ CRP-hs in IHHE (3.608 ± 3.448 mg/L vs. 2.237 ± 1.527 mg/L)

↓ NTproBNP in IHHE (27.5 ± 45.1 pmol/L vs. 20.4 ± 34.2 pmol/L)

Between-group comparisons

↓ ALT in IHHE compared to sham IHHE (post-test: 29.0 ± 15.3 u/L vs. 36.2 ± 21.5 u/L)

↓ NTproBNP in IHHE compared to sham IHHE (post-test: 20.4 ± 34.2 pmol/L vs. 34.9 ± 62.1 pmol/L)

↓ Δ-BMI in IHHE compared to sham IHHE (-0.9 ± 0.5 vs. 0.3 ± 0.6)

↓ Δ-Waist circumference in IHHE compared to sham IHHE (− 5.2 ± 2.4 vs. 0.7 ± 1.8)

↓ Δ-Hip circumference in IHHE compared to sham IHHE (− 3.8 ± 1.7 vs. 3.4 ± 1.0)

↓ Δ-Total cholesterol in IHHE compared to sham IHHE (− 0.8 ± 0.8 vs. 0.3 ± 0.1)

↓ Δ-Triglyceride in IHHE compared to sham IHHE (− 0.3 ± 0.4 vs. 0.1 ± 0.5)

↓ Δ-Low-density lipoprotein in IHHE compared to sham IHHE (− 0.8 ± 0.7 vs. 0.3 ± 0.8)

↓ Δ-ALT in IHHE compared to sham IHHE (− 8.3 ± 14.6 vs. 5.4 ± 9.2)

↓ Δ-AST in IHHE compared to sham IHHE (− 4.5 ± 12.1 vs. 3.2 ± 6.3)

↓ Δ-NTproBNP in IHHE compared to sham IHHE (− 7.1 ± 13.6 vs. 9.0 ± 18.0)