The effects of aerobic and anaerobic exercises on circulating soluble-Klotho and IGF-I in young and elderly adults and in CAD patients.

Different studies support the notion that chronic aerobic exercises training can influence the circulating levels of soluble-Klotho (s-Klotho) and insulin-like growth factor 1 (IGF-I). The effects of s-Klotho include improving the quality of life, alleviating the negative impact of age on the body's work capacity, and possibly increasing longevity. This review provides an overview of the latest findings in this field of research in humans. The different modes of dynamic exercise and their impact on circulating levels of s-Klotho and IGF-I in young adult athletes, untrained young adults, trained healthy older adults, untrained healthy older adults, and coronary artery disease (CAD) patients are reviewed and discussed. Together these findings suggest that long-lasting (chronic) aerobic exercise training is probably one of the antiaging factors that counteract the aging and CAD process by increasing the circulating s-Klotho and lowering the IGF-I levels. However, following anaerobic exercise training the opposite occurs. The exact metabolic and physiological pathways involved in the activity of these well-trained young and master sportsmen should be further studied and elucidated. The purpose of this review was to provide a clarification regarding the roles of s-Klotho and intensities and durations of different exercise on human health.

GNAS A-1121G variant is associated with improved diastolic dysfunction in response to exercise training in heart failure patients.

ß1-adrenergic receptors (ADRB1) and Gαs proteins (GNAS) play important roles in the regulation of cardiac function. The present study sought to investigate whether ADRB1 Arg389Gly (rs1801253), GNAS -1211 G/A (rs6123837) and GNAS 2291 C/T (rs6026584) variants are associated with left ventricular function and exercise tolerance in heart failure patients. 61 heart failure patients completed a 6-month exercise-training programme. Left ventricular ejection fraction (LVEF), mitral inflow velocities (deceleration time, and E/A ratio) and exercise tolerance (METs) were assessed at baseline and following exercise training. There were no associations between the studied variants and LVEF or E/A ratio measured at baseline and after exercise training. Deceleration time of early mitral flow was higher at baseline in GNAS -1211G allele carriers compared with -1211A allele homozygotes (P<0.05). Exercise training attenuated deceleration time in -1211G allele carriers (P<0.05) but not in -1211A allele homozygotes. Moreover, ADRB1 389Gly homozygotes had a greater training-induced increase in exercise tolerance than 389Arg homozygotes (P=0.04). This study shows that the functional GNAS -1121 G/A polymorphism is associated with diastolic function at baseline and in response to exercise training in heart failure patients. Furthermore, our data suggest that ADRB1 Arg389Gly polymorphism may influence exercise tolerance.

Effect of different sprint training regimes on the oxygen delivery-extraction in elite sprinters.

AIM: The effects of sprint training regimes of varying distance schedules on the oxygen delivery-extraction relationship were investigated in 15 young (22+/-1 years) healthy males national-level sprinters. METHODS: During one session subjects performed four sprints, in a schedule of increasing distance order (100, 200, 300 and 400 m), and during the other session, in a schedule of decreasing distance order (400, 300, 200, and 100 m). All sprint bouts were performed on a treadmill at a speed of 22 km/h-1, which corresponds to 85% of subjects' maximal speeds. The order of the running sequences during sessions was balanced over subjects. RESULTS: During both sprint schedules, all variables except for oxygen extraction in the incremented training regime, increased significantly from rest to exercise. Training regimes were not different with regard to cardiac output and absolute oxygen uptake. However, the decreasing compared to the increasing scheme was characterized by significantly (P<0.05) higher mean values of heart rate (194.5+/-4.1 185.2+/-5.7 beats/min-1, respectively), oxygen extraction (54.3+/-3.8 and 47.1+/-3.4 mL/L-1, respectively) and lactate (10.6+/-0.5 and 9.2+/-0.7 mmol/L-1, respectively), while stroke volume was significantly (P<0.05) lower (100.4+/-4.5 and 109.7+/-4.4 mL, respectively). CONCLUSION: The present study indicates that in sprinters performing a similar distance at the same speed, but under different training regimes interplay exists between oxygen delivery and extraction, suggesting a link between the type of training scheme and physiological cardiovascular and skeletal muscle metabolic adaptations. This may explain the absence of differences between the conditions in absolute oxygen uptake and peak power output.

CK-MM gene polymorphism does not influence the blood CK activity levels after exhaustive eccentric exercise.

Gene variants, such as creatine kinase (CK) polymorphisms, have been suggested to explain the inter-individual blood CK response to eccentric exercise. However, since this association is still doubtful, the purpose of this study was to analyse the relationship between the magnitudes of the CK response to exercise with the occurrence of muscle CK-MM NcoI polymorphism in young healthy subjects. Blood CK activity was assessed in 70 subjects immediately before and 3, 24, 48, 72, 96, 120, 168 h after strenuous eccentric exercise. Based on the amount of CK release by each subject, the sample was distributed in quartiles and the genotype and allele frequency distribution was compared among quartiles. Despite the inter-individual variability of CK response observed between subjects, there were no differences in genotype and allele frequencies among quartiles. The results allowed us to conclude that CK response after exhaustive eccentric exercise is not associated with CK-MM Ncol polymorphism.

Do PPARGC1A and PPARalpha polymorphisms influence sprint or endurance phenotypes?

Functional Gly482Ser (rs8192678) and G/C (rs4253778) polymorphisms in the Peroxisome proliferator-activated receptor gamma coactivator1 (PPARGC1A) and Peroxisome proliferator-activated receptor alpha (PPARalpha) genes, respectively, have been associated with mRNA and protein activity. The aim of this study was to determine their frequency distribution among 155 Israeli athletes (endurance athletes and sprinters) and 240 healthy controls. Results showed that there was a significant difference in PPARGC1A Ser482Gly polymorphism genotype frequencies between endurance athletes and sprinters (P=0.005) as well as between endurance athletes and controls (P=0.0003). However, the sprinters' genotype and allele frequencies were similar to that of the control group. A significantly lower proportion of PPARGC1A Ser482 allele (0.25) was noted for the endurance athletes compared with controls (0.43, P=0.0001). Endurance athletes showed a trend of a higher yet a not significant proportion of the PPARalpha GG genotype compared with sprinters (P=0.051). As we compared between the subgroups of top-level endurance athletes and top-level sprinters, as well as between those of top-level and national-level endurance athletes, we reached more prominent results. In conclusion, our data indicate that a lower frequency of the Ser482 allele and possibly a higher frequency of the GG genotype are associated with increased endurance performance ability.

Is there an ACE ID - ACTN3 R577X polymorphisms interaction that influences sprint performance?

Functional R577X (rs.1815739) and ID (rs.5186) polymorphisms in the alpha-actinin-3 ( ACTN3) and the angiotensin converting enzyme (ACE) genes, respectively, have been associated with sprint performance. The aim of this study was to determine their effect on sprint performance among 81 Israeli sprinters and 240 healthy controls. Results revealed that the ACE II genotype+ ACTN3 R allele (P=0.003 for sprinters vs. controls), and the ACTN3 RR genotype +ACE I allele (P=0.001 for sprinters vs. controls) might be the genotype for sprinters. In the whole cohort the probability of ACTN3 RR genotype+ ACE I allele being a sprinter (odds ratio 2.67, 95% confidence interval 1.45-4.93) and of ACE II genotype+ ACTN3 R allele being a sprinter (odds ratio 3.57, 95% confidence interval 1.78-7.15) was significantly higher than that in the controls. In conclusion, the above data suggest that ACE ID/ ACTN3 R577X genotype combination is associated with sprint ability. However, ACE ID/ ACTN3 R577X genotype combination is not related to the level of performance.

ACTN3 R577X polymorphism and Israeli top-level athletes.

A common genetic variation in the alpha-actinin-3 ( ACTN3) gene causes a replacement of an arginine (R) with a premature stop codon (X) at amino-acid 577 (rs1815739). While the R allele has been found to be associated with power-oriented performance, the XX genotype may be linked with endurance ability. To test this hypothesis, we studied the distribution of ACTN3 genotypes in 155 Israeli athletes (age=35.9+12.2 years) classified by sport (endurance runners and sprinters) and in 240 sedentary individuals. The sprinters' allele frequencies (AF: R/X=0.7/0.3) and 577RR genotype distribution percentage (GD: RR=52%) differed markedly from those of the endurance athletes (AF: R/X=0.53/0.47, p=0.000007; GD: RR=18%, p=0.00009) and the control group (AF: R/X=0.55/0.45, p=0.0002; GD: RR=27.3%, p=0.000003). A comparison between the top-level and national-level sprinters revealed that the R allele occurs more often in the top-level sprinters. A significantly higher proportion of the XX genotype was observed in endurance athletes (34%) compared with controls (18%, p=0.02) and sprinters (13%, p=0.002). However, top-level and national level endurance athletes had similar allele and genotype frequencies. We conclude that the ACTN3 R allele is associated with top-level sprint performance and the X allele and XX genotypes may not be critical but rather additive to endurance performance.

Acute incremental exercise to maximal performance does not cause alterations in serum oxidant levels of healthy young individuals.

AIM: This study was designed to analyze serum oxidative stress (OS) levels in healthy young individuals performing a routine maximal aerobic exercise and to evaluate the correlation between OS levels and physiological parameters. METHODS: Serum OS levels were studied by thermochemiluminescence (TCL) parameters at rest and following maximal aerobic exercise in 85 healthy young subjects. Levels were measured by a real time on line TCL assay (higher TCL-Ratio and TCL-H3 = lower OS level). RESULTS: Aerobic capacity had no effect on baseline OS levels. Post-exercise OS levels correlated with maximal oxygen uptake (V.O(2max)) (P<0.005), delta V.O(2) (V.O(2max)- V.O(2)rest) (P<0.005), anaerobic threshold (VTH) (P<0.01), and total oxygen uptake (especially O(2) after VTH), (P<0.005). TCL-Ratio was related to total running time (P<0.01), as well. Post-exercise OS levels for the whole study group did not vary from baseline values. However, individuals with higher fitness level (V.O(2max) >percentile 60) had significantly lower values of TCL-H3 (P=0.04) and tended to have lower TCL-Ratio, indicating they had elevated OS levels. In a multivariate analysis OS level was most affected by V.O(2) after VTH (anaerobic phase of the test) (P=0.003; adjusted odds ratio of 3.41, 95% confidence interval: 1.55-7.48). CONCLUSIONS: In conclusion, acute incremental exercise to maximal performance does not cause alterations in serum oxidant levels of healthy young individuals. In healthy individuals performing maximal aerobic exercise, OS levels correlate with maximal aerobic power.

Effects of different sprint cycling bouts on left ventricular function in top cyclists.

AIM: The study investigated lactic acid and left ventricular function in response to two different sprint cycling schedules varying in their time schedule, in 15 healthy national level cyclists (23+/-1 years). METHODS: During one testing session subjects performed four strenuous bouts in a schedule of increasing time order: 1, 2, 3 and 4 min. In the other session, they performed a decreasing order: 4, 3, 2 and 1 min. Resting time between bouts in the increasing schedule were 2, 3, and 4 min, respectively. Resting times for the decreasing schedules were 4, 3 and 2 min, respectively. Exercise bouts were performed on an electrical cycle ergometer at 85% of each subject's maximal speed velocity. RESULTS: In both sprint cycling schemes, mean end-systolic volume and mean end-diastolic volume decreased significantly (P < 0.05) with bout's time. However, there was a significant interaction effect regarding schedule order and lactate accumulation. In the incremented scheme, lactate accumulated gradually during the session, while a high level of lactate was maintained throughout the decremented scheme (from 3.8+/-0.7 to 11.8+/-1.8 and from 9.5+/-1.5 to 10.8+/-1.9 mmol.L-1, respectively). Furthermore, analysis of cardiac function during the two schemes demonstrates different physiological responses. The decreasing scheme was characterized by a higher mean heart rate, a lower mean stroke volume and a lower mean end-diastolic volume (P < 0.05) indicating that during the two schemes, the functional mechanisms underlying cardiac response, are different. CONCLUSION: Our data suggest that in the face of high levels of lactic acid, during the decreasing scheme, venous return may be impeded, most likely due to reduced left ventricular filling time and inadequate vasodilatation of the arteries during the early phase of cycling bout. In addition, it suggests that the decreasing scheme may yield a better anaerobic and cardiovascular training method.

Weight lifting training and left ventricular function in adolescent subjects.

AIM: Training during adolescence may influence the myocardium's adaptation. Effects of exercise training on left ventricular function differ depending whether they result from pressure or volume overload. Accordingly, the present study was designed to examine, by echocardiography studies, the effects of endurance versus weight lifting training modes on left ventricular contractility in healthy adolescent boys. METHODS: Sixty healthy adolescent boys were randomly and evenly divided into 3 groups: weightlifting training, run-training, and control. Exercising groups underwent 28-week training programs, 3-4 times a week, 35 min each session. The weight lifting program for consisted of training on 6 dynamic resistive machines at resistance corresponding to 6-repetition maximum. The running program was composed of aerobic exercise training at 65% of their VO(2max). RESULTS: At rest, only in the runners end diastolic volume and end systolic pressure-volume ratio differed significantly (P<0.05) from pre- to post-testing. During post-testing session at peak exercise, runners compared to weightlifters demonstrated improvement respectively in: wall stress (245+/-42 and 290+/-35 103 dyn.cm(2)), end systolic pressure-volume ratio (7.2+/-.7 and 6.4+/-.5 ratio) and ejection fraction (82+/-5% and 76+/-5%). Maximal oxygen uptake (48.2+/-3.2 and 43.8+/-3.5 mL.kg(-1).min(-1)), also improved significantly (P<0.05). Maximal load was significantly (P<0.05) higher in the runners and weight lifters than in the control group with significantly (P<0.05) higher values for the weight lifters than runners. CONCLUSION: This study has showed that in adolescent boys the mode of exercise training leads to significant differences in left ventricular function and contractility, related to differences in volume-after-load relationship and not to fundamental differences in the properties of the myocardium.

Effects of gradient and load carried on human haemodynamic responses during treadmill walking.

This study examined the effects of different loads carried and gradients, on haemodynamic and cardiovascular responses during 45 min of treadmill walking. A group of 20 male endurance-trained athletes [mean maximal oxygen uptake 61.4 (SD 4) ml x kg(-1) x min(-1)] volunteered for this study. The subjects took part in three separate trials. The first involved a backpack weighing 25 kg, the second a 35 kg backpack, and the third trial, unladen, while walking on a treadmill at a speed of 5 km x h(-1). The subjects began walking on the treadmill with the randomized load at 0% gradient. After 15 min, the gradient was increased by 5% every 15 min for a total of 45 min. The order of the loads carried was randomized among subjects. No significant differences were noted for all the variables measured attributable to loads between 25 kg and 35 kg. However, significant (P<0.05) differences were seen for all variables each time the gradient was increased. Cardiac output increased from 11.4 (SD 0.6) 1 x min(-1) at 0% to 13.6 (SD 0.8) l x min(-1) at 5% and to 17.6 (SD 1.3) l x min(-1) at 10% carrying the 35 kg load. Similarly, lactic acid concentrations in the blood increased from 2.8 (SD 0.2) to 3.1 (SD 0.6) and to 5.3 (SD 1.3) mmol x l(-1), respectively. Similar changes were observed for all variables while carrying the 25 kg load. In addition, steady states in oxygen uptake and other physiological variables were obtained throughout the course of the tests. These data suggest that during isodynamic exercise, one of the main factors determining metabolic and haemodynamic responses will be the change in gradient and to a lesser extent, the mass of the load carried.

Role of physical activity training in attenuation of height loss through aging.

BACKGROUND: Although the genetic contribution to variability in bone mass has been estimated to be as high as 80%, evidence continues to accumulate suggesting that factors such as physical activity can influence bone mass which may avoid compression of the vertebrae leading to slower stature decline with age. OBJECTIVES: This study examines whether regular exercise has the potential of positively affecting the aging process with regard to height loss. METHODS: The height of 957 females and 1,088 males who were 35-55 years of age in 1965 were measured again in 1995. Based on a questionnaire, the subjects were divided into four groups. Group A (80 females, aged 73. 2 +/- 6 years, and 141 males, aged 72.1 +/- 5.7 years) represented subjects who were engaged in moderate vigorous aerobic activity throughout their lives; group B (95 females, aged 73.6 +/- 5.5 years, and 207 males, aged 71.7 +/- 6.1 years) were subjects who started their moderate vigorous aerobic activity around the age of 40 and kept their activity until the present time; group C (362 females, aged 73.2 +/- 5 years, and 390 males, aged 71.1 +/- 6 years) were persons who were active as young adults, but did not continue to exercise, and group D (425 females, aged 72.8 +/- 5.3 years, and 350 males, aged 70.9 +/- 6.1 years) were subjects who had not exercised regularly throughout their lives. RESULTS: All subjects lost height due to aging. However, significant (p < 0.05) differences in rate of height loss were found among the A, B, C, and D groups: for females 3.4 +/- 0.7, 3.5 +/- 0.8, 6.0 +/- 0.5, and 6.5 +/- 0.7 cm, respectively; for males 2.6 +/- 0.5, 3.1 +/- 0.4, 5.3 +/- 0.4, and 5. 5 +/- 0.5 cm, respectively. In addition, the females' height loss rate was significantly (p < 0.05) higher than that of the males in all four activity categories. CONCLUSIONS: These data suggest that lifelong moderate endurance training, especially after the age of 40 years, is associated with attenuation of height loss in both sexes. However, the magnitude of the attenuation is significantly higher in males.

Left ventricular contractility and function at peak aerobic and anaerobic exercises.

PURPOSE: The present study compared and evaluated left ventricular function and contractility at peak incremental aerobic type exercise and all-out explosive anaerobic effort in young healthy trained subjects. METHODS: Twenty-two young healthy trained subjects (19 +/- 1 yr) were studied by two-dimensional direct M-mode echocardiography at peak aerobic and at peak all-out anaerobic exercises, performed on cycle ergometer. RESULTS: All subjects completed the study without any electrocardiographic abnormalities. Significant (P < 0.05) differences between the aerobic and the anaerobic efforts were noted for peak cardiac output (24 +/- 2.0 and 15.0 +/- 1.1 L x min (-1), respectively), left ventricular pressure-volume ratio (5.8 +/- 0.6 and 4.7 +/- 0.5 respectively), end systolic volume (33 +/- 4 and 42 +/- 5 mL, respectively), ejection fraction (79 +/- 7 and 66 +/- 5%, respectively), and total peripheral resistance (TPR) (367 +/- 90 and 704 +/- 90 dynes x s(-1) x cm(- 5), respectively). CONCLUSIONS: These data suggest that left ventricular at peak all out anaerobic effort differed markedly from those observed at peak aerobic exercise. These differences are presumably due to the different after-load responses between the two exercise modes. Therefore, it is suggested that anaerobic-type effort should be performed with great caution in normal young healthy subjects.

Dilated inferior vena cava: a common echocardiographic finding in highly trained elite athletes.

Typical structural features of the athlete's heart as defined by echocardiography have been extensively described; however, information concerning extracardiac structures such as the inferior vena cava (IVC) is scarce. Fifty-eight top-level athletes and 30 healthy members of a matched control group underwent a complete Doppler echocardiographic study. IVC diameter was determined in the subxiphoid approach 10 to 20 mm away from its junction to the right atrium. Measures reflect the median values between maximal inspiratory and expiratory values. IVC respiratory collapsibility index was determined as well. IVC in athletes was 2.31 +/- 0.46 cm compared with 1.14 +/- 0.13 cm in the control group (P <.001). Swimmers had an IVC diameter of 2.66 +/- 0.48 cm compared with 2.17 +/- 0.41 cm in other athletes (P <.05). The IVC was normal (/=2.6 cm) in 24.1% of athletes. The collapsibility index was 58% +/- 6.4% in athletes compared with 70.2% +/- 4.9% in the control group (P <. 001). Correlation was found between IVC size and VO(2) max (r = 0.81, P <.001) and the right ventricle (r = 0.81, P <.001) and with collapsibility index (r = -0.57, P <.05). Multiple regression analysis showed the impact of VO(2) max, cardiac index, and right ventricular and left ventricular end-diastolic dimensions on IVC diameter. IVC dilatation probably represents adaptation of an extracardiac structure to chronic strenuous exercise in top-level, elite athletes.

Direct vs. indirect blood pressure measurement at peak anaerobic exercise.

The present study compared the direct intra-arterial method with the indirect conventional sphygmomanometer during all-out anaerobic exercise, in young healthy subjects. Systolic and diastolic blood pressures were measured by intraarterial means and by auscultation. Fourteen young healthy males (23+/-2 yrs) were measured at rest and during all-out anaerobic exercise. Comparisons were made with simultaneously determined intra-arterial catheter and auscultation measurements. The data suggest that indirect systolic pressure is highly correlated with the direct method at rest (r = 0.684), with mean of 107+/-7 and 101+/-6 mmHg, respectively, and during all-out anaerobic exercise (r = 0.87), with mean of 197+/-11 and 191+/-9 mmHg, respectively. Indirect diastolic blood pressure correlates well with intra-arterial at rest (r = 0.62), with mean of 84+/-11 and 77+/-9 mmHg, respectively. However, during all-out anaerobic exercise, the correlation coefficient between the direct and the indirect methods was low (r = 0.36), with mean of 101+/-12 and 103+/-9 mmHg, respectively. These results suggest that when utilizing an all-out anaerobic exercise, the indirect method is not valid for assessment of diastolic pressure. In addition, although the anaerobic test is a dynamic type of exercise, its blood pressure responses for both direct and indirect methods were similar to those seen during isometric exercise.

Perceptual responses to exercise: the effect of load-awareness on physiological responses during an isometric bout.

To evaluate the effect of awareness of load on cardiovascular and metabolic responses, thirty males were compared in three different loads during upright deadlift isometric exercise, at 25%, 30% and 35% of maximal voluntary contraction for 3 min. Significant differences (P < 0.05) were found from rest to 25%, 30% and 35% for all physiological variables, heart rate (66.5+/-9.0, 104.0+/-12.0, 115.0+/-9.0, and 123.0+/-11.0 beats x min(-1), respectively), and for lactic acid (2.2+/-0.4, 4.6+/-0.7, 5.7+/-1.1, and 6.3+/-1.5 mM x l(-1), respectively). However, no significant differences were revealed between the various conditions when rate-perceived exertion data were analyzed, despite increased absolute loads. These data indicate that the psychological manipulation introduced in this study did not affect physiological responses during isometric exercise, in contrast to that seen during dynamic exercise.

The effect of gender on left ventricular function immediately after the wingate test.

The effect of gender on left ventricular systolic function and exercise haemodynamics in healthy young subjects was studied during 30-s all-out sudden strenuous dynamic exercise. A group of 22 men [19.3 (SD 1) years] 20 women [19.1 (SD 1) years] volunteered to participate in this study. Two-dimensional direct M-mode and Doppler echocardiograph studies were performed with the subject in the sitting position. The Doppler examination of flow was located with continuous-wave, interrogating ascending aorta measurements. The subjects completed the study without showing any electrocardiograph abnormalities. An interaction effect with stroke volume (P < 0.05) was characterized by a decrease in the men and an increase of stroke volume in the women. Cardiac output rose significantly (P < 0.05) up to 14.5 (SD 6) 1.min-1) for the men and 12.1 (SD 4) 1.min-1 for the women compared to the rest values [5.8 (SD 0.4) and 4.7 (SD 0.5) 1.min-1, respectively]. Flow velocity integral and acceleration time differed significantly between the two groups at rest (P < 0.05). During exercise these differences showed an interaction effect (P < 0.05). These results would indicate that normal men and women respond to sudden strenuous exercise by reducing their left ventricular systolic function, with a significantly greater decrease in women (P < 0.05). The gender differences in the haemodynamic responses during the present study, may, as suggested by others, be attributable to differences in energy metabolism. In addition, changes in Doppler parameters of aortic flow, haemodynamics and blood pressure responses during sudden strenuous exercise differed markedly from those seen before with endurance exercise.

Effects of chronic overload training and aging on left ventricular systolic function.

To examine the effects of age and chronic overload training on left ventricular systolic function during static exercise, Doppler echocardiography studies were performed in 14 young (28 +/- 6 years) and 10 older (51 +/- 3 years) weight lifters and also in 14 young (29 +/- 6 years) and 10 older (52 +/- 1.1 years) normal individuals during upright dead-lift isometric exercise, at 30% of maximal voluntary contraction for 3 min. At rest, older weight lifters demonstrated impaired left ventricular systolic function as compared with the other three groups. During exercise, peak and mean velocity values increased significantly (p < 0.05) from resting values in the young groups, but remained unchanged in the older groups. Flow period and acceleration and deceleration times were significantly (p < 0.05) lower in the younger subjects than those observed for the old ones, with the highest (p < 0.05) values obtained by the old weight lifters. This study suggests that the differences between the groups are related to differences in impedance and not to fundamental changes in the properties of the myocardium.