Comparison of hemorheological changes in patients after acute coronary events,intervention and ambulatory rehabilitation

Abstract

During the past decades, our group have investigated the hemorheological parameters (HPs) of more than 1,000 patients with various forms of ischemic heart disease (IHD). Our data indicate that HPs are altered in patients with IHD and the extent of the alterations is in good correlation with the clinical severity of the disease. Our findings have also proven that HPs play a critical role in the pathogenesis of myocardial ischemia.

The lack of regular exercise is an important cardiovascular risk factor. Regular physical activity – as part of the cardiovascular rehabilitation training program (CRP) – is recommended for the treatment of IHD and the prevention of first or further cardiovascular events. To estimate the beneficial hemorheological effects of CRP, compared to patients after a coronary event or intervention and not participating in CRP, the data of four of our prospective studies (three non-CRP and one CRP-participating) were evaluated.

Hematocrit (Hct), plasma and whole blood viscosity (WBV), Hct/WBV ratio significantly (p < 0.05) increased in the non-CRP groups during the 6–12 months follow-up, while in the CRP group they significantly decreased (p < 0.05). Red blood cell aggregation decreased in a much greater manner in the CRP group.

Our results indicate that CRP has beneficial hemorheological effects and is able to reverse the deterioration of HPs after coronary events or intervention.

Keywords

Ischemic heart disease cardiovascular prevention acute coronary syndrome percutaneous coronary intervention hemorheological parameters

1 Introduction

In the past few decades, mortality of coronary artery disease (CAD) has decreased substantially in the developed countries due to the improving pharmacological therapies, revascularization procedures and prevention programs. According to the latest American College of Cardiology, American Heart Association and European Society of Cardiology guidelines, cardiovascular rehabilitation programs (CRP) are recommended in the treatment of CAD and in the prevention of first or further cardiovascular events [1 , 38]. These programs address high-risk patients using professional multidisciplinary methods to restore quality of life and to improve or at least maintain functional capacity in patients with known CAD [29, 37]. CRPs include risk stratification, individualized regular physical training, basic medical education, dietary consultation, smoking cessation, psychological and social management as well as drug therapies [29].

Patients with previous acute myocardial infarction (AMI), coronary artery bypass grafting, percutaneous coronary intervention, stable angina pectoris or stable chronic heart failure should undergo a minimum 30 minute lasting moderate-to-vigorous intensity (at 70–85% of the peak heart rate or 40–60% of heart rate reserve) aerobic exercise training at least 3–5 times a week [1 , 38]. Aerobic exercise training programs have been shown to reduce cardiovascular mortality by 20–30% in subjects with CAD [15, 36], improve exercise performance and endothelial function [9, 23], have antithrombotic effect [24, 26], postpone the development of cardiovascular risk factors and induce myocardial ischemic preconditioning [37].

Blood flow of the coronary vessel system is primarily determined by hemodynamic factors, but under certain conditions (e.g. a significant stenosis) the role of hemorheological parameters (HPs) increases. The alterations of HPs in CAD have been described by several prospective epidemiological studies, moreover the Framingham Study [16], the Edinburgh Artery Study [20, 25], the MONICA Augsburg Cohort Study [19], the Physicians’ Health Study [27], the Caerphilly Study and the Speedwell Study [35, 47] identified elevated hematocrit (Hct), whole blood viscosity (WBV), plasma viscosity (PV) and plasma fibrinogen level as primary cardiovascular risk factors. In the Edinburgh Artery Study WBV, PV and plasma fibrinogen level linearly correlated with carotid intima-media thickness – accepted marker of sub-clinical stage of atherosclerosis – even on multivariate analysis. After adjusting all common cardiovascular risk factors, elevated WBV and fibrinogen level still significantly correlated with carotid intima-media thickness [20]. The latter data suggest that HPs have a close relation even to the earliest stages of atherosclerosis.

2 Aims

The effects of physical activity on HPs have mostly been investigated in healthy subjects. However, only limited data is available of its long-term hemorheological effects in patients with cardiovascular disease.

The alteration of HPs in stable CAD has been well reported [30, 39]. Cross-sectional and prospective studies found elevated Hct, WBV, PV, and red blood cell (RBC) aggregation values in patients with acute coronary syndrome (ACS) [30, 41], moreover after the hospital phase they persisted or even further deteriorated despite proper pharmacotherapy [28, 42]. A recent prospective study from our group reported positive long-term hemorheological effects in a relatively large population of ischemic heart disease patients participating in CRP [33].

Report of the European Cardiac Rehabilitation Inventory Survey indicates that fewer than half of the eligible cardiovascular patients benefit from CRPs in most European countries [3]. According to the World Health Organization two thirds of the population aged over 15 years in the European Union do not reach recommended level of physical activity (30 minutes/day on most weekdays), accounting for one million deaths per year and 8.3 million disability-adjusted life-years in the European Region [45]. Thus, we aimed to estimate the beneficial hemorheological effects of regular exercise training program compared to those CAD patients who do not participate in CRP.

3 Patients and methods

On the basis of the current cardiovascular practice guidelines, no controlled trials are allowed; it would have been unethical and unprofessional to design such study in CAD patients, therefore the data of four of our previous studies were analyzed to evaluate the hemorheological benefit of CRP:

one prospective study, where CAD patients participated in CRP [45];

three prospective studies, involving patients admitted due to AMI, ACS or for percutaneous transluminal coronary angioplasty (PTCA); these patients – due to the lack of well-established rehabilitation guidelines at those times – did not participate in CRP [17 , 42].

The detailed description of these studies can be found in the cited articles, here the main aspects will be provided. Subject characteristics, risk factors and medications are listed in Table 1, while the measured HPs and used instruments are provided in Table 2. All studies were approved by the Regional Ethics Committee of the University of Pecs and written informed consent was signed by all subjects prior to entering the studies.

3.1 3.1. Design of the original studies

3.1.1 Acute myocardial infarction (AMI group)

22 patients, hospitalized due to AMI, were enrolled, 17 of which were followed for 6 months. HPs were measured at admission, discharge (6±2 days), 1 and 6 months. Blood was obtained from cubital veins into EDTA anticoagulated tubes. Measurements were performed within 1 hour from blood sampling [42].

3.1.2 Percutaneous transluminal coronary angioplasty (PTCA group)

19 stable CAD patients, undergoing elective PTCA were followed for 6 months. Li-heparin anticoagulated blood samples were taken before the procedure, 30 minutes, 1, 2, 5 days, 1, 6 months after PTCA. Baseline and 30-minute samples were gained from femoral veins, while all the others from cubital veins. All measurements were performed within 3 hours from sampling [17].

3.1.3 Acute coronary syndrome (ACS group)

159 patients admitted to hospital due to ACS (67 [42%] STEMI, 92 [58%] NSTEMI) were involved. HPs were measured after admission, on the 2nd and 6th days (discharge), after 1, 6 and 12 months. Blood samples were taken into Li-heparin coated tubes from cubital vein after 12-hour fasting, except for baseline values, which were done as soon as possible after admission [28].

3.1.4 Cardiovascular rehabilitation program (CRP group)

79 non-smoker patients with stable CAD participating in CRP were followed. Physical training lasted for 1 hour, 3 times a week. HPs were measured before CRP, after 12 and 24 weeks, under 12-hour fasting condition. Blood samples were obtained from cubital vein into Li-heparin coated tubes. During the study, medication remained constant.

The patients began with warm-up exercises for 5–10 minutes, followed by a moderate-intensity (50–70% of peak VO₂) training. The training involved static (exercises with medicine ball, half-squats, toe raises, body flexions) and dynamic (walking, jogging and ball games) exercise elements. The aerobic phase lasted for 35–40 minutes. The training programs ended with stretching and breathing exercises, performed for 10 minutes [33].

3.2 Statistical analysis

From the original raw data Hct, PV, WBV and RBC aggregation records were extracted, Hct/WBV ratio was calculated and used for statistical analysis.

Some of the analyzed studies differ in the applied instruments (AMI study vs. the others), baseline values, sampling tubes (AMI study vs. the others) (Table 2) and there is a relative large time-interval between the studies, therefore only relative changes are presented. For the same reason merely the in-study changes were analyzed.

Normal distribution was analyzed by Shapiro-Wilk test. All populations were found to have normal distribution and their variances were statistically equal. Continuous variables are presented as mean±SD, except for relative changes, where mean±S.E.M format is used. Differences were analyzed using Student’s t-test. A two-tailed p-value less than 0.05 was considered statistically significant. Analyses were performed using IBM SPSS 22.

4 Results

4.1 Hematocrit

In the AMI, PTCA and ACS groups Hct decreased significantly (p < 0.05) during the hospital phase. After discharge it increased above baseline values and – with the exception of the AMI group – became significantly (p < 0.05) higher compared to baseline. In the CRP group Hct became significantly (p < 0.05) lower after 6 months (Fig. 1).

4.2 Whole blood viscosity

WBV in the AMI group significantly (p < 0.05) increased during the whole follow-up period. In the PTCA and ACS groups it showed a slight decrease during the hospital phase, followed by a significant (p < 0.05) elevation afterwards. On the contrary, in the CRP group WBV continuously decreased and after 6 months it became significantly (p < 0.05) lower compared to baseline (Fig. 2).

4.3 Hematocrit per whole blood viscosity ratio

In the AMI, PTCA and ACS groups Hct/WBV ratio significantly (p < 0.05) decreased while in the CRP group it significantly (p < 0.05) increased compared to baseline (Fig. 3).

4.4 Plasma viscosity

In the AMI and PTCA groups no significant (p > 0.05) changes were observed, while in the ACS group PV significantly (p < 0.05) increased during the follow-up, while in the CRP group it decreased significantly (p < 0.05) (Fig. 4).

4.5 Red blood cell aggregation

The M parameter decreased significantly in both ACS and CRP groups, but the extent was much greater in the latter one (–14% vs. –45%). The M1 parameter showed no significant decrease in the ACS group, while in the CRP group it was significantly lower even after 3 months (Fig. 5).

5 Discussion

It is generally agreed that rigorous physical exercise increases Hct, WBV and PV due to the fluid shift from the vessels [10, 40]. Several factors stand in its background: redistribution of red cells in the circulation; splenocontraction, increasing number of circulating RBCs; enrichment of plasma proteins; loss of water by sweating and entrapment of water into muscle cells [40]. Regarding RBC aggregation and deformability literature data is not concordant. Most of the studies reported decreased RBC deformability [32, 46], assuming increased lactate level, oxidative stress and mechanical trauma in the background [4 , 46]. Yalcin et al. (2003) reported significantly impaired RBC deformability above 4 mmol/l plasma lactate concentration [46]. Contrarily, some authors observed improved RBC deformability [6 , 44]. Connes et al. (2004) observed that increased lactate level differently affected RBC rigidity in sedentary healthy subject compared to athletes [7]. RBC aggregation has been described to increase [12, 46] – with or without elevation of fibrinogen level – or remain constant [43] in different studies. These discrepancies might be explained by the variances of the selected populations, type of exercise performed, training periods, study designs and measurement methods. Few hours or days after cessation of exercise, plasma volume expands (autohemodilution), reversing acute exercise-induced hyperviscosity [11 , 40].

Cross-sectional and prospective studies have confirmed that sportsmen have lower Hct, Hgb concentration, WBV, PV and better RBC deformability compared to non-trained healthy subjects [12 , 21]. Smith et al. (1999) reported higher amount of young deformable RBCs in athletes than in sedentary subjects [34], which might be explained by the higher turnover of RBCs resulting from the upregulated EPO synthesis [14].

Although studies have well described the effects of physical training in healthy subjects, limited data is available in patients with cardiovascular diseases. Ernst et al. (1987) found that WBV, PV and RBC aggregation decreased and RBC filterability increased in patients with peripheral artery disease during 2 months long exercise [13]. Levine et al. (1995) reported no hemorheological changes in CAD patients after 10 weeks of CRP [22]. Reinhart et al. (1998) found no significant changes in WBV and PV in post-AMI patients after daily cycling and walking for 8 weeks [31]. Church et al. (2002) observed no change of Hct, but significant decrease of WBV and PV after 12 week long CRP [5].

Recently Sandor et al. (2014) conducted a 24 week long prospective study, reporting decreased Hct, WBV, PV, RBC aggregation and increased Hct/WBV ratio in stable coronary artery disease patients participating in CRP [33]. Our previous prospective studies on CAD patients, not participating in CRP, show that the basically impaired hemorheological parameters did not just remain elevated, but the deterioration continued after the acute events during the long-term follow-up period [28, 42]. Our data suggests that CRP was not just able to stop, but it was able to reverse these effects. The observed rheological changes (decreased Hct, WBV, RBC aggregation) are likely to reduce the cardiovascular risk of CAD patients.

Both hemodynamic and hemorheologic factors are of crucial importance to be considered in the coronary circulation, since there is a continuous change in blood flow, perfusion pressure and shear rate during each cardiac cycle [40]. The myocardium is the organ with the highest oxygen consumption per one gram of tissue, and no further increase in oxygen extraction is possible, thus only increased coronary perfusion can provide higher oxygen delivery to the myocardium. Blood flow of the coronary vessel system is primarily determined by hemodynamic factors, but under certain conditions (e.g. a significant stenosis) the role of rheological parameters increases. In vitro and ex vivo studies showed that the effect of Hct, WBV, RBC aggregation and deformability is greatly compensated through vascular mechanisms, but in case of limited vascular compensation – such as in CAD in our case – any of them can produce severe alterations of flow resistance thus oxygen supply [2]. The observed decrease of Hct and WBV decreases flow resistance mainly in the macrocirculation, while the lower PV in the microcirculation [2]. The decreased RBC aggregation can alter flow properties in distinct ways. On one hand, decreased RBC aggregation increases flow resistance by decreasing axial migration of RBCs, promoting Fahraeus effect and plasma skimming [37], while on the other hand it decreases low shear viscosity, which may affect flow resistance in large blood vessels when shear forces are sufficiently low. RBC aggregates must be dispersed in order to enter the microcirculation, therefore in case of decreased RBC aggregation, lower force is required, which decreases microvascular flow resistance [2].

This comparison has its limitations. The studies were conducted over a decade period, and seasonal effect were not taken into consideration. The limited control of confounding variables (co-morbidities, different medication according to the different guidelines) also makes the comparison harder. Creating a control group of CAD patients is very hard. According to the applied guidelines only those CAD patients can be involved who are unable or unwilling to participate in CRP (e.g. severe heart failure, severe claudication or amputation, young employed patients, who do not have time for it), but this control group can not be matched regarding co-morbidities, age and other important confounding factors.

6 Conclusion

The summarized results suggest the beneficial hemorheological effects of CRP over CVD patients, not participating in any regular training program.

Footnotes

Acknowledgments

The present scientific contribution is dedicated to the 650th anniversary of the foundation of the University of Pecs, Hungary.

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