INTRODUCTION

Heart failure - the final stage of most heart diseases and the main cause of death of patients with ischemic heart disease in the United States of America and other Western countries^[1] - is characterized by the inability of the heart to provide adequate blood supply to all tissues of the body, impairing patients’ functional capacity and quality of life (QoL). As the disease advances further, morbidity and mortality increase^[2,3]. Therapeutic refractory heart failure necessarily culminates in death, being heart transplant (HT) the only alternative to avoid this outcome^[4]. This treatment has immeasurable benefits such as prolonging survival by approximately 10 years following surgery and also improving symptoms of heart failure, enabling a more active lifestyle and improving QoL for the 85% of individuals that survive the first year after HT surgery^[5].

However, during surgical procedure, transplanted hearts are implanted without afferent and efferent nerve connections, remaining completely denervated for approximately one year. Consequently, heart rate (HR) control by the autonomic nervous system (ANS) is impaired, leading to increased resting HR, increased metabolic demand, and fatigue, which can negatively impact QoL of HT recipients due physiological, clinical, and behavioral profile impairments, such as the need for more daily-use medications for HR controlling^[6,7]. Usually, there are evidence of reinnervation occurring in the second year after surgery, reaching myocardial muscle, sinoatrial node, and coronary vessels, but remaining incomplete and regionally limited many years after the transplant. Nevertheless, restoration of cardiac innervation can improve exercise capacity as well as blood flow regulation in the coronary arteries, and hence improve QoL^[8].

In the present study, we hypothesized the association of hemodynamics and autonomic function as predictors of QoL in HT recipients, which could be future monitoring and therapeutic target for improving QoL of this population.

METHODS

RESULTS

A total of 22 volunteers were included in the study, five women (22.7%) and 17 men (77.3%), with mean age of 53.4 (9.3) years old. The HT indications were: chagasic cardiomyopathy, myocarditis, ischemic heart disease, and valvar dysfunction due to rheumatic disease, each with four cases (18.2%); and alcoholic, idiopathic, and peripartum cardiomyopathy with three (3.7%), two (9.1%), and one case (4.5%), respectively. Also, the mean time since surgery was 4.3 (2.5) years. The main comorbidities were hypertension (50.0%), diabetes (31.8%), obesity (27.2%), dyslipidemia (22.7%), hypothyroidism (13.7%), chronic kidney disease (13.7%), and hyperthyroidism (4.5%).

Table 1 shows the crude means and SD of hemodynamics, the time, frequency, and nonlinear domains of HRV, and QoL domains of the studied sample. The non-adjusted association analysis is presented in Tables S1 and S2.

Table 1 - Baseline characteristics of patients included in the study.

Table S1 - Associations between hemodynamics and heart rate variability variables with SF-36 Physical Composite domains (non-adjusted analysis).

Table S2 - Associations between hemodynamics and heart rate variability variables with SF-36 Mental Composite domains (non-adjusted analysis).

The associations of hemodynamics and HRV with QoL domains are depicted in Tables 2 and 3. SBP and DP were negatively associated with the physical functioning domain (Table 2). DP, NN50, and PNN50 exhibited negative association with the physical role domain (Table 2), while only NN50 and PNN50 were significantly associated with bodily pain (Table 2), social functioning, and emotional role domains (Table 3). For the vitality domain (Table 3), only SBP was negatively associated. Considering general (Table 2) and mental health (Table 3) domains, none of hemodynamic or HRV variables demonstrated significant association. Finally, DP, NN50, and PNN50 were negatively associated with the total score of QoL (Table 4).

Table 2 - Associations of hemodynamics and heart rate variability variables with SF-36 Physical Composite domains.

Table 3 - Associations of hemodynamics and heart rate variability variables with SF-36 Mental Composite domains.

Table 4 - Associations of hemodynamics and heart rate variability variables with SF-36 total score.

DISCUSSION

The main finding of the present study was the negative association of hemodynamic and autonomic function indexes with QoL in HT recipients. The benefits of heart transplantation for health-related QoL are well described for several domains/areas such as physical, psychological, and social^[14-16] but the role of hemodynamic and autonomic function variables as predictors of QoL has never been previously described. Briefly, the main variables exhibiting its association were SBP, DP, NN50, and PNN50.

Considering hemodynamics, the higher the SBP, the worse the physical function and vitality domains of QoL. Both elevated BP and total peripheral resistance and also attenuated BP and total peripheral resistance responses during orthostatic maneuvers are observed in HT recipients, probably due low-pressure cardiopulmonary baroreceptor denervation. Moreover, efferent sympathetic denervation leads to diminished cardiac output response to isometric exercise after heart transplantation. Together, those physiological impairments impose negative functional consequences to HT recipients^[17] that could explain the observed negative association of SBP with domains of QoL. In addition, as observed in the present study, the higher the DP, the worse the physical function and physical role domains of QoL. As an index of myocardial oxygen consumption previously used during exercise testing in patients with coronary heart disease, DP reflects cardiac workload, being a well-established index of energy consumption of heart^[18]. Therefore, increases in DP at rest could indicate a small DP reserve (difference between rest and maximal exercise DP) that has greater prognostic power than metabolic equivalents, maximal HR, or SBP^[19], reflecting the efficiency of the myocardium^[20]. Then, elevated resting DP could impair physical function - and by consequence, the clinical status of those patients - due to elevated resting myocardial oxygen consumption and low exercise capacity by reduced cardiac reserve^[21], worsening QoL.

Considering autonomic function, NN50 and PNN50 (indexes associated with parasympathetic activity^[22], more reliable in short-term observations^[23]) increases were contradictorily associated with reduction of physical role, bodily pain, social functioning, and emotional role domains and total score. PNN50 was already correlated to decreases in physical function^[24].

Despite the expected improvement in QoL due to increased parasympathetic activation, that could ameliorate hemodynamics by reducing resting HR, SBP, and finally DP, improving DP reserve and, as consequence, cardiac reserve and exercise capacity, which would result in clinical improvements, it was not demonstrated in the present study. Since parasympathetic fibers only innervate nodal peacemakers’ cells, the main influence of its activation should be the stimulation of HR reduction, or more precisely, the inhibition of HR elevation due to humoral adrenergic stimulation^[25,26].

In fact, parasympathetic influence on HR is absent in the majority of patients up to eight years after cardiac transplantation^[27], as are in the population of the present study, in which mean time since transplantation was near four years. Furthermore, HR exhibited no association with QoL domains. A possible explanation to such contradiction could be the peripheral effect of parasympathetic nerve stimulation by releasing the neurotransmitter acetylcholine on muscular and endothelial layers of blood vessels, that induces smooth muscle cells contraction, leading to increase of peripheral resistance that, at last, increases SBP^[28]. It can be demonstrated by the impairment of cardiac performance during exercise in orthotopic HT recipients, in which acute beta-adrenergic blockade accentuates the impairment in ventricular performance and appears to be detrimental in these patients, probably by reduction in myocardial contractility and increase in peripheral resistance^[7]. Thus, this pathophysiological mechanism evidences the impact of ANS imbalance (previously indicating both parasympathetic and sympathetic activation^[29]) on physical and emotional functions, which can worse social interactions. Finally, the elevated adrenergic stimulation and plasma circulating catecholamine levels, already associated to pain syndromes via adrenergic receptors stimulation, are suggested in HT recipients^[29,30], being a possible mechanism underlining the inverse association of parasympathetic activation and bodily pain QoL domain^[31].

Beyond physiological, laboratorial, or clinical variables and morbidities, mortality, and other classical medical hard outcomes, QoL - which reflects “the individual’s perception of their insertion in life, in the context of the culture and value systems in which a person lives and in relation to their goals, expectations, standards and concerns” - is a major outcome for patients’ life, so the majority of healthcare assistance treatment strategy should be focused on its improvement, ensuring that the treatment is centered on the patient rather than the disease^[32,33].

However, in clinical practice, it is not easy to assess QoL, mainly because its subjectivity, but also the complexity of health-related QoL questionaries, and the difficulty for some patients in understanding and answering it. So, based on the results, the main implication for practice was the identification of some hemodynamic and autonomic variables associated with QoL, which may provide a less subjective way for corroborate the interpretation of this relevant outcome, and finally improve clinical management. Despite the need for more research about those associations, maybe the clinical approach of those variables should impact in improvement in QoL for HT patients. So, as noninvasive, cheap, and easy to perform, HRV - a promising tool for clinically monitoring of autonomic dysfunction prior to several cardiovascular disease occurrence and also for monitoring cardiovascular disease progression^[34,35] - together with hemodynamic basic measurements, such as BP and DP, could be more than an instrument for ambulatorial clinical follow-up, perhaps being added as clinical therapeutic targets for improving QoL (the main objective of heart transplantation), as suggested by our results.

CONCLUSION

The present study demonstrated DP and HRV as predictors of QoL in HT recipients. These innovative results can become a relevant therapeutic target for improving QoL in HT recipients prior to its deterioration.