The contribution of granger causality analysis to our understanding of cardiovascular homeostasis: from cardiovascular and respiratory interactions to central autonomic network control

Homeostatic regulation plays a fundamental role in maintenance of multicellular life. At different scales and in different biological systems, this principle allows a better understanding of biological organization. Consequently, a growing interest in studying cause-effect relations between physiological systems has emerged, such as in the fields of cardiovascular and cardiorespiratory regulations. For this, mathematical approaches such as Granger causality (GC) were applied to the field of cardiovascular physiology in the last 20 years, overcoming the limitations of previous approaches and offering new perspectives in understanding cardiac, vascular and respiratory homeostatic interactions. In clinical practice, continuous recording of clinical data of hospitalized patients or by telemetry has opened new applicability for these approaches with potential early diagnostic and prognostic information. In this review, we describe a theoretical background of approaches based on linear GC in time and frequency domains applied to detect couplings between time series of RR intervals, blood pressure and respiration. Interestingly, these tools help in understanding the contribution of homeostatic negative feedback and the anticipatory feedforward mechanisms in homeostatic cardiovascular and cardiorespiratory controls. We also describe experimental and clinical results based on these mathematical tools, consolidating previous experimental and clinical evidence on the coupling in cardiovascular and cardiorespiratory studies. Finally, we propose perspectives allowing to complete the understanding of these interactions between cardiovascular and cardiorespiratory systems, as well as the interplay between brain and cardiac, and vascular and respiratory systems, offering a high integrative view of cardiovascular and cardiorespiratory homeostatic regulation.