Attivazione neuro-ormonale e modulazione autonomica nella sindrome di Takotsubo: un’analisi integrata di Neuropeptide Y e Heart Rate Variability

Title: Neurohormonal Activation and Autonomic Modulation in Takotsubo Syndrome: An Integrated Analysis of Neuropeptide Y and Heart Rate Variability Background. Takotsubo syndrome (TTS) is an acute and reversible stress-induced cardiomyopathy whose pathophysiology remains only partially elucidated. Sympathetic hyperactivation, microvascular dysfunction, and systemic inflammation are all believed to contribute, but have never been assessed simultaneously in the acute phase. Neuropeptide Y (NPY), a sympathetic, may play a critical role in stress-related myocardial stunning. Likewise, heart rate variability (HRV) provides a non-invasive measure of sympathovagal balance, while the Systemic Immune-Inflammation Index (SII) reflects the degree of systemic inflammatory activation. No previous study has integrated these three physiopathological domains in TTS. Objective. To evaluate neurohormonal activation (NPY), autonomic dysfunction (HRV), and systemic inflammation (SII) in acute TTS, comparing these findings with STEMI patients and healthy controls, and to investigate their potential mechanistic relevance and inter-relationships. Methods. In this prospective case–control study, we enrolled 20 TTS patients, 19 anterior STEMI patients, and 30 healthy controls (4 excluded for technical issues). Plasma NPY was quantified via ELISA. Time- and frequency-domain HRV indices (heart rate, SDNN, RMSSD, LF, HF, LF/HF ratio) were obtained during the acute phase. The SII was calculated from complete blood counts. Standard cardiac biomarkers, ECGs, and echocardiograms were also collected. Group comparisons used ANOVA with Tukey post-hoc testing. Pearson correlation examined the relationship between NPY and LF/HF. Results. NPY levels showed a progressive increase across groups (Controls < TTS < STEMI): Controls: 140.63 ± 18.08 pg/mL; TTS: 302.76 ± 39.86 pg/mL; STEMI: 389.94 ± 62.6 pg/mL; ANOVA showed a significant overall difference (p < 0.001). TTS patients had significantly higher NPY than controls (p < 0.01), while STEMI showed the highest levels. TTS exhibited the most severe autonomic impairment, with higher heart rate, markedly reduced SDNN and RMSSD, lower HF, and a significantly higher LF/HF ratio compared with both controls and STEMI. Notably, LF/HF was the only HRV parameter that differed significantly between TTS and STEMI, indicating a more extreme sympathetic predominance in TTS. No correlation was found between plasma NPY and LF/HF, suggesting that neurohormonal sympathetic activation and autonomic modulation act through parallel but physiologically independent pathways. SII was significantly higher in TTS than STEMI (1517 ± 76 vs. 1276 ± 85, p = 0.04), indicating a pronounced systemic inflammatory response in TTS, consistent with recently described myocardial and systemic immune activation in this condition. Conclusions. This is the first study to concurrently evaluate NPY, HRV, and SII in patients with acute TTS. Our findings show that TTS is characterized by severe sympathovagal imbalance, moderate neurohormonal activation, and a heightened systemic inflammatory response—together defining a complex cardio–neuro–immune phenotype. The absence of correlation between NPY and LF/HF supports the concept of dual, independent sympathetic pathways involved in TTS. These results contribute to an integrated pathophysiological framework and highlight the need for larger studies to investigate the prognostic and clinical utility of NPY, HRV, and SII as markers of neurocardiac vulnerability.