Arrhythmia is a prevalent form of cardiovascular disease that could lead to mortality [1]. Long QT syndrome (LQTS) is an inherited form of arrhythmia that occurs in approximately one in 2,000 individuals, often resulting in syncope, cardiac arrest, and sudden death, particularly among young individuals [[2], [3], [4]]. LQTS is characterized by the QT interval prolongation in electrocardiogram recordings that could be triggered by drug side effects, genetic disposition, emotional and physical stress [2,3,5]. From the 17 clinical subtypes, the KCNQ1 (LQTS Type 1: LQTS1), KCNH2 (LQTS2), and SCN5A (LQTS3) genes are associated with 90% of all LQTS cases [4,[6], [7]]. From these, the KCNQ1 gene encodes the α-subunit of the K+ channel Kv7.1, generating the depolarizing IKs current crucial for QT adaptation [6]. The pathophysiological basis for LQTS1 relies on a reduction in outward potassium currents during repolarization or an increase in inward sodium or calcium currents during depolarization states [6]. LQTS1 has been modelled successfully in transgenic mouse models carrying Kcnq1null and Kcnq1A340E/A340E genotype, paving the way for molecular, functional, and pharmacological studies [8,9].

The heart function is sensed and controlled by a dense innervation pattern through a hierarchical organization of the nervous system [10]. Under different physiological conditions, heart rate is tightly regulated by the autonomic nervous system, including sympathetic and parasympathetic, and sensory neurons [11]. By releasing norepinephrine, sympathetic neurons enhance heart rate, contractility, and conduction velocity, facilitating rapid adjustments during stress, exercise, or "fight or flight" response. Parasympathetic neurons slow the heart rate and reduce contractility by releasing acetylcholine, which supports rest and energy conservation [12]. Sensory neurons relay signals to central regulatory centers in the brainstem regarding physiological parameters like stretch, pressure, and pain, allowing reflexive adjustments in cardiac function [13]. Based on this, dysregulation or dysfunction of autonomic or sensory neurons can significantly impact cardiovascular health, contributing to conditions such as arrhythmia, heart failure, and hypertension. A few studies have focused on cardiac innervations histologically and at the whole heart level by analysing various aspects of cardiac nerve density, distribution, and nerve endings [11,14,15]. It is still unclear how alterations and remodeling of the heart innervations are associated with functional outputs of heart rate, contractility, and rhythm.

Following ischemic-cardiac damage, remodeling of cardiac innervation by hyperinnervation or denervation was shown to be associated with cardiac dysfunction in canines [16]. Several histological studies in human specimens demonstrated neural remodeling in post-ischemic hearts and indicated a potential contribution to the development of arrhythmias [17,18]. Although remodeling of cardiac innervations in diseased states was described in several animal models [[19], [20], [21]] and humans [17], the mechanism and contribution to cardiac pathologies and arrhythmia remain to be understood.

To date, no report has explored the relationship between arrhythmia or other hereditary cardiac conditions with global heart innervation patterns. Here, to fill this gap, we revealed the whole-heart innervation maps and branching patterns in Kcnq1A340E/A340E LQTS1 transgenic mice model compared to wild-type (WT) controls. Our data showed no significant differences in total nerve fiber density, branching number, branch length, or junction count between Kcnq1A340E/A340E LQTS1 transgenic and wild-type mice; however, a reduced prevalence of small-diameter nerve fibers was observed in LQTS1 hearts. Interestingly, our findings revealed that every heart has its own “heartprint” of innervations, similar to a unique fingerprint for each individual. This investigation may provide valuable insights into the understanding of specific cardiac neural patterns of the healthy state, as well as genetic forms of cardiac diseases.