Abstract
Proteins exist as multiple chemical and sequence-specific proteoforms, each of which may serve as a critical mediator of physiological or pathological signalling. This diversity arises from processes such as alternative splicing of gene transcripts, translation into amino acid sequences, and various post-translational modifications (PTMs), leading to an exponential increase in biological complexity. This manuscript provides an overview of the mechanisms underlying proteoform generation in biological systems and highlights strategies for their analysis using mass spectrometry (MS)-based proteomics and bioinformatics. Additionally, it focuses on recent findings linking PTMs to cardiovascular disease (CVD), highlighting the MS-based methods and workflows that have been used to study uncommon PTMs and their role in CVD. This review provides a comprehensive collection of tools and knowledge to explore the breadth of proteoforms, particularly PTMs, within their specific areas of interest in cardiovascular physiology.