IJCS | Volume 31, Nº6, November / December 2018

654 Mesquita et al. HFPEF phenotypes Int J Cardiovasc Sci. 2018;31(6)652-661 Review Article - N2B (stiffer) andN2BA (more compliant). Changes in the ratio of one isoform to the other and phosphorylation of the fibers, as well as oxidative stress can have an impact on myocardial compliance, leading to stiffness. 9,18 Disruption of sarcomere structure is the mechanical factor of ventricular relaxation. It is an energy- consuming reaction, and, for this reason, the lack of energy stores impairs a normal left ventricular relaxation. Recent studies have demonstrated a decreased phosphate creatinine/adenosine ratio in patients with HFPEF, which is consistent with a decline in myocardial energy store. 21-23 In addition to interstitial (collagen-related changes) and structural (regulation of constituent proteins) changes, unbalanced levels of chemical mediators, especially of monophosphate cyclic guanine (cGMP), may also explain myocardial stiffness in HEPEF. Activation of protein kinase G (PKG) by cGMP results in phosphorylation cascade of proteins important for cardiomyocyte integrity – phosphorylation of titins inhibits cardiac hypertrophy and increases myocardial compliance, phosphorylation of potassium channels inhibits tissue ischemia, and phosphorylation of troponin I increases left ventricular relaxation. Also, PKG activation by cGMP increases calcium reuptake by sarcoplasmic reticulum. 9 Low BNP, microvascular inflammation and oxidative stress, which are common in several conditions, such as obesity and insulin resistance, suppresses GMPc synthesis pathways. This, in turn, inhibits PKG phosphorylation cascade and culminates in myocardial stiffness, characteristic of HFPEF. 8,9 Although HFPEF is commonly referred as diastolic HF, the disease is not limited to ventricular relaxation problems. A study 24 demonstrated that myocardial contractilitymay be decreased inHFPEF, even if the end- systolic elastance (ESE) – used to measure myocardial contractility – is increased. 24 This apparent contradiction may be explained by the influence of cardiac chamber geometry on ESE. Concentric hypertrophy, characteristic of HFPEF, independently increases ESE, even with reduced left ventricular contractility. 21 InHFPEF, vascular stiffness is generalized, resulting in elevated pressure, which aggravates ventricular stiffness and attenuates vascular dilation in exercise, thereby decreasing blood supply to musculoskeletal system. Increased vessel stiffness, associated with elevated left heart pressure, increases pulmonary pressure and consequently the mortality of these patients. 21 Defects indiastolic, systolic, vascular andchronothropic functions elucidate the heterogeneous nature and complexity of HFPEF. Its multiple pathophysiological factors indicate the need of phenotyping of these patients, and identification of specific causes of the worsening of each phenotype. This strategy has become increasingly possiblewith biomolecular advances inmedicine andwill possibly guide therapeutic decisions based on specific pathophysiological changes. Modulation of HFPEF phenotypes by epigenetics – a new frontier Epigenetics is an emerging science involving the study of changes in the regulation of genes and their expression, regardless of their sequences. Environmental factors can affect intracellular signaling pathways in a way that can affect chromatin structure, resulting in the passage of altered gene expression patterns to the offspring by epigenetic memory, affecting the phenotypes of the diseases. 25,26 New evidence suggests the involvement of epigenetic regulation in target cells related to cardiovascular pathogenesis, includingHF and its different phenotypes. 27 Cardiomyocytes, for example, can adapt to environmental stress by epigenetic regulation. This dysregulation in genetic expression provides information about the pathogenesis of cardiac and vascular remodeling, dysfunction of progenitor cells and endogenous repair system, inflammation, fibrosis and cardiac dysfunction. 28,29 Four epigeneticmechanisms in cardiovascular diseases have been identified – DNA methylation, chromatin remodeling by adenosine triphosphate (ATP)-dependent enzymes, histonemodification andmicroRNA-dependent mechanisms. 30-32 Recent findings have associated these mechanisms with HFPEF-related diseases; however, evidence on the role of epigenetics in changes in cardiac function and structure, and clinical trials corroborating theories involving both epigenetics and cardiovascular disease are still lacking. Advances in studies on this field should contribute to HF prevention and provide enough evidence for the stratification of HF phenotypes. Clinical phenotypes and phenotypic mapping Current phenotyping tools combined with advances in genetics and systems biology have the potential to improve the classification of complex, heterogeneous systems, such as HFPEF. Analysis of patients’ data aiming to establish a pattern of these variables may be performed