Year: 2014
Type: article
Abstract: The diastole is the phase of the cardiac cycle in which the ventricles fill with the blood deriving from the atria, ready to be pumped into the pulmonary or peripheral circulation during systole. The initial phase of the diastole is the myocardial relaxation, in which calcium reuptake in the sarcoplasmic reticulum and the release of the actin-myosin bonds allow for an energy-dependent elongation of the fibers allowing for a pressure gradient-dependent flow of blood from the atria to the ventricle. Abnormalities in the myocardial relaxation delay the rate of ventricular pressure decline leading to delayed opening of the atrioventricular valves, which, due to the gradual increase in atrial pressure, occurs at a higher value of ventricular pressure, and rapid equalization of the pressure limiting the gradient and limiting early ventricular filling. Late ventricular filling on the other hand is more dependent on the elastic properties of the ventricle (elastance=1/compliance). A hypertrophic or fibrotic left ventricle will oppose more resistance to filling, and thus impairs late ventricular filling. Impairment in the myocardial relaxation and/or of the ventricular compliance determines the presence of diastolic dysfunction. Diastolic dysfunction in the heart may occur as a result of normal ageing, but it more often is caused by metabolic or structural abnormalities in the myocardium, which are the substrate for diastolic heart failure (or heart failure with preserved ejection fraction – HFpEF) (Borlaug 2014). The pathophysiology of diastolic dysfunction and heart failure is poorly understood. In particular, it is not clear how acute metabolic changes, such as ischaemia, hypoxia or inflammation, cause impairment in myocardial relaxation (Butler et al. 2014). In this issue of Acta Physiologica, Hillestad and colleagues shed light on this field, by showing that Interleukin-18 (IL-18) mediates diastolic dysfunction secondary to ambient (alveolar) hypoxia in the mouse (Hillestad et al. 2014) (Fig. 1). Hypoxia to the heart may occur in the setting of a significant reduction of blood flow, which can be regional (ischaemia) or global (shock), or it may occur when low oxygen tension is found in the alveoli such as in the setting of high altitude (ambient hypoxia), chronic lung diseases or acute inflammation or infection of the lungs. Independent of the cause of hypoxia, the cellular stress response is activated and in the heart leads to impaired diastolic function. In this study, mice were exposed to chronic ambient hypoxia to artificially diminish oxygen tension. They found that the left ventricular relaxation time constant, Tau, and the isovolumetric relaxation time (IVRT) were increased following hypoxia, indicating diastolic dysfunction due to impaired myocardial relaxation. Using the same mouse model, the same research group had previously shown that plasma levels of IL-18 are increased during hypoxia (Larsen et al. 2008). They now show that the treatment with IL-18 binding protein (IL-18 BP) during hypoxia restores diastolic function, normalizing Tau and the IVRT. At a molecular level, chronic hypoxia reduced phosphorylation of phospholamban (PLN) in the heart (Larsen et al. 2008, Hillestad et al. 2014). PLN is a key regulator of the intracellular calcium level; therefore, changes in its activity alter both contraction and relaxation. Treatment with IL-18 BP normalized PLN phosphorylation, a finding that contributes to explain the recovery of diastolic function in the IL-18 BP-treated mice. Finally, no changes were observed in the collagen production. This is particularly important because it suggests that the pathophysiological activity of IL-18 in this model mostly affects the active phases of the diastole and not the compliance of the ventricle. IL-18 is a pro-inflammatory cytokine of the IL-1 family (Dinarello et al. 2013). It is released by leucocytes upon the formation of an active inflammasome and signals through a single membrane receptor (Dinarello et al. 2013). An association between IL-18 and heart disease has been proposed by clinical studies linking higher levels of IL-18 with increased risk of acute myocardial infarction, heart failure and cardiac death (O'Brien et al. 2014). Experimental animal models have clearly shown that IL-18 is produced in the heart, also by cardiomyocytes, and also has very specific effects affecting cardiomyocyte function in vitro and in vivo (O'Brien et al. 2014). IL-18 induces hypertrophy of cardiomyocytes and impairs the systolic function (O'Brien et al. 2014, Toldo et al. 2014). Daily injections of IL-18 impaired diastolic function in the mouse heart, inhibiting myocardial relaxation, probably through an effect on the intracellular calcium transients (Woldbaek et al. 2005). Prolonged treatment with IL-18 also induces a phenotype of HFpEF in which impaired diastolic function is associated with elevated LV filling pressures, LV hypertrophy and interstitial fibrosis (Woldbaek et al. 2005, Platis et al. 2008). Experimental data also suggest that IL-18 has negative effects on the heart following myocardial ischaemia and in acute myocarditis (O'Brien et al. 2014). Hillestad and colleagues now not only confirm the central role of IL-18 in a model of hypoxia in the mouse, and the effects on PLN (Larsen et al. 2008), but also identify in IL-18 BP a potentially clinically valuable strategy. Recombinant human IL-18 BP is already being tested in phase II clinical trials (Dinarello et al., 2013; O'Brien et al. 2014). The clinical relevance of the new data presented is therefore large. IL-18 may provide the elusive link between metabolic derangements, that is, hypoxia, and cardiac diastolic dysfunction. There is a clear association between chronic obstructive pulmonary disease and diastolic dysfunction (Funk et al. 2008), and a strategy of IL-18 blockade may prove valuable in both limiting lung injury as well as restoring cardiac diastolic function. Moreover, the large pre-clinical evidence linking IL-18 and heart failure suggests that a strategy of IL-18 blockade may be valuable also in heart failure unrelated to pulmonary disease. In this regard, the prevalence of HFpEF is growing exponentially and contrary to systolic heart failure, there are no current therapeutic strategies proven efficacious for the treatment of diastolic heart failure. Testing IL-18 blockade in other models of diastolic dysfunction will help to understand whether this strategy may be effective to treat diastolic dysfunction and HFpEF beyond the dysfunction associated with hypoxia. Dr. Toldo is supported by an American Heart Association Post-Doctoral Grant. During the last 36 months, Dr. Abbate has received research grants from Novartis (Basel, Switzerland) and AB2 Bio (Losanne, Switzerland).
Source: Acta Physiologica
DOI: 10.1111/apha.12403
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funder: American Heart Association
OpenAlex ID: W2102034262