Jump to
Soluble fms-Like Tyrosine Kinase-1 and Heart Failure (p 678)
Heart failure is a major cause of morbidity and mortality worldwide. Soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor (PLGF), has been shown to be implicated in the pathogenesis of cardiovascular disease. We have already revealed that production of sFlt-1 is reduced in chronic kidney disease (CKD) and correlates with the development of atherosclerosis and cardiovascular events. Elevated levels of placental growth factor are also associated with a greater risk of cardiovascular events in patients with CKD. However, the significance of sFlt-1 in heart failure remains unclear. Therefore, we investigated the role of sFlt-1 in heart failure, using sFlt-1-knockout mice. In the present study, we demonstrated that decreased sFlt-1 production exacerbates pressure overload–induced infiltration of macrophages into the left ventricle, left ventricular hypertrophy, fibrosis, and subsequent heart failure. Recombinant sFlt-1 protein administration confirmed these findings, and treatment with an anti–placental growth factor-neutralizing antibody (α placental growth factor) or neutralizing monocyte chemoattractant protein-1 antibody inhibited the progression of cardiac hypertrophy and heart failure. Considering the downregulation of sFlt-1 production in CKD, our findings provide a new insight into the molecular mechanism responsible for cardiac remodeling and heart failure accompanied by CKD. Taken together, regulation of endogenous sFlt-1 could be a novel therapeutic target of cardiovascular disease in CKD.
Parental Hypertension and Offspring Arterial Stiffness (p 584)
High arterial stiffness is increasingly recognized as a key antecedent of hypertension. Arterial stiffness is moderately heritable, but studies evaluating familial clustering of high arterial stiffness are sparse. Specifically, it is not known whether nonhypertensive offspring of individuals predisposed to develop high blood pressure (by virtue of a positive family history) have higher levels of arterial stiffness relative to their counterparts without parental hypertension. In our community-based sample of young, nonhypertensive adults, we observed greater arterial stiffness indices (carotid-femoral pulse wave velocity, augmentation index, and forward pressure wave amplitude) in those who had parents with hypertension compared with those without parental hypertension. Moreover, offspring who had both parents with hypertension had greater arterial stiffness indices than offspring who had only 1 hypertensive parent. Furthermore, higher arterial stiffness aggregated within families. Additional clinical studies of multiethnic cohorts are warranted to replicate our findings. The clinical corollary of our findings, if confirmed, is that higher aortic stiffness may serve as a valuable clinical biomarker for stratifying the risk of developing high blood pressure in young individuals with a familial predisposition. Potentially, nonhypertensive individuals with parental hypertension who have higher arterial stiffness may be a high-risk group that could be targeted aggressively with nonpharmacological means to prevent future hypertension, a premise that warrants further investigation. The familial aggregation of vascular stiffness suggests that the presence of elevated vascular stiffness in a parent may be an important indicator of higher vascular stiffness in their offspring.
MR in Isoproterenol-Induced Vascular Dysfunction (p 726)
Rising circulating catecholamines levels and adrenergic receptor stimulation are common features of many cardiovascular disorders, including hypertension, myocardial infarction, congestive heart failure, and acute cerebrovascular events. Although the hyperadrenergic state has a major and independent prognostic impact in these conditions, the vascular effects of β-adrenoceptor (β-AR) overstimulation are still less understood. In this issue, Victorio et al showed genomic and nongenomic activity of vascular mineralocorticoid receptor (MR) in a model of β-AR overstimulation induced by isoproterenol treatment. The MR blockade with spironolactone prevented the increased vasoconstriction, as well as the reduced nitric oxide levels (Figure) and vascular oxidative stress induced in response to β-AR overstimulation. This beneficial vascular effect of spironolactone was associated with an increased dimerization of the endothelial nitric oxide synthase (Figure) and the chaperone HSP90, suggesting a vasculoprotective signaling induced by MR blockade in hyperadrenergic state. Perivascular adipose tissue has been suggested to be a source of MR ligands including aldosterone and glucocorticoids. The authors reported that β-AR overstimulation can exacerbate glucocorticoid production by perivascular fat without significant changes in circulating levels of this hormone. These results imply that β-AR overstimulation regulates perivascular levels of glucocorticoids and vascular MR activity, revealing an additional mechanism for the benefits of MR blockade in cardiovascular disorders associated with sympathetic overactivation.
- © 2016 American Heart Association, Inc.
This Issue
Jump to
Article Tools
Share this Article
- Clinical Implications
