Journal of Hypertension:
From hypertension to hypertrophy to heart failure: the role of cardiotrophin-1
Schillaci, Giuseppea,b; Pucci, Giacomoa,b; Perlini, Stefanoc
aDipartimento di Medicina Clinica e Sperimentale, Università di Perugia, Perugia
bStruttura Complessa di Medicina Interna, Ospedale ‘S. Maria’, Terni
cClinica Medica II, Dipartimento di Medicina Interna, Fondazione IRCCS San Matteo, Università di Pavia, Italy
Correspondence to Professor Giuseppe Schillaci, Unità di Medicina Interna, Università degli Studi di Perugia, Ospedale ‘S. Maria’, viale Tristano di Joannuccio, 1, IT-05100 Terni, Italy. Tel: +39 0744 205201; e-mail: firstname.lastname@example.org
Heart failure is a major and growing public health issue, with high prevalence, poor clinical outcomes, and large healthcare costs . Hypertension, a leading risk factor for congestive heart failure, represents the most common comorbidity in patients with heart failure , and carries an attributable risk of over 40% at the population level . According to the American College of Cardiology/American Heart Association guidelines, all hypertensive patients without symptoms of heart failure and without structural heart disease should be classified as belonging to stage A, which denotes a high risk for heart failure, whereas those with structural heart involvement denoted, for instance, by left ventricular (LV) hypertrophy should be classified as belonging to stage B .
Transition from hypertension to overt heart failure is characterized by a number of functional and structural alterations, which include LV hypertrophy and asymptomatic LV systolic and diastolic dysfunction . Although LV systolic chamber function is almost invariably normal or even above normal in uncomplicated patients with essential hypertension [6,7], the use of the more physiologic midwall mechanic indexes identifies reduced myocardial systolic function in a large subgroup of hypertensive patients, whose chamber function is still preserved thanks to a more concentric LV geometry [8–9]. In individuals with untreated essential hypertension, the prevalence of asymptomatic LV systolic dysfunction is as low as 4% when considering traditional endocardial or chamber mechanics [10,11], and increases to 18% when assessed through midwall fractional shortening . Also, midwall fractional shortening has a strong, independent, inverse relationship with a number of prognostically adverse markers including relative wall thickness as an index of LV concentric geometry , LV mass , and an inappropriately high LV mass, that is, beyond values required to compensate cardiac workload at a given body size and sex . The coexistence of a low midwall fractional shortening and a high LV mass identifies a subgroup of hypertensive patients at a particularly high risk for cardiac morbidity and mortality . Moreover, LV hypertrophy regression and normalization of chamber geometry during antihypertensive treatment are associated with improved midwall function .
Epidemiological studies have identified clinical and demographic factors that increase the risk of developing LV systolic dysfunction in hypertension, including age, male sex, smoking, LV hypertrophy, and uncontrolled blood pressure [10,12,16]. However, knowledge of these risk factors alone cannot provide the means to predict the presence of systolic dysfunction, holds no real specificity and sensitivity, and is not useful in a clinically relevant context. As such, analytic measurements that would be easy to use and cost-effective for the detection of LV systolic dysfunction in an ambulatory setting would have significant clinical import. Although hemodynamic factors play a well recognized role in the transition from hypertension to heart failure, the role of a wide array of nonhemodynamic factors has also been recognized [17,18]. Table 1 provides a list of biological markers that have been associated to LV systolic dysfunction.
In 2005, González et al. proposed cardiotrophin-1, a cytokine belonging to the interleukin 6 family, as a new serological marker for LV mass, suggesting its use in serial assessment of hypertensive cardiac damage. Indeed, cardiotrophin-1 induces cell proliferation, hypertrophy, and secretion of extracellular matrix proteins in aortic vascular smooth muscle cells both in vitro and in vivo, suggesting a role for cardiotrophin-1 in arterial fibrosis and stiffness. Moreover, elevated plasma concentrations of cardiotrophin-1 have been reported in patients with a variety of diseases, including hypertension  and aortic stenosis , indicating that this cytokine may contribute to the development of chronic pressure overload LV hypertrophy and dysfunction. Two recent studies also suggest a potentially important role of cardiotrophin-1 in the development of cardiovascular fibrosis. On the contrary, in normotensive Wistar rats chronic cardiotrophin-1 administration induces blood pressure-independent cardiac, vascular and renal fibrosis, associated with increased LV volumes, reduced fractional shortening and ejection fraction, vascular media thickening, and increased arterial stiffness and glomerular and tubulointerstitial fibrosis. . On the contrary, lifelong cardiotrophin-1 absence increases median longevity in senescent cardiotrophin-1-null mice together with decreased arterial fibrosis, stiffness, and senescence, likely through downregulating apoptotic, senescence, and inflammatory pathways .
The role of cardiotrophin-1 in hypertensive heart disease is also supported by a number of clinical studies. López et al. found that plasma cardiotrophin-1 was higher in hypertensive patients than in normotensive controls, and even higher in the presence of hypertensive LV hypertrophy. Other studies from the same research group reported a cross-sectional association in hypertensive patients of plasma cardiotrophin-1 with inappropriately high LV mass  and with clinically overt heart failure . Interestingly, treatment-induced decrease of plasma cardiotrophin-1 paralleled LV hypertrophy regression in treated hypertension [19,25]. Data also support an association between cardiotrophin-1 and LV mass in other pathologic states, including hypertrophic  and dilated cardiomyopathy . Other authors could not confirm, however, the above findings. In a study carried out in 446 patients, plasma cardiotrophin-1 levels did not allow to discriminate referent healthy control patients from patients with LV hypertrophy but no evidence of heart failure, and patients with LV hypertrophy and diastolic heart failure . In the same study, a panel of biomarkers of extracellular matrix remodeling and myocyte stress, including matrix metalloproteinases, tissue inhibitors of metalloproteinases, procollagen peptides, and N-terminal probrain natriuretic peptide, were able to predict the presence of LV hypertrophy and diastolic heart failure .
In the current issue of the Journal, Ravassa et al. report on the relationship between cardiotrophin-1 and LV systolic function in human hypertension. Serum cardiotrophin-1 was significantly higher in 278 patients with essential hypertension and LV ejection fraction more than 50% than in 25 healthy controls. More importantly, in hypertensive patients serum cardiotrophin-1 concentration had an inverse correlation with LV midwall fractional shortening, which was independent of the presence of LV hypertrophy, or inappropriately high LV mass.
The impact of serum cardiotrophin-1 on asymptomatic LV systolic dysfunction had not been compared directly previously in hypertensive patients. In this regard, the study by Ravassa et al. is original and conveys new, clinically relevant information, which suggests that determination of serum cardiotrophin-1 might serve as a test for screening hypertensive heart disease. Nonetheless, the study leaves some questions open. First, although the relation between cardiotrophin-1 and midwall fractional shortening was found to be independent of LV hypertrophy, no adjustment was allowed for LV mass and relative wall thickness as continuous variables in the whole sample of 278 patients. The authors only report a significant independent inverse relation among the 178 patients with LV hypertrophy. A more appropriate approach would be testing whether the association stands in the whole population, and subsequently whether LV hypertrophy is a significant effect modifier of the relation. Second, the limited sample size and the tiny number of normotensive controls (only 25 patients) make it difficult to draw definite conclusions on the independent contribution of cardiotrophin-1 in stratifying the risk of LV systolic dysfunction. Third, most of the published studies on the association between circulating cardiotrophin-1 and LV structure and function have been obtained by the same research group [19–22,24–27,30], whereas studies from other groups could not confirm the same findings . Also, the inclusion of hypertensive patients under blood pressure-lowering drug treatment may be misleading in the interpretation of the study results.
Does the available evidence support the use of cardiotrophin-1 as a screening tool for hypertensive heart disease in the clinical practice? A few years ago, Morrow and De Lemos  had proposed a set of three criteria to be fulfilled in order to define a new biological marker as clinically useful. First, accurate, reproducible, accessible assays with rapid turn-around and at a reasonable cost must be available to the clinician. Second, the biomarker must provide information that adds to or improves upon the current clinical assessment and is validated in more than one study. Third, knowing the result of the test should help in clinical decision-making. In our opinion, despite a growing body of evidence, cardiotrophin-1 may not yet fulfil the above criteria. Overall, the time is not yet ripe for recommending the widespread use of circulating cardiotrophin-1 as a clinically valuable tool for the biochemical detection and follow-up of hypertensive heart disease. However, the study by Ravassa et al. represents a step toward a more comprehensive understanding of the factors underlying the role of cardiotrophin-1 in hypertensive heart disease, and their findings are provocative enough to be explored further in intervention trials aimed at assessing whether clinical monitoring guided by cardiotrophin-1 may improve the management of patients with hypertension-related cardiac disease. Moreover, the relationships between cardiotrophin-1 and systolic/diastolic (dys)function in hypertensive heart disease should be further evaluated in larger samples of patients, to properly evaluate the link between this biomarker and the extent of chronic pressure overload cardiac damage.
Conflicts of interest
There are no conflicts of interest.
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