Salt-sensitive hypertension in young people: How can we predict the risk of hypertensive heart disease?

Salt-sensitive hypertension (SSHT) is characterized by blood pressure (BP) elevation in response to high dietary salt intake and is considered to increase the risk of cardiovascular (CV) disease and mortality beyond its effects on BP. This concept has been authoritatively underlined by a recent Scientific Statement of the American Heart Association (AHA) that defined SSHT as “a risk factor for CV mortality and morbidity, independent of and as powerful as BP.”¹

Despite since the beginning of the 20th century the relationship between sodium intake and BP is one of the most investigated aspects of the pathophysiology of hypertension, is not yet entirely clear how high salt intake is mechanistically associated with high BP. Two main hypotheses have been advanced in this long research journey, often opposed to each other. Indeed, it has been suggested that SSHT may be the consequence of impaired renal regulation of intravascular volume and, therefore, cardiac output (renal dysfunction theory) or, alternatively, resulting from altered regulation of vascular tone in resistance arteries (vaso-dysfuntion theory).²

Although the criteria for detecting salt-sensitivity are not standardized, it has been reported that approximately 40% of hypertensive individuals and 20% of normotensive individuals are salt-sensitive.³ Salt-sensitivity has been consistently shown to increase with age, which has been linked to impaired renal sodium handling and a decline in renal function, even in the absence of kidney disease, and with comorbidities associated with altered kidney and vascular function such as renal disease, diabetes, obesity and hypertension.⁴ This condition affects females more frequently, regardless of menopause, Asian and African-American populations.⁵ Whether salt-sensitivity increases the risk of cardiac and extracardiac organ damage (an intermediate step linking unhealthy risk factors to CV disease) independent of other risk factors, such as BP and obesity remains a subject of debate.^6-8 Even more unclear is the topic regarding clinical correlates and predictors of subclinical organ damage in patients with SSHT.

In this issue of the Journal Wan and colleagues⁹ focus on an issue of great interest, namely the factors associated with left ventricular hypertrophy (LVH) in young patients with SSHT. Before addressing in detail the results of this study some more general considerations on current evidence in this research area and related topics may warrant some considerations.

The mechanisms underlying the development of LVH, a cardinal marker of target organ damage in the setting of hypertension have not been fully elucidated. Chronic BP overload load has long been considered the closest and most important factor responsible for this process. It has been consistently demonstrated, however, that BP, even when accurately measured with ambulatory monitoring that reflects the 24-h global BP load accounts for approximately 30%−40% of the observed variance of LV mass (LVM). A large body of experimental and clinical studies supports the view that neurohormones, growth factors and cytokines (i.e., angiotensin II, aldosterone, catecholamines endothelin I and insulin-like growth factor), in association with ethnic/genetic predisposition and unhealthy lifestyle habits such as excessive alcohol consumption, smoking and salt intake concur to trigger, maintain and worsen cardiac organ damage over time. In particular, growing and consistent evidence has accumulated on the key role of circulating and local renin–angiotensin–aldosterone system (RAAS) in developing of myocardial hypertrophy and fibrosis, regardless of the hemodynamic load on the heart.¹⁰ A large amount of information provided by experimental and human investigations suggests a link between dietary sodium intake, SSHT and risk of LVH.^11-13 Seminal experimental studies showed that saline overload induces a progressive increase in LVM. Conversely, dietary salt restriction has been reported to regress LVH in hypertensive rats and similar findings have been obtained in patients with SSHT. Although the mechanisms of myocardial and fibrous tissue growth induced by sodium overload remain incompletely understood, activation of sympathetic nervous system and RAAS is believed to have a role in this process. High dietary salt intake also activates myocardial growth through hemodynamic mechanisms such as BP and volume overload and stimulates phospholipase C-activity mediated by platelet-derived growth factors. Focusing on the relationship between sodium intake and cardiac structure in the clinical setting a couple of studies carried out in general population samples deserve to be mentioned. The Strong Heart Family Study including 1065 young adults revealed that an increase in sodium/potassium ratio was related with higher LVM index in prehypertensive or hypertensive individuals but not in their normotensive counterparts.⁸ The African-PREDICT study, aimed to assess whether LVM associates with sodium excretion in 681 young adults free from overt CV disease (41% men, 50% black), indicated that a higher salt intake may have an independent role in promoting an increase in LVM in the fraction of individuals with masked hypertension but not in normotensives.⁷ However, clinical evidence on the association between salt-sensitivity and CV outcomes is still limited. Recently, a longitudinal study investigated the predictive value of the salt-sensitivity phenotype in the development of CV events and hypertensive target organ damage (i.e., LVH, albuminuria carotid atherosclerosis) in a small cohort of essential hypertensive patients.¹⁴ During 16 years of follow-up the relative risk of developing CV events was 12-fold higher and the development of moderate to severe organ damage was 10 times higher in patients with SSHT than in their counterparts without it. It should be noted that interpreting of the findings provided by of the current literature on this topic we cannot ignore the fact that the definition of the SSHT phenotype is based on heterogeneous criteria, and the extent of the response above which the patient is considered to be salt-sensitive varies largely among studies. Among the various methods of testing for salt-sensitivity, the carefully controlled out-dietary protocol has been suggested to provide the highest test-retest repeatability for identifying salt-sensitive subjects.¹⁵ The so-called “inpatient acute protocol” aimed to measure BP responses to furosemide immediately after venous infusion of saline solution might be viewed as an indirect test of salt-sensitivity. At the current time, unfortunately, tests for salt-sensitivity applicable in clinical practice have yet to be identified.¹⁶

In their study, Wan and colleagues⁹ salt-sensitivity was assessed using a modified acute saline test based on a 4-hour intravenous infusion of 2000 mL of 0.9% saline and followed by oral administration of furosemide at the standard dose of 40 mg. An increase in the mean arterial pressure (MAP) > 5 mmHg after acute salt loading and/or a decrease in MAP > 10 mmHg after furosemide (i.e., furosemide sensitivity test) were considered diagnostic criteria for SSHT. 580 patients (35% female) without severe cardiovascular and renal disease (22.5% obese, 18.7% treated with BP-lowering drugs and 9.8% with diabetes,) aged 18−45 who met the criteria for SSHT were included in the study and underwent blood biochemical examination, standard echocardiography and ambulatory BP monitoring. The prevalence of LVH (i.e., LVMI > 115 g/m² in men and 95 g/m² in women) in the total population was 25.2%. It is worth noting that patients with LVH had markedly higher office systolic BP values ​​than patients with normal LVMI (183 ± 17 vs. 167 ± 17 mmHg) but unexpectedly similar mean 24-h SBP values (158 ± 21 vs. 156 ± 21 mmHg). Equally noteworthy is the fact, in line with many data provided by experimental studies in animals with SSHT, approximately 80% of patients had concentric LVH.¹⁷ In this clinical context, Wan and colleagues⁹ demonstrated that a nomogram including seven variables such as age, gender, office systolic BP, duration of hypertension, abdominal obesity, triglyceride-glucose index, and estimated glomerular filtration rate (eGFR) allowed to identify patients with LVH with a high coefficient of precision. This study deserves to be appreciated as it sheds light on the relationship between a still insufficiently studied hypertensive phenotype and subclinical cardiac organ damage. However, factors associated with LVH in this SSHT cohort are essentially no different than those consistently reported in the general hypertensive population, including to the greater exposure to the risk of subclinical organ damage in women.¹⁸ Overall, the contribution of this study to current knowledge remains rather elusive due to some important methodological limitations. The cut-off used for classifying SSHT (i.e., a change in MAP of at least 5 mmHg) was lower than that generally applied in the setting of hypertension (i.e., 8−10 mmHg) thus including patients whose SSHT trait is borderline, often not reproducible, and therefore characterized by uncertain clinical significance. The lack of a hypertensive control group did not allow to prove whether and to what extent patients with SSHT have a higher prevalence of LVH compared to salt-resistant counterparts, to investigate differences in LV geometry and, more importantly, to compare the clinical variables linked to LVH. Although the study in developing the nomogram for the prediction of LVH considered variables routinely available in clinical practice, it would have been of extreme interest to include among the predictors nocturnal BP which is known to be associated with sodium sensitivity.¹⁹

Further nonmethodological observations concern the following points. One, the extension of the results of this study to the general population of hypertensives with SSHT should be taken with extreme caution as focused on a cohort of hospitalized patients with high prevalence of severe hypertension. Although previous evidence suggests that women are more exposed to the pressure effects of sodium sensitivity,²⁰ they represented only about a third of the sample analyzed in the present study.⁹

In conclusion, the study by Wan and colleagues⁹ undoubtedly has the merit of having indirectly underlined the limits of the protocols to assess salt-sensitive and the need to develop reliable biomarkers in the near future that allow the identification of SSHT in daily clinical practice.

The authors declare no conflicts of interest.