Diagnostic tools for hypertension and salt sensitivity testing

Abstract

Purpose of review: One-third of the world's population has hypertension and it is responsible for almost 50% of deaths from stroke or coronary heart disease. These statistics do not distinguish salt-sensitive from salt-resistant hypertension or include normotensives who are salt-sensitive even though salt sensitivity, independent of blood pressure, is a risk factor for cardiovascular and other diseases, including cancer. This review describes new personalized diagnostic tools for salt sensitivity.

Recent findings: The relationship between salt intake and cardiovascular risk is not linear, but rather fits a J-shaped curve relationship. Thus, a low-salt diet may not be beneficial to everyone and may paradoxically increase blood pressure in some individuals. Current surrogate markers of salt sensitivity are not adequately sensitive or specific. Tests in the urine that could be surrogate markers of salt sensitivity with a quick turn-around time include renal proximal tubule cells, exosomes, and microRNA shed in the urine.

Summary: Accurate testing of salt sensitivity is not only laborious but also expensive, and with low patient compliance. Patients who have normal blood pressure but are salt-sensitive cannot be diagnosed in an office setting and there are no laboratory tests for salt sensitivity. Urinary surrogate markers for salt sensitivity are being developed.

FIGURE 1

Venn diagram of the distribution of individuals with hypertension, salt sensitivity, or both in the US population [7,8,11]. The prevalence of hypertension increased from 23.9% in 1988–1994 to 28.5% in 1999–2000, but did not change significantly between 1999–2000 (28.1%) and 2007–2008 (30.9%) [7,11,12]. Women are slightly more likely than men to have hypertension, with 35 million women and 30 million men with the disease [12]. The prevalence of hypertension is highest in persons 65 years and older (69.7%), persons with Medicare coverage (68.1%), followed by those with less than high school education (42.1%), non-Hispanic Blacks (38.6%), non-Hispanic Whites (32.3%), Asian Americans (39%), and Mexican Americans (17.3%) [–14]. However, the prevalence of hypertension in foreign-born African Americans and black persons living outside the United States is similar to other ethnic groups [14].

FIGURE 2

Diagrammatic representation of two protocols for testing for salt sensitivity. The first method requires 29 days to administer. A diagnosis of salt sensitivity is made if the individual has a 5–10% increase or decrease in blood pressure following an increase or decrease in salt intake, relative to blood pressure on a normal salt intake (data from [–25,26▪,34▪▪]).

FIGURE 3

The distribution of salt-sensitive, salt-resistant, and inverse salt-sensitive individuals in a population of 183 individuals tested for salt sensitivity is shown. Elevated blood pressure occurs in salt-sensitive individuals on a high-salt diet and paradoxically in inverse salt-sensitive individuals on a low-salt diet [34▪▪]. Mean arterial pressure (MAP) increases over 7 mmHg on a high-salt diet were classified as salt-sensitive, whereas blood pressure decreases over 7mmHg were considered as inverse-salt-sensitive (data from [34▪▪]).

FIGURE 4

All salt-sensitive hypertensive individuals have at least three GRK4 gene variants, but hypertensive individuals with no GRK4 gene variants were salt-resistant. There was an inverse relationship between the increase in mean arterial blood pressure (ΔMAP) and fold increase in sodium excretion (UNaV fold Δ) with the change in salt intake from low to high in hypertensive MAP classified according to the number of GRK4 variant alleles. The ΔMAP is shown by the bars, while the fold increase in sodium excretion is depicted by the circles connected by a continuous line and right-hand axis. The number of salt-resistant (SR) subjects/number of salt-sensitive (SS) individuals is shown in parenthesis for each bar in the bar graph. *P<0.05 vs. at least three alleles, factorial ANOVA, Newman-Keuls test. Data are mean±SE; there are no error bars in instances in which the symbol is bigger than the SE (modified with permission [39]).

FIGURE 5

The GRK4 486V allele is associated with an increase in systolic blood pressure (SBP) in hypertensive patients (HT), regardless of sex (male HT, MHT) and obesity (obese HT, OHT) but not in normotensive patients (NT). The total allele effect on SBP was over 30mmHg (data from [103]).