Krishna K. Gaddam

Effects of Dietary Sodium Reduction on Blood Pressure in Subjects With Resistant Hypertension Results From a Randomized Trial

Observational studies indicate a significant relation between dietary sodium and level of blood pressure. However, the role of salt sensitivity in the development of resistant hypertension is unknown. The present study examined the effects of dietary salt restriction on office and 24-hour ambulatory blood pressure in subjects with resistant hypertension. Twelve subjects with resistant hypertension entered into a randomized crossover evaluation of low (50 mmol/24 hours×7 days) and high sodium diets (250 mmol/24 hours×7 days) separated by a 2-week washout period. Brain natriuretic peptide; plasma renin activity; 24-hour urinary aldosterone, sodium, and potassium; 24-hour ambulatory blood pressure monitoring; aortic pulse wave velocity; and augmentation index were compared between dietary treatment periods. At baseline, subjects were on an average of 3.4±0.5 antihypertensive medications with a mean office BP of 145.8±10.8/83.9±11.2 mm Hg. Mean urinary sodium excretion was 46.1±26.8 versus 252.2±64.6 mmol/24 hours during low- versus high-salt intake. Low- compared to high-salt diet decreased office systolic and diastolic blood pressure by 22.7 and 9.1 mm Hg, respectively. Plasma renin activity increased whereas brain natriuretic peptide and creatinine clearance decreased during low-salt intake, indicative of intravascular volume reduction. These results indicate that excessive dietary sodium ingestion contributes importantly to resistance to antihypertensive treatment. Strategies to substantially reduce dietary salt intake should be part of the overall treatment of resistant hypertension.

Characterization of Resistant Hypertension: Association Between Resistant Hypertension, Aldosterone, and Persistent Intravascular Volume Expansion

BACKGROUND Resistant hypertension is a common clinical problem and greatly increases the risk of target organ damage. METHODS We evaluated the characteristics of 279 consecutive patients with resistant hypertension (uncontrolled despite the use of 3 antihypertensive agents) and 53 control subjects (with normotension or hypertension controlled by using <or=2 antihypertensive medications). Participants were prospectively examined for plasma aldosterone concentration, plasma renin activity, aldosterone to renin ratio, brain-type natriuretic peptide, atrial natriuretic peptide, and 24-hour urinary aldosterone (UAldo), cortisol, sodium, and potassium values while adhering to a routine diet. RESULTS Plasma aldosterone (P < .001), aldosterone to renin ratio (P < .001), 24-hour UAldo (P = .02), brain-type natriuretic peptide (P = .007), and atrial natriuretic peptide (P = .001) values were higher and plasma renin activity (P = .02) and serum potassium (P < .001) values were lower in patients with resistant hypertension vs controls. Of patients with resistant hypertension, men had significantly higher plasma aldosterone (P = .003), aldosterone to renin ratio (P = .02), 24-hour UAldo (P < .001), and urinary cortisol (P < .001) values than women. In univariate linear regression analysis, body mass index (P = .01), serum potassium (P < .001), urinary cortisol (P < .001), urinary sodium (P = .02), and urinary potassium (P < .001) values were correlated with 24-hour UAldo levels. Serum potassium (P = .001), urinary potassium (P < .001), and urinary sodium (P = .03) levels were predictors of 24-hour UAldo levels in multivariate modeling. CONCLUSIONS Aldosterone levels are higher and there is evidence of intravascular volume expansion (higher brain-type and atrial natriuretic peptide levels) in patients with resistant hypertension vs controls. These differences are most pronounced in men. A significant correlation between 24-hour urinary aldosterone levels and cortisol excretion suggests that a common stimulus, such as corticotropin, may underlie the aldosterone excess in patients with resistant hypertension.

Spironolactone reduces severity of obstructive sleep apnoea in patients with resistant hypertension: A preliminary report

Obstructive sleep apnoea (OSA) and hyperaldosteronism are very common in subjects with resistant hypertension. We hypothesized that aldosterone-mediated chronic fluid retention may influence OSA severity in patients with resistant hypertension. We tested this in an open-label evaluation by assessing the changes in the severity of OSA in patients with resistant hypertension after treatment with spironolactone. Subjects with resistant hypertension (clinical blood pressure (BP) ⩾140/90 mm Hg on ⩾3 antihypertensive medications, including a thiazide diuretic and OSA (defined as an apnoea–hypopnoea index (AHI) ⩾15) had full diagnostic, polysomnography before and 8 weeks after spironolactone (25–50 mg a day) was added to their ongoing antihypertensive therapy. In all, 12 patients (mean age 56 years and body mass index 36.8 kg m–2) were evaluated. After treatment with spironolactone, the AHI (39.8±19.5 vs 22.0±6.8 events/h; P<0.05) and hypoxic index (13.6±10.8 vs 6.7±6.6 events/h; P<0.05), weight and clinic and ambulatory BP were significantly reduced. Plasma renin activity (PRA) and serum creatinine were significantly higher. This study provides preliminary evidence that treatment with a mineralocorticoid receptor antagonist substantially reduces the severity of OSA. If confirmed in a randomized assessment, it will support aldosterone-mediated chronic fluid retention as an important mediator of OSA severity in patients with resistant hypertension.

Rapid Reversal of Left Ventricular Hypertrophy and Intracardiac Volume Overload in Patients With Resistant Hypertension and Hyperaldosteronism A Prospective Clinical Study

We have shown previously that patients with resistant hypertension and hyperaldosteronism have increased brain natriuretic peptide suggestive of increased intravascular volume. In the present study, we tested the hypothesis that hyperaldosteronism contributes to cardiac volume overload. Thirty-seven resistant hypertensive patients with hyperaldosteronism (urinary aldosterone ≥12 &mgr;g/24 hours and plasma renin activity ≤1.0 ng/mL per hour) and 71 patients with normal aldosterone status were studied. Both groups had similar blood pressure and left ventricular mass, whereas left and right ventricular end-diastolic volumes measured by cardiac MRI were greater in high versus normal aldosterone subjects (P<0.05). Spironolactone treatment (19 patients in the high aldosterone group and 15 patients from the normal aldosterone group participated in the follow-up) resulted in a significant decrease in clinic systolic blood pressure, right and left ventricular end diastolic volumes, left atrial volume, left ventricular mass, and brain natriuretic peptide at 3 and 6 months of follow-up in patients with high aldosterone, whereas in those with normal aldosterone status, spironolactone decreased blood pressure and left ventricular mass without changes in ventricular or atrial volumes or plasma brain natriuretic peptide. Hyperaldosteronism causes intracardiac volume overload in patients with resistant hypertension in spite of conventional thiazide diuretic use. Mineralocorticoid receptor blockade induces rapid regression of left ventricular hypertrophy irrespective of aldosterone status. In subjects with high aldosterone, mineralocorticoid receptor blockade induces a prominent diuretic effect compared with a greater vasodilatory effect in subjects with normal aldosterone status.

Relation of Dietary Salt and Aldosterone to Urinary Protein Excretion in Subjects With Resistant Hypertension

Experimental data indicate that the cardiorenal effects of aldosterone excess are dependent on concomitant high dietary salt intake. Such an interaction of endogenous aldosterone and dietary salt has not been observed previously in humans. We assessed the hypothesis that excess aldosterone and high dietary sodium intake combine to worsen proteinuria in patients with resistant hypertension. Consecutive subjects with resistant hypertension (n=84) were prospectively evaluated by measurement of 24-hour urinary aldosterone (Ualdo), sodium, and protein (Uprot) excretion. Subjects were analyzed according to aldosterone status (high: Ualdo ≥12 &mgr;g/24 hours; or normal: <12 &mgr;g/24 hours) and dietary salt intake based on tertiles of urinary sodium. The mean clinic blood pressure for all of the subjects was 161.4±22.4/89.8±13.5 mm Hg on an average of 4.3 medications. There was no blood pressure difference between study groups. Uprot was significantly higher in the 38 subjects with high Ualdo compared with the 46 subjects with normal Ualdo (143.0±83.8 versus 95.9±81.7 mg/24 hours; P=0.01). Among subjects with high Ualdo, Uprot increased progressively across urinary sodium groups (P<0.05). In contrast, there was no difference in Uprot across sodium tertiles among subjects with normal Ualdo. A positive correlation between Uprot and urinary sodium (r=0.47; P=0.003) was observed in subjects with high Ualdo but not in subjects with normal Ualdo (r=0.18; P value not significant). These results suggest that aldosterone excess and high dietary salt combine to increase urinary protein excretion.

Mechanisms and treatment of resistant hypertension

Resistant hypertension is defined as blood pressure (BP) that remains uncontrolled in spite of the use of ≥3 antihypertensive medications. Stricter BP goals, higher obesity rates, older age, and increased use of exogenous BP‐elevating substances are related to an increasing prevalence of resistant hypertension. The evaluation of patients with resistant hypertension is focused on identifying contributing and secondary causes of hypertension, including hyperaldosteronism, obstructive sleep apnea, chronic kidney disease, renal artery stenosis, and pheochromocytoma. Hyperaldosteronism is now recognized as the most common cause of resistant hypertension, and all patients with resistant hypertension should be screened with a plasma aldosterone/renin ratio even if the serum potassium level is normal. Treatment includes removal of contributing factors, appropriate management of secondary causes, and use of effective multidrug regimens. Recent studies indicate that the addition of spironolactone to standard treatment induces significant BP reduction in most patients with resistant hypertension.

Relation of torsion and myocardial strains to LV ejection fraction in hypertension.

OBJECTIVES The goal of this study was to define the mechanism of preserved ejection fraction (EF) despite depressed myocardial strains in hypertension (HTN). BACKGROUND Concentric left ventricular (LV) remodeling in HTN may have normal or supranormal EF despite depressed myocardial strains. The reason for such discordance is not clear. The aim of this study was to comprehensively evaluate the LV mechanics in a well-defined HTN population to define underlying reasons for such a paradox. METHODS Sixty-seven patients with resistant HTN and 45 healthy control subjects were studied by cardiac magnetic resonance imaging and tissue tagging with 3-dimensional analysis. Amplitude and directional vector of longitudinal (Ell), circumferential (Ecc), and principal strain for maximal shortening (E3) were computed at basal, mid, and distal LV levels, respectively. LV torsion, defined as the rotation angle of apex relative to base, and LV twist, which accounts for the effects of differential LV remodeling on torsion for comparison among the 2 groups, were also calculated. RESULTS LV mass index and LV mass/LV end-diastolic volume ratio were significantly higher in the HTN group compared with controls, consistent with concentric LV remodeling. Ell and Ecc were significantly decreased in amplitude with altered directional vector in HTN compared with controls. However, the amplitude of E3 was similar in the 2 groups. Torsion and twist were significantly higher in HTN, which was mainly due to increase in apical rotation. The HTN group demonstrated significantly increased LV wall thickening compared with controls that resulted in greater LVEF in the HTN group compared with controls (70% vs. 65%, p < 0.001, respectively). CONCLUSIONS In compensated LV remodeling secondary to HTN, there is increased LV wall thickening with preserved E3 and increased torsion compared with normal controls. This, therefore, contributes to supranormal LVEF in HTN despite depressed longitudinal and circumferential strains.

Aldosterone excess and resistance to 24-h blood pressure control

Background Aldosterone excess has been reported to be a common cause of resistant hypertension. To what degree this represents true treatment resistance is unknown. Objective The present study aimed to compare the 24-h ambulatory blood pressure monitoring (ABPM) levels in resistant hypertensive patients with or without hyperaldosteronism. Methods Two hundred and fifty-one patients with resistant hypertension were prospectively evaluated with an early-morning plasma renin activity (PRA), 24-h urinary aldosterone and sodium, and 24-h ABPM. Daytime, night-time, and 24-h blood pressure (BP) and nocturnal BP decline were determined. Hyperaldosteronism (H-Aldo) was defined as suppressed PRA (<1.0 ng/ml per h or <1.0 μg/l per h) and elevated 24-h urinary aldosterone excretion (≥ 12 μg/24-h or ≥ 33.2 nmol/day) during ingestion of the patients routine diet. Results In all patients, the mean office BP was 160.0 ± 25.2/89.4 ± 15.3 mmHg on an average of 4.2 medications. There was no difference in mean office BP between H-Aldo and normal aldosterone status (N-Aldo) patients. Daytime, night-time, and 24-h systolic and diastolic BP were significantly higher in H-Aldo compared to N-Aldo males. Daytime, night-time, and 24-h systolic BP were significantly higher in H-Aldo compared to N-Aldo females. Multivariate analysis indicated a significant interaction between age and aldosterone status such that the effects of aldosterone on ambulatory BP levels were more pronounced with increasing age. Conclusions In spite of similar office BP, ABPM levels were higher in resistant hypertensive patients with H-Aldo. These results suggest that high aldosterone levels impart increased cardiovascular risk not reflected by office BP measurements.

Hypertension and Cardiac Failure in its Various Forms

Hypertension clearly increases the risk of systolic or diastolic heart failure. With aging population and advancements in treatment of cardiovascular diseases, the prevalence of heart failure is ever-increasing and is a principal cause of cardiovascular morbidity and mortality. Treating hypertension has been shown to decrease the risk of development of heart failure and hence underscores the early recognition and treatment of hypertension and hypertensive heart disease. Antihypertensive treatment with drugs from all classes except direct vasodilators is effective in reversing LVH and preventing heart failure. Also, all of the major classes of antihypertensive drugs, particularly beta-blockers and RAS antagonists, with the exception of calcium antagonists, have been shown to improve survival in patients who have LV systolic dysfunction. However, phenotyping and identifying the pathophysiology and appropriate treatments for patients who have diastolic dysfunction and heart failure with preserved ejection fraction has been a daunting task. At this time, treatment of these patients is largely empiric, focusing on BP control, and treating or avoiding intravascular volume overload.

Effect of spironolactone on diastolic function in hypertensive left ventricular hypertrophy

We have previously shown rapid reversal of left ventricular hypertrophy (LVH) with 6 months of spironolactone therapy in patients with resistant hypertension (HTN), preserved left ventricular ejection fraction and no history of heart failure. In this substudy, we investigated the effect of mineralocorticoid receptor blockade with spironolactone on pre-clinical diastolic dysfunction. Thirty-four patients (19 with high and 15 with normal aldosterone levels) were treated with spironolactone and followed with cardiac magnetic resonance with tissue tagging at baseline, 3 and 6 months of treatment. Serum markers of collagen turnover (C-propeptide of type-I procollagen and carboxy-terminal telopeptide of type-I collagen) were measured at baseline and at 6 months. At baseline, patients demonstrated reduced E/A ratio (volumetric normalized peak early filling rate/late filling rate, normalized to left ventricular end-diastolic volume), lower peak early-diastolic mitral annular velocity and lower peak early-diastolic circumferential strain rates compared to the reference values obtained from 45 normal controls without HTN or cardiac disease (all comparisons, P<0.01). No significant change occurred in diastolic filling, relaxation parameters or collagen markers with spironolactone therapy at 6 months irrespective of aldosterone status despite significant reduction in left ventricular mass index in both high- and normal-aldosterone groups. In conclusion, resistant HTN patients with LVH demonstrate significant pre-clinical diastolic dysfunction. Short-term spironolactone therapy may not lead to improvement in diastolic function despite rapid reversal of LVH.