Spironolactone Reduces Aortic Stiffness in Patients With Resistant Hypertension Independent of Blood Pressure Change.

Background Aortic stiffness is an independent predictor of cardiovascular events in patients with arterial hypertension. Resistant hypertension is often linked to hyperaldosteronism and associated with adverse outcomes. Spironolactone, a mineralocorticoid receptor antagonist, has been shown to reduce both the arterial blood pressure (BP) and aortic stiffness in resistant hypertension. However, the mechanism of aortic stiffness reduction by spironolactone is not well understood. We hypothesized that spironolactone reduces aortic stiffness in resistant hypertension independently of BP change. Methods and Results Patients with uncontrolled BP (≥140/90 mm Hg) despite use of ≥3 antihypertensive medications (including diuretics) were prospectively recruited. Participants were started on spironolactone at 25 mg/d, and increased to 50 mg/d at 4 weeks while other antihypertensive medications were withdrawn to maintain constant mean BP. Phase-contrast cardiac magnetic resonance imaging of the ascending aorta was performed in 30 participants at baseline and after 6 months of spironolactone treatment to measure aortic pulsatility, distensibility, and pulse wave velocity. Pulse wave velocity decreased (6.3±2.3 m/s to 4.5±1.8 m/s, P<0.001) and pulsatility and distensibility increased (15.9%±5.3% to 22.1%±7.9%, P<0.001; and 0.28%±0.10%/mm Hg to 0.40%±0.14%/mm Hg, P<0.001, respectively) following 6 months of spironolactone. Conclusions Our results suggest that spironolactone improves aortic properties in resistant hypertension independently of BP, which may support the hypothesis of an effect of aldosterone on the arterial wall. A larger prospective study is needed to confirm our findings.

Plasma xanthine oxidase activity is related to increased sodium and left ventricular hypertrophy in resistant hypertension.

BACKGROUND: The extra-renal effects of aldosterone on left ventricular (LV) structure and function are exacerbated by increased dietary sodium in persons with hypertension. Previous studies demonstrated endothelial dysfunction and increased oxidative stress with high salt diet in normotensive salt-resistant subjects. We hypothesized that increased xanthine oxidase (XO), a product of endothelial cells, is related to 24-h urinary sodium and to LV hypertrophy and function in patients with resistant hypertension (RHTN). METHODS: The study group included persons with RHTN (n = 91), defined as a blood pressure > 140/90 mmHg on ≥ 3 medications at pharmacologically effective doses. Plasma XO activity and 24-h urine were collected, and cardiac magnetic resonance imaging (MRI) was performed to assess LV function and morphology. Sixty-seven normotensive persons on no cardiovascular medications served as controls. A subset of RHTN (n = 19) received spironolactone without salt restriction for six months with follow-up XO activity measurements and MRI analyses. RESULTS: XO activity was increased two-fold in RHTN vs. normal and was positively correlated with LV mass, LV diastolic function, and 24-h urinary sodium. In RHTN patients receiving spironolactone without salt restriction, LV mass decreased, but LV diastolic function and XO activity did not improve. Baseline urinary sodium was positively associated with rate of change of LV mass to volume ratio and the LV E/A ratio. CONCLUSIONS: These results demonstrate a potential role of endothelium-derived oxidative stress and excess dietary salt in the pathophysiology of LV hypertrophy and diastolic dysfunction in persons with RHTN unaffected by the addition of spironolactone.

Left ventricular torsion shear angle volume analysis in patients with hypertension: a global approach for LV diastolic function.

BACKGROUND: Torsion shear angle φ is an important measure of left ventricular (LV) systolic and diastolic functions. Here we provide a novel index utilizing LV normalized torsion shear angle φ ^ volume V ^ loop to assess LV diastolic functional properties. We defined the area within φ ^ V ^ loop as torsion hysteresis area, and hypothesized that it may be an important global parameter of diastolic function. We evaluated the φ ^ changes to increased V ^ during early diastole - d φ ^ / d V ^ as a potential measure of LV suction. METHODS: Sixty resistant hypertension patients (HTN), forty control volunteers were studied using cardiovascular magnetic resonance with tissue tagging. Volumetric and torsional parameters were evaluated. RESULTS: HTN demonstrated concentric remodeling with preserved ejection fraction. HTN had significantly decreased normalized early filling rate, early diastolic mitral annulus velocity and E/A (1.33 ± 1.13 vs. 2.19 ± 1.07, P < 0.0001) vs. control. Torsion hysteresis area was greater (0.11 ± 0.07 vs. 0.079 ± 0.045, P < 0.001) and peak - d φ ^ / d V ^ at early diastole was higher (10.46 ± 8.51 vs. 6.29 ± 3.85, P = 0.002) than control. Torsion hysteresis area was significantly correlated with E/A (r = -0.23, P = 0.025). Thirteen HTN patients had both E/A ratio < 1.12 (Control mean E/A-1SD) and torsion hysteresis area > 0.12 (Control mean torsion hysteresis area + 1SD). CONCLUSIONS: Torsion hysteresis area and peak early diastolic - d φ ^ / d V ^ were significantly increased in hypertensive concentric remodeling. The φ ^ V ^ loop takes into account the active and passive recoil processes of LV diastolic and systolic phases, therefore provides a new global description of LV diastolic function.

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.

Developments in heart failure 2011.

Last year, the authors reviewed all studies in the field of heart failure (HF) published in the year 2010. Another year of exciting new developments has gone by and several important papers have been published. Summarized are the important studies published in the year 2011 that may be a useful review for cardiologists and other health care professionals who care for patients with HF.

Antihypertensive therapy versus alternative therapeutic options for prehypertension: an evidence-based approach.

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) defines hypertension as systolic blood pressure (BP) ≥140 mmHg or diastolic BP ≥90 mmHg. The JNC-7 defines 'prehypertension' to include systolic BP values between 120 and 139 mmHg and diastolic BP values between 80 and 89 mmHg. Individuals with blood pressure in the prehypertension range are clearly at increased risk of developing hypertension in the future and have an increased risk of cardiovascular morbidity and mortality, compared with those with normal BP. However, there is paucity of evidence to intervene in these patients. In this article we discuss an evidence-based approach to therapeutic options in patients with prehypertension.

Developments in heart failure 2010.

In spite of substantial improvement in outcomes in the past 2 decades, we continue to face significant challenges in treating patients with HF. There have been several epidemiologic, pathophysiologic, and randomized controlled trials evaluating different treatment modalities published in the past year. In this review, we summarize the most relevant studies that we believe could significantly impact the understanding and management of HF.

Metabolic syndrome and heart failure--the risk, paradox, and treatment.

The constellation of obesity, hypertension, dyslipidemia, and insulin resistance-together referred to as metabolic syndrome (MetS)-is increasing in prevalence in the American population and also worldwide. The individual components of MetS and MetS as a whole increase the risk of heart failure, cardiovascular mortality, and all-cause mortality. Despite this adverse association, numerous studies have documented an obesity paradox, in which overweight and obese people with established cardiovascular disease, including hypertension, coronary heart disease, heart failure, and peripheral arterial disease, have a better prognosis than patients who are not overweight or obese. Current treatment strategies for these patients include weight loss, control of blood pressure and cholesterol levels, and treatment of hyperglycemia. Because of increasing evidence for the obesity paradox, some physicians question whether obesity should be treated when it is associated with heart failure. Several studies have shown improvement in left ventricular function and decreased mortality and morbidity from heart failure with weight loss and treatment of elevated blood pressure, cholesterol, and hyperglycemia. The most reasonable approach at this time appears to be weight loss and exercise, lowering blood pressure to less than 130/80 mm Hg, low-density lipoprotein (LDL) cholesterol to less than 100 mg/dL, and glycosylated hemoglobin levels to less than 7%.

Severity of obstructive sleep apnea is related to aldosterone status in subjects with resistant hypertension.

BACKGROUND: We previously described a significant correlation between plasma aldosterone concentration (PAC) and severity of obstructive sleep apnea (OSA) in patients with resistant hypertension. This investigation examines the relationship between aldosterone status and OSA in patients with resistant hypertensive-with and without hyperaldosteronism. METHODS AND RESULTS: One hundred and nine consecutive patients with resistant hypertension were prospectively evaluated with plasma renin activity (PRA), PAC, 24-hour urinary aldosterone excretion (UAldo), and polysomnography. Hyperaldosteronism (PRA < 1 ng x mL(-1) x h(-1) and UAldo > or = 12 microg/24-h) prevalence was 28% and OSA prevalence was 77%. In patients with hyperaldosteronism, OSA prevalence was 84%, compared with 74% in hypertensive patients with normal aldosterone levels. There were no significant differences in body mass index or neck circumference between aldosterone groups. PAC and UAldo were both significantly correlated with apnea-hypopnea index (AHI) in the high-aldosterone group (p = 0.568, p = 0.0009; p = 0.533, p = 0.002, respectively). UAldo correlated weakly with apnea-hypopnea index in the normal-aldosterone group, but there was no significant correlation between PAC and AHI in the normal-aldosterone group (p = 0.224, p = 0.049; p = 0.015, p = 0.898, respectively). CONCLUSIONS: Our analysis of patients with resistant hypertension confirms a markedly high prevalence of OSA in this group. Furthermore, severity of OSA was greater in those patients with hyperaldosteronism and related to the degree of aldosterone excess. The correlation between OSA severity and aldosterone supports the hypothesis that aldosterone excess contributes to greater severity of OSA.

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 x 7 days) and high sodium diets (250 mmol/24 hours x 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.

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.

Emerging diuretics for the treatment of heart failure.

Heart failure continues to be a major global concern. Despite greater understanding of the 'maladaptive' mechanisms that contribute to its development and progression, morbidity and mortality from heart failure remain high. Existing treatment modalities have been hampered by the development of electrolyte abnormalities, diuretic resistance and the cardiorenal syndrome. This review focuses on the pharmacological properties and clinical data of therapeutic agents under investigation that target vasopressin and adenosine receptors for the treatment of patients with heart failure.

Aldosterone and cardiovascular disease.

Aldosterone is an adrenal hormone that regulates sodium, fluid, and potassium balance. Jerome Conn first described the syndrome of autonomous and excessive aldosterone secretion or "primary aldosteronism." Contrary to the historical belief, recent studies indicate that primary aldosteronism is a common cause of hypertension with a prevalence of 5-10% among general hypertensive patients. Various animal models have demonstrated that aldosterone in association with a high salt diet results in target-organ inflammation and fibrosis. Similarly, cross-sectional and observational human studies have demonstrated the association of aldosterone with development and severity of hypertension, congestive heart failure, coronary artery disease, chronic kidney disease, and metabolic syndrome. Several interventional studies have also demonstrated the beneficial effects of mineralocorticoid receptor antagonists in these disease processes, particularly hypertension, heart failure, and post myocardial infarction, further supporting the role of aldosterone in their pathogenesis. We review the role of aldosterone in these various cardiovascular disease processes along with potential mechanisms and treatment.

Diastolic dysfunction and heart failure with preserved ejection fraction: rationale for RAAS antagonist/CCB combination therapy.

A large number of patients who present with signs or symptoms of heart failure (HF) do not have evidence of left ventricular systolic dysfunction. As a result, HF in the presence of normal or preserved ejection fraction, or diastolic HF, is increasingly recognized as a health care challenge. Guidelines have been issued for the classification, diagnosis, and prevention of HF from diastolic dysfunction, but treatment of this condition remains problematic. Antihypertensive agents that have been proven in clinical trials to improve outcomes in HF with systolic dysfunction, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers, have not yet demonstrated comparable benefits in patients with diastolic dysfunction. Combination therapy using an antagonist of the renin-angiotensin-aldosterone system and a calcium-channel blocker has potential advantages over monotherapy and is being explored in several ongoing clinical trials.

Advanced heart failure and management strategies.

The global healthcare burden attributable to heart failure is ever increasing. Patients presenting with refractory heart failure should be evaluated for compliance with medical regimens and sodium and/or fluid restriction, and every attempt should be made to optimize conventional strategies. Reversible causes such as ischemia should be identified and revascularization considered in persistently symptomatic patients, particularly those with a viable myocardium. Carefully selected patients who continue to deteriorate clinically in spite of optimization of medical therapy may be considered for advanced treatment strategies, such as continuous inotropic infusions, mechanical circulatory support devices, cardiac transplantation, or referral to hospice care. We discuss the clinical presentation and management of patients with advanced/refractory (Stage D) heart failure.

Renin inhibition: should it supplant ACE inhibitors and ARBS in high risk patients?

PURPOSE OF REVIEW: The direct renin inhibitor aliskiren has recently been approved for the treatment of hypertension in humans. The potential for these newer agents having an advantage over the existing renin-angiotensin-aldosterone system (RAAS) antagonists in the treatment of hypertension and related target organ damage has drawn the interest of several investigators. In this review, we discuss the potential advantages and disadvantages of this newest antihypertensive class over other available RAAS antagonists. RECENT FINDINGS: The antihypertensive efficacy of aliskiren monotherapy has been compared with that of other RAAS antagonists and combinations of aliskiren with these agents. These studies have shown that aliskiren is equally effective as angiotensin receptor blockers and may be slightly more effective than angiotensin converting enzyme inhibitors in lowering blood pressure. In contrast to the other RAAS antagonists, aliskiren shuts down the entire downstream RAAS cascade. This results in greatly increased plasma renin concentration due to removal of angiotensin II-mediated feedback inhibition of renin release, which has raised concerns about whether direct renin inhibition adds anything to inhibition of downstream components of the RAAS cascade. SUMMARY: The potential advantages and disadvantages of aliskiren therapy versus existing RAAS antagonists in treating hypertension and target organ damage are under investigation.

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

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 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 >or=12 microg/24 hours; or normal: <12 microg/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.