Cardiopulmonary Baroreflex Control of Renal Sympathetic Nerve Activity Is Impaired in Dogs With Left Ventricular Dysfunction.

BACKGROUND: Activation of neurohormonal systems contributes to the progression of heart failure (HF). The mechanism(s) whereby these systems become activated is(are) not fully explained. We determined whether vagal cardiopulmonary baroreflex control of renal sympathetic nerve activity is abnormal in dogs with left ventricular (LV) dysfunction in the absence of clinical HF, and the relationship of abnormalities in baroreflexes to the development of the neurohumoral excitatory state. METHODS: LV end-systolic and end-diastolic dimensions (echocardiography), arterial baroreflex sensitivity (slope of ΔRR/Δsystolic BP during phenylephrine or nitroglycerin bolus), and neurohumoral profiles (plasma norepinephrine, renin activity, and arginine vasopressin) were measured serially in conscious dogs (n=24) with progressive LV dysfunction due to rapid ventricular pacing. LV dimensions were used to define groups with mild, moderate, and marked LV dilatation (LVD; increase in LV end-diastolic volume <15%, 15-30%, and >30% of control, respectively). Changes in renal nerve activity (RNA) were recorded in response to increases in pulmonary capillary wedge pressure (PCWP) induced by volume infusion in anesthetized, sinoaortic-denervated dogs. RESULTS: Cardiopulmonary baroreflex sensitivity (slope of %ΔRNA/ΔPCWP) for mild LVD (-17.8%/mmHg) was the same as controls (-17.7%/mmHg). However, the slopes of moderate (-5.8%/mmHg) and severe LVD (-1.9%/mmHg) were decreased significantly compared with controls (P < .05). Arterial baroreflex sensitivity was preserved at all stages of LVD. Plasma norepinephrine, renin activity, and arginine vasopressin remained unchanged after 4, 7, and 11 days of pacing. CONCLUSIONS: Vagal cardiopulmonary baroreflex control of renal sympathetic nerve activity is blunted early in the development of LVD. These abnormalities precede neurohumoral excitation and abnormal arterial baroreflexes and become apparent when LV end-diastolic volume starts to increase.

Does the benefit from treating to lower blood pressure targets vary with age? A systematic review and meta-analysis.

BACKGROUND: Recommendations differ regarding how blood pressure targets should vary with age. Crucial to this controversy is whether treatment benefit varies with age. METHODS: Systematic searches were conducted for trials randomizing treatment in intensive arms to the recommended SBP targets: 120-140 mmHg. Head-to-head meta-analyses and meta-regression were conducted. RESULTS: Sixteen trials met criteria. Relative to higher targets, lower targets reduced cardiovascular events, but treatment benefit differed significantly among trials due to patient age. Treatment significantly benefited older patients (mean age 77, SD = 72-81), relative risk (RR) = 0.77 (0.61,0.97), P = 0.025, but not younger patients (mean age 61, SD = 53-70), RR = 0.90 (0.78,1.03), P = 0.121, even though the latter had much greater statistical power. The (RR in 80 year olds)/(RR in 55 year olds) = 0.68 (0.47,0.97), P = 0.036. Though statistically nonsignificant, corresponding trends for more specific outcomes favored older patients: Coronary artery disease 0.80, stroke 0.85, heart failure 0.54, and total mortality 0.76. For adverse effects this trend was 0.86 (0.33,2.26). The number needed to treat to lower targets to prevent one cardiovascular event over 10 years in eight populations declined with age by 94%+. CONCLUSION: In these novel results, for both RR and absolute risk, treating to SBPs of 120-140 mmHg versus higher targets benefited older patients more than younger patients without an age-related increase in the RR for adverse effects. Nonetheless, because all clinical trials excluded the most frail older patients, clinicians must consider individual patient characteristics such as frailty, autonomy, and cognitive ability when choosing blood pressure targets.

Hydrochlorothiazide vs chlorthalidone, indapamide, and potassium-sparing/hydrochlorothiazide diuretics for reducing left ventricular hypertrophy: A systematic review and meta-analysis.

Left ventricular hypertrophy develops in 36%-41% of hypertensive patients and independently predicts cardiovascular events and total mortality. Moreover, drug-induced reduction in left ventricular mass (LVM) correlates with improved prognosis. The optimal thiazide-type diuretic for reducing LVM is unknown. Evidence regarding potency, cardiovascular events, sodium, and potassium suggested the hypothesis that "CHIP" diuretics (CHlorthalidone, Indapamide, and Potassium-sparing diuretic/hydrochlorothiazide [PSD/HCTZ]) would reduce LVM more than HCTZ. Systematic searches of five databases were conducted. Among the 38 randomized trials, a 1% reduction in systolic blood pressure (SBP) predicted a 1% reduction in LVM, P = 0.00001. CHIP-HCTZ differences in reducing LVM differed across trials (ie, heterogeneity), making interpretation uncertain. However, among the 28 double-blind trials, heterogeneity was undetectable, and HCTZ reduced LVM (percent reduction [95% CI]) by -7.3 (-10.4, -4.2), P < 0.0001. CHIP diuretics surpassed HCTZ in reducing LVM: chlorthalidone -8.2 (-14.7, -1.6), P = 0.015; indapamide -7.5 (-12.7, -2.3), P = 0.005; and all CHIP diuretics combined -7.7 (-12.2, -3.1), P < 0.001. The comparison of PSD/HCTZ with HCTZ had low statistical power but favored PSD/HCTZ: -6.0 (-14.1, +2.1), P = 0.149. Thus, compared to HCTZ, CHIP diuretics had twice the effect on LVM. CHIP diuretics did not surpass HCTZ in reducing systolic or diastolic blood pressure: -0.3 (-5.0, +4.3) and -1.6 (-5.6, +2.4), respectively. The strength of evidence that CHIP diuretics surpass HCTZ for reducing LVM was high (GRADE criteria). In conclusion, these novel results have demonstrated that CHIP diuretics reduce LVM 2-fold more than HCTZ among hypertensive patients. Although generally related to LVM, blood pressure fails to explain the superiority of CHIP diuretics for reducing LVM.

Subcutaneous Furosemide in Heart Failure: Pharmacokinetic Characteristics of a Newly Buffered Solution.

Parenteral diuretics form the cornerstone of decongestion in heart failure. However, parenteral therapy routinely requires emergency room or inpatient care. A novel buffered furosemide formulation with neutral pH was developed to offer "hospital-strength" diuresis for outpatient use, including self-administration at home. Subcutaneous infusion using a biphasic delivery profile resulted in complete bioavailability (99.65%) and equivalent diuresis when compared with intravenous administration. Subcutaneous administration of buffered furosemide was well tolerated with no evidence of any drug-induced skin reactions. Subcutaneous infusion of buffered furosemide in the outpatient setting or home may help to reduce the burden of heart failure.

Hydrochlorothiazide and alternative diuretics versus renin-angiotensin system inhibitors for the regression of left ventricular hypertrophy: a head-to-head meta-analysis.

BACKGROUND: Found in 36-41% of hypertension, elevated left ventricular mass (LVM) independently predicts cardiovascular events and total mortality. Conversely, drug-induced regression of LVM predicts improved outcomes. Previous studies have favored renin-angiotensin system inhibitors (RASIs) over other antihypertensives for reducing LVM but ignored differences among thiazide-type diuretics. From evidence regarding potency, cardiovascular events, and electrolytes, we hypothesized a priori that 'CHIP' diuretics [CHlorthalidone, Indapamide and Potassium-sparing Diuretic/hydrochlorothiazide (PSD/HCTZ)] would rival RASIs for reducing LVM. METHOD AND RESULTS: Systematic review yielded 12 relevant double-blind randomized trials. CHIPs were more closely associated with reduced LVM than HCTZ (P = 0.004), indicating that RASIs must be compared with each diuretic separately. Publication bias favoring RASIs was corrected by cumulative analysis. For reducing LVM, HCTZ tended to be less effective than RASIs. However, the following surpassed RASIs: chlorthalidone Hedge's G: -0.37 (95% CI -0.72 to -0.02), P = 0.036; indapamide -0.20 (-0.39 to -0.01), P = 0.035; all CHIPs combined (with 61% of patients in one trial) -0.25 (-0.41to -0.09), P = 0.002. Statistical significance (P < 0.05) did not depend on any one trial. CHIPs reduction in LVM was 37% greater than that from RASIs. CHIPs superiority tended to increase with trial duration, from a negligible effect at 0.5 year to a maximal effect at 0.9-1.0 years: -0.26 (-0.43 to -0.09), P = 0.003. Fifty-eight percent of patients had information on echocardiographic components of LVM: relative to RASIs, CHIPs significantly reduced end-diastolic LV internal dimension (EDLVID): -0.18 (-0.36 to -0.00), P = 0.046. Strength of evidence favoring CHIPs over RASIs was at least moderate. CONCLUSION: In these novel results in patients with hypertension, CHIPs surpassed RASIs for reducing LVM and EDLVID.

Use of Diuretics in the Treatment of Heart Failure in Older Adults.

Diuretics are the most commonly prescribed class of drugs in patients with heart failure, and in the short term they remain the most effective treatment for relief from fluid congestion. This article reviews the mode of action of the various diuretic classes and the physiologic adaptations that follow and sets up the basis for their use in the treatment of volume-retaining states, particularly as applies to the elderly. In addition, the article reviews the common side effects related to diuretics.

Diuretics for Hypertension: A Review and Update.

This review and update focuses on the clinical features of hydrochlorothiazide (HCTZ), the thiazide-like agents chlorthalidone (CTDN) and indapamide (INDAP), potassium-sparing ENaC inhibitors and aldosterone receptor antagonists, and loop diuretics. Diuretics are the second most commonly prescribed class of antihypertensive medication, and thiazide-related diuretics have increased at a rate greater than that of antihypertensive medications as a whole. The latest hypertension guidelines have underscored the importance of diuretics for all patients, but particularly for those with salt-sensitive and resistant hypertension. HCTZ is 4.2-6.2 systolic mm Hg less potent than CTDN, angiotensin-converting enzyme inhibitors, beta blockers, and calcium channel blockers by 24-hour measurements and 5.1mm Hg systolic less potent than INDAP by office measurements. For reducing cardiovascular events (CVEs), HCTZ is less effective than enalapril and amlodipine in randomized trials, and, in network analysis of trials, it is less effective than CTDN and HCTZ-amiloride. Combined with thiazide-type diuretics, potassium-sparing agents decrease ventricular ectopy and reduce the risk for sudden cardiac death relative to thiazide-type diuretics used alone. A recent synthesis of 44 trials has shown that the relative potencies in milligrams among spironolactone (SPIR), amiloride, and eplerenone (EPLER) are approximately from 25 to 10 to 100, respectively, which may be important when SPIR is poorly tolerated. SPIR reduces proteinuria beyond that provided by other renin angiotensin aldosterone inhibitors. EPLER also reduces proteinuria and has beneficial effects on endothelial function. While guidelines often do not differentiate among specific diuretics, this review demonstrates that these distinctions are important for managing hypertension.

Dose doubling, relative potency, and dose equivalence of potassium-sparing diuretics affecting blood pressure and serum potassium: systematic review and meta-analyses.

BACKGROUND: Potassium-sparing diuretics (PSDs) are valuable antihypertensives with additional benefits unrelated to control of systolic blood pressure (SBP). However, their key parameters affecting SBP and serum potassium are poorly defined, fostering underutilization. METHOD: Consequently, we conducted systematic reviews and meta-analyses, yielding 3668 articles and ultimately 84 randomized comparisons. RESULTS: For office SBP, overall placebo-adjusted changes were triamterene -1.9 (low dose only), amiloride -9.9, spironolactone -13.2, and eplerenone -9.2. Differences in antihypertensive effect were due to potency rather than efficacy. Doubling amiloride, eplerenone, and spironolactone doses reduced SBP (95% confidence limits) on average by -2.3 (-3.1, -1.5). Relative antihypertensive potencies were spironolactone>amiloride>eplerenone. Spironolactone had significantly greater antihypertensive potency than amiloride, -4.0 (-7.4, -0.6), and eplerenone, -5.5 (-7.4, -3.6). Dose equivalencies were eplerenone-spironolactone 4.5-to-1 (e.g., eplerenone 125∼spironolactone 25), amiloride-spironolactone 3.3-to-1, and eplerenone-amiloride 1.4-to-1. Increases in serum potassium from amiloride and spironolactone at commonly used doses averaged 0.14-0.29 mEq/l; the dose doubling effect was 0.16 (0.10, 0.22). Spironolactone caused greater hyperkalemia than amiloride across their dose ranges: 0.14, P = 0.043. Seven features make important bias unlikely: a comprehensive literature search, adjustment for covariates, all models explaining 95-100% of the between-study variability, similar dose doubling effects among PSDs, two different methods giving the same potency sequence, similar results from double blind comparisons, and similar results for eplerenone versus spironolactone from analysing direct comparison data (i.e., no meta-regression) for office and 24-h SBP. CONCLUSION: This synthesis accomplishes for PSDs what has already been achieved for thiazide-type diuretics and other antihypertensives and can guide the application of these underutilized medicines.

High Fat High Cholesterol Diet (Western Diet) Aggravates Atherosclerosis, Hyperglycemia and Renal Failure in Nephrectomized LDL Receptor Knockout Mice: Role of Intestine Derived Lipopolysaccharide.

A high fat meal, frequently known as western diet (WD), exacerbates atherosclerosis and diabetes. Both these diseases are frequently associated with renal failure. Recent studies have shown that lipopolysaccharide (LPS) leaks into the circulation from the intestine in the setting of renal failure and after WD. However, it is not clear how renal function and associated disorders are affected by LPS. This study demonstrates that circulatory LPS exacerbates renal insufficiency, atherosclerosis and glucose intolerance. Renal insufficiency was induced by 2/3 nephrectomy in LDL receptor knockout mice. Nx animals were given normal diet (Nx) or WD (Nx+WD). The controls were sham operated animals on normal diet (control) and WD (WD). To verify if LPS plays a role in exaggerating renal insufficiency, polymyxin (PM), a known LPS antagonist, and curcumin (CU), a compound known to ameliorate chronic kidney disease (CKD), was given to Nx animals on western diet (Nx+WD+PM and Nx+WD+CU, respectively). Compared to control, all other groups displayed increased circulatory LPS. The Nx+WD cohort had the highest levels of LPS. Nx group had significant renal insufficiency and glucose intolerance but not atherosclerosis. WD had intense atherosclerosis and glucose intolerance but it did not show signs of renal insufficiency. Compared to other groups, Nx+WD had significantly higher cytokine expression, macrophage infiltration in the kidney, renal insufficiency, glucose intolerance and atherosclerosis. PM treatment blunted the expression of cytokines, deterioration of renal function and associated disorders, albeit not to the levels of Nx, and was significantly inferior to CU. PM is a non-absorbable antibiotic with LPS binding properties, hence its beneficial effect can only be due to its effect within the GI tract. We conclude that LPS may not cause renal insufficiency but can exaggerate kidney failure and associated disorders following renal insufficiency.

Head-to-head comparisons of hydrochlorothiazide with indapamide and chlorthalidone: antihypertensive and metabolic effects.

Hydrochlorothiazide (HCTZ) has often been contrasted with chlorthalidone, but relatively little is known about HCTZ versus indapamide (INDAP). This systematic review retrieved 9765 publications, and from these, it identified 14 randomized trials with 883 patients comparing HCTZ with INDAP and chlorthalidone on antihypertensive potency or metabolic effects. To make fair comparisons, the dose of the diuretic in each arm was assigned 1 of 3 dose levels. In random effects meta-analysis, INDAP and chlorthalidone lowered systolic blood pressure more than HCTZ: -5.1 mm Hg (95% confidence interval, -8.7 to -1.6); P=0.004 and -3.6 mm Hg (95% confidence interval, -7.3 to 0.0); P=0.052, respectively. For both comparisons, there was minimal heterogeneity in effect across trials and no evidence for publication bias. The HCTZ-INDAP contrast was biased in favor of greater HCTZ potency because of a much greater contribution to the overall effect from trials in which the HCTZ arm had a higher dose level than the INDAP arm. For the HCTZ-INDAP comparison, no single trial was responsible for the overall result nor was it possible to detect significant modifications of this comparison by duration of follow-up, high- versus low-bias trials, or the presence or absence of background medications. There were no detectable differences between HCTZ and INDAP in metabolic adverse effects, including effects on serum potassium. In conclusion, these head-to-head comparisons demonstrate that, like chlorthalidone, INDAP is more potent than HCTZ at commonly prescribed doses without evidence for greater adverse metabolic effects.

Not just chlorthalidone: evidence-based, single tablet, diuretic alternatives to hydrochlorothiazide for hypertension.

Accounting for 15 % of deaths worldwide, hypertension is often treated with hydrochlorothiazide (HCTZ) (50 million prescriptions annually). HCTZ has a <24-h duration of action, is less potent than chlorthalidone and all major antihypertensive drug classes, and is inferior to four antihypertensive drugs for cardiovascular event (CVE) reduction. If there were alternative diuretics, why prescribe HCTZ? Chlorthalidone is often offered as an alternative to HCTZ, but has limited pharmaceutical formulations. However, there are seven evidence-based, single-tablet, alternative diuretics. For reducing CVE, the following are superior to their comparators: chlorthalidone versus four antihypertensives in multiple hypertensive populations; indapamide versus placebo in elderly Chinese (and versus enalapril for left ventricular hypertrophy), triamterene-HCTZ versus placebo in elderly Europeans, amiloride-HCTZ versus three antihypertensives, and indapamide-perindopril versus placebo in three populations. Additionally, chlorthalidone-azilsartan and spironolactone-HCTZ are potent combinations The aldosterone antagonist component of the latter combination has been shown to reduce total mortality by 30 % in heart failure. Five of these seven have multiple dose formulations. Six cost $4-$77 monthly. In conclusion, based on both scientific and practical grounds, new prescriptions for HCTZ are rarely justified.

Assessment and management of hypertension in transplant patients.

Hypertension in renal transplant recipients is common and ranges from 50% to 80% in adult recipients and from 47% to 82% in pediatric recipients. Cardiovascular morbidity and mortality and shortened allograft survival are important consequences of inadequate control of hypertension. In this review, we examine the epidemiology, pathophysiology, and management considerations of post-transplant hypertension. Donor and recipient factors, acute and chronic allograft injury, and immunosuppressive medications may each explain some of the pathophysiology of post-transplant hypertension. As observed in other patient cohorts, renal artery stenosis and adrenal causes of hypertension may be important contributing factors. Notably, BP treatment goals for renal transplant recipients remain an enigma because there are no adequate randomized controlled trials to support a benefit from targeting lower BP levels on graft and patient survival. The potential for drug-drug interactions and altered pharmacokinetics and pharmacodynamics of the different antihypertensive medications need to be carefully considered. To date, no specific antihypertensive medications have been shown to be more effective than others at improving either patient or graft survival. Identifying the underlying pathophysiology and subsequent individualization of treatment goals are important for improving long-term patient and graft outcomes in these patients.

Mineralocorticoid Receptor Antagonists for Treatment of Hypertension and Heart Failure.

Spironolactone and eplerenone are both mineralocorticoid-receptor antagonists. These compounds block both the epithelial and nonepithelial actions of aldosterone, with the latter assuming increasing clinical relevance. Spironolactone and eplerenone both affect reductions in blood pressure either as mono- or add-on therapy; moreover, they each afford survival benefits in diverse circumstances of heart failure and the probability of renal protection in proteinuric chronic kidney disease. However, as use of mineralocorticoid-blocking agents has expanded, the hazards inherent in taking such drugs have become more apparent. Whereas the endocrine side effects of spironolactone are in most cases little more than a cosmetic annoyance, the potassium-sparing effects of both spironolactone and eplerenone can prove disastrous, even fatal, if sufficient degrees of hyperkalemia emerge. For most patients, however, the risk of developing hyperkalemia in and of itself should not discourage the sensible clinician from bringing these compounds into play. Hyperkalemia should always be considered a possibility in patients receiving either of these medications; therefore, anticipatory steps should be taken to minimize the likelihood of its occurrence if long-term therapy of these agents is being considered.

Public-use blood pressure measurement: the kiosk quandary.

It is important to note the opportunity that validated public-use kiosks offer the U.S. healthcare system in terms of ease of public access, reduced cost of screening/monitoring, and the opportunity to support coordinated care between physicians, pharmacists, and patients. It is equally important to recognize that all public-use BP kiosks are not equivalent. Members of the AAMI Sphygmomanometer Committee and other ''concerned citizens'' are working with FDA officials to try to improve both device validation and cuff range performance of these devices. In reality, regulatory changes will be slow to take effect, and for the foreseeable future, the burden of device accuracy assessment lies with the private sector and the public. There is a device currently available that has undergone full validation testing and offers a wide-range cuff validated for almost all US adult arms. We recognize the importance of innovation in out-of-office BP measurement. Therefore, in the interest of public health, we strongly urge those business professionals buying such devices, and those health professionals advising patients on their use, to become better informed and more discriminant in their device selection.

Detection, evaluation, and treatment of severe and resistant hypertension: proceedings from an American Society of Hypertension Interactive forum held in Bethesda, MD, U.S.A., October 10th 2013.

The epidemiology, evaluation, and management of severe and resistant hypertension in the United States (US) are evolving. The American Society of Hypertension held a multi-disciplinary forum in October 2013 to review the available evidence related to the management of resistant hypertension with both drug and device therapies. There is strong evidence that resistant hypertension is an important clinical problem in the US and many other regions of the world. Complex drug therapy is effective in most of the patients with severe and resistant hypertension, but there are certain individuals who may be refractory to multiple-drug regimens or have adverse effects that make adherence to the regimen difficult. When secondary forms of hypertension and pseudo-resistance, such as medication nonadherence, or white-coat hypertension based on marked differences between clinic and 24-hour ambulatory blood pressure monitoring, have been excluded, the impact of device therapy is under evaluation through clinical trials in the US and from clinical practice registries in Europe and Australia. Clinical trial data have been obtained primarily in patients whose resistant hypertension is defined as systolic clinic blood pressures of ≥160 mm Hg (or ≥ 150 mm Hg in type 2 diabetes) despite pharmacologic treatment with at least three antihypertensive drugs (one of which is a thiazide or loop diuretic). Baroreceptor stimulation therapy has shown modest benefit in a moderately sized sham-controlled study in drug-resistant hypertension. Patients selected for renal denervation have typically been restricted to those with preserved kidney function (estimated glomerular filtration rate ≥ 45 mL/min/1.73 m2). The first sham-controlled safety and efficacy trial for renal denervation (SYMPLICITY HTN-3) did not show benefit in this population when used in addition to an average of five antihypertensive medications. Analyses of controlled clinical trial data from future trials with novel designs will be of critical importance to determine the effectiveness of device therapy for patients with severe and resistant hypertension and will allow for proper determination of patient selection and whether it will be acceptable for clinical practice. At present, the focus on the management of severe and resistant hypertension will be through careful evaluation for pseudo-resistance and secondary forms of hypertension, appropriate use of combination pharmacologic therapy, and greater utility of specialists in hypertension.

Aldosterone and volume management in hypertensive heart disease.

Aldosterone-receptor antagonists dose-dependently reduce both the epithelial and nonepithelial actions of aldosterone. These compounds are used commonly in the treatment of hypertension, with or without aldosteronism, and in the volume-overload periods of various forms of heart failure, cirrhosis, and renal failure. In this regard, the relevant site of action for these compounds is compartmentalized to the distal nephron. The cardiac benefits of aldosterone-receptor blockade now are sufficiently well established to warrant routine use of these compounds for their survival benefits in moderate to advanced stages of heart failure. Aldosterone-receptor antagonists spironolactone and eplerenone commonly are used in the treatment of resistant forms of hypertension. Spironolactone, but not eplerenone, is a commonly used add-on diuretic that provides incremental benefit for salt-and-water excretion in excess of what may be seen with a loop diuretic given together with a thiazide-type diuretic. The dose-response relationship for natriuresis with spironolactone has not been explored completely as to its combination therapy responses. The quite high doses of spironolactone used in patients with cirrhosis and ascites would infer that the overall treatment effect with this compound exceeds simple receptor blockade and may include a nervous system effect that operationally reduces renal sympathetic nerve traffic. The adverse electrolyte and renal function side effects with aldosterone-receptor antagonists are not uncommon in at-risk patients, such as those with chronic kidney disease, and require that dosing be mindful of the tendency of these drugs to importantly increase serum potassium levels.