Murray Epstein

Diabetes, Hypertension, and Cardiovascular Disease: An Update

Abstract—Cardiovascular diseases (CVDs) are the major causes of mortality in persons with diabetes, and many factors, including hypertension, contribute to this high prevalence of CVD. Hypertension is approximately twice as frequent in patients with diabetes compared with patients without the disease. Conversely, recent data suggest that hypertensive persons are more predisposed to the development of diabetes than are normotensive persons. Furthermore, up to 75% of CVD in diabetes may be attributable to hypertension, leading to recommendations for more aggressive treatment (ie, reducing blood pressure to <130/85 mm Hg) in persons with coexistent diabetes and hypertension. Other important risk factors for CVD in these patients include the following: obesity, atherosclerosis, dyslipidemia, microalbuminuria, endothelial dysfunction, platelet hyperaggregability, coagulation abnormalities, and “diabetic cardiomyopathy.” The cardiomyopathy associated with diabetes is a unique myopathic state that appears to be independent of macrovascular/microvascular disease and contributes significantly to CVD morbidity and mortality in diabetic patients, especially those with coexistent hypertension. This update reviews the current knowledge regarding these risk factors and their treatment, with special emphasis on the cardiometabolic syndrome, hypertension, microalbuminuria, and diabetic cardiomyopathy. This update also examines the role of the renin-angiotensin system in the increased risk for CVD in diabetic patients and the impact of interrupting this system on the development of clinical diabetes as well as CVD.

Renal failure in the patient with cirrhosis: The role of active vasoconstriction

Renal hemodynamics were studied with the 133 Xe washout technic and renal arteriography in fifteen patients with cirrhosis and varying degrees of renal functional impairment. In cirrhotic patients with renal failure extreme hemodynamic instability was encountered, characterized by variability and irregularity of xenon washout, in contrast to patients with renal failure of other etiology. Marked instability was more frequent in cirrhotic patients with azotemia, and was so severe in three instances that the curves were unanalyzable. The remaining curves revealed a decrease in both mean renal blood flow and the percentage of flow in the rapid flow component in approximate proportion to the decrease in creatinine clearance, suggesting a reduction in cortical perfusion. The arteriographic findings, including the absence of a cortical nephrogram and unrecognizable renal cortical vasculature in the patients with the most severe degree of renal failure, support the concept of a reduction in renal cortical perfusion. The finding of marked hemodynamic instability strongly suggests that the renal ischemia is secondary to active vasoconstriction. Consistent reversal of all the vascular abnormalities in the kidneys of five cirrhotic patients at postmortem angiography provides further evidence for the functional basis of the renal failure, operating through active renal vasoconstriction. Phentolamine infusion into the renal artery in four patients did not significantly alter renal hemodynamics indicating that increased sympathetic nervous system activity was not responsible for the active vasoconstriction and cortical ischemia.

Selective Aldosterone Blockade with Eplerenone Reduces Albuminuria in Patients with Type 2 Diabetes

Previous studies have shown that the selective aldosterone blocker eplerenone, in doses of up to 200 mg/d, reduces albuminuria in patients with type 2 diabetes. This study was conducted to ascertain whether lower doses of eplerenone (50 or 100 mg/d) co-administered with the angiotensin-converting enzyme (ACE) inhibitor enalapril would produce a similar antialbuminuric effect while obviating the hyperkalemia observed previously. After open-label run-in with enalapril 20 mg/d, patients with diabetes and a urinary albumin:creatinine ratio (UACR) > or = 50 mg/g were randomly assigned to receive enalapril plus one of three double-blind daily treatments for 12 wk: placebo, eplerenone 50 mg (EPL50), or eplerenone 100 mg (EPL100). After week 4, amlodipine 2.5 to 10 mg/d was allowed for BP control (systolic/diastolic BP < or = 130/80 mmHg). The primary study end points were the percentage change from baseline at week 12 in UACR and the incidence of hyperkalemia. Secondary end points included percentage changes from baseline in UACR at weeks 4 and 8 and changes from baseline in systolic and diastolic BP. Treatment with EPL50 or EPL100 but not placebo significantly reduced albuminuria from baseline. By week 12, UACR was reduced by 7.4% in the placebo group, by 41.0% in the EPL50 group, and by 48.4% in the EPL100 group (both eplerenone groups, P < 0.001 versus placebo). The incidences of sustained and severe hyperkalemia were not significantly different in any of the three treatment arms and did not differ on the basis of quartile of estimated GFR (all NS). For the secondary end points, both eplerenone treatment groups significantly reduced albuminuria from baseline as early as week 4 (P < 0.001), whereas placebo treatment (including enalapril) did not result in any significant decreases in UACR. Systolic BP decreased significantly in all treatment groups at all time points, but, generally, all treatment groups experienced similar decreases in BP. Co-administration of EPL50 or EPL100 with an ACE inhibitor as compared with an ACE inhibitor alone significantly reduces albuminuria in patients with diabetes without producing significant increases in hyperkalemia.

Narrative Review: The Emerging Clinical Implications of the Role of Aldosterone in the Metabolic Syndrome and Resistant Hypertension

Pathophysiology A new paradigm indicates that elevated levels of plasma aldosterone mediate several maladaptive changes that contribute to the pathogenesis of the metabolic syndrome, resistant hypertension, and associated cardiovascular and renal structural and functional abnormalities. Accumulating evidence indicates that adipose tissue produces aldosterone secretory factors that promote excessive adrenal aldosterone production. Elevated plasma aldosterone levels in turn promote insulin resistance, inflammation, oxidative stress, and sodium retention. These maladaptive processes contribute to the development of a hypertensive state that is relatively resistant to pharmacologic therapy. Clinical Implications Evidence is emerging that mineralocorticoid receptor blockade is useful in treating hypertensive patients who have both the metabolic syndrome and resistant hypertension. Mineralocorticoid antagonism therapy seems to have considerable clinical utility for reducing cardiovascular and renal disease associated with the metabolic syndrome, diabetes, and resistant hypertension. The prevalences of obesity, diabetes, hypertension, and cardiovascular and chronic kidney disease are increasing in the United States. Data from NHANES (National Health and Nutrition Examination Survey) III suggest that the prevalence of hypertension increases progressively with increasing body mass index from about 15% among people with a body mass index less than 25 kg/m2 to approximately 40% among those with a body mass index of 30 kg/m2 or greater (1). Obesity, insulin resistance, and hypertension commonly cluster with other risk factors for cardiovascular or chronic kidney disease to form the metabolic syndrome, which is associated with increased cardiovascular disease morbidity and mortality (15). Our understanding of the role of the reninangiotensinaldosterone system in insulin resistance through the action of aldosterone has undergone a paradigm shift in recent years. We know now that aldosterone participates in the pathogenesis of the metabolic syndrome (46). Recent evidence shows that elevated plasma aldosterone levels directly contribute to the pathogenesis of insulin resistance and endothelial dysfunction, processes that in turn contribute to maladaptive renal and cardiovascular remodeling (46). These actions of aldosterone promote the development of resistant hypertensiondefined as the need for 3 or more antihypertensive medications to control blood pressurein association with obesity and the metabolic syndrome. The Emergence of a New Paradigm for Aldosterone Aldosterone was isolated and characterized by Simpson and Tait (7) more than 50 years ago and was initially termed electrocortin. During the subsequent 4 decades, clinicians and medical investigators thought of aldosterone as acting primarily to regulate extracellular fluid volume and potassium handling. Classic agonistantagonist experiments in the toad bladder model in the 1960s (7, 8) revealed that alterations in sodiumpotassium ion flux did not occur immediately after aldosterone administration. This delay was due to aldosterones binding to cytosolic steroid receptors; translocation to the nucleus; interaction with DNA; and, finally, genomic transcription and translation of effector proteins. Investigators applied molecular biology techniques over the next several decades to understand aldosterone-mediated gene transcription and subsequent protein synthesis (8, 9). In 1992, investigators reported rapid, nongenomic effects of aldosterone that did not require signaling through the classic pathways of gene activation, transcription, and protein synthesis. These nongenomic actions included regulation of intracellular cations, cell volume, redox status, metabolic signaling, and endothelial-mediated relaxation (5, 8, 10). It is increasingly evident that these nongenomic effects, which occur independent of hemodynamic factors, are a substantial part of the mechanisms by which aldosterone contributes to the pathogenesis of the metabolic syndrome and resistant hypertension, as well as enhanced risk for cardiovascular and chronic kidney disease (915). Regulation of Aldosterone Secretion and Mineralocorticoid Receptor Activation For decades, we believed that activation of the reninangiotensin system, largely in response to intravascular volume contraction, regulated the biosynthesis of aldosterone (59). Hyperaldosteronism may occur when the relationship between salt ingestion or volume status and aldosterone secretion is perturbed (Figure 1). In fact, inappropriate aldosterone secretion occurs in diverse disease states, including the metabolic syndrome, heart failure, and chronic kidney disease, despite high salt and volume retention. Figure 1. Systemic effects of aldosterone on insulin sensitivity and hypertension. High salt intake, obesity, inactivity, and other environmental factors interact to activate the reninangiotensinaldosterone system, with subsequent inflammation and oxidative stress that drive maladaptive tissue responses. ACE = angiotensin-converting enzyme; ACTH = adrenocorticotropic hormone; Aldo = aldosterone; Ang I = angiotensin I; Ang II = angiotensin II; ASCVD = atherosclerotic cardiovascular disease; AT1 = angiotensin type 1 receptor; AT2 = angiotensin type 2 receptor; CAD = coronary artery disease; CHF = congestive heart failure; CRH = corticotropin-releasing hormone; LVH = left ventricular hypertrophy; MR = mineralocorticoid receptor; SNS = sympathetic nervous system. Mounting evidence in recent years suggests that mineralocorticoid receptors on the surface of nonepithelial cells send extracellular signals that do not require gene transcription for their action. These so-called nongenomic actions of aldosterone are involved in the pathophysiology of insulin resistance and endothelial dysfunction (Figure 1). The mineralocorticoid receptor has a high affinity for both aldosterone and 11-hydroxyglucocorticoids (4). Cells at the distal end of the nephron have relatively high levels of the enzyme 11-hydroxysteroid dehydrogenase, which prevents glucocorticoids from acting in the distal tubule and collecting duct. However, cardiovascular and metabolic tissue, such as skeletal muscle, liver, and fat, have much lower levels of this enzyme, which allows glucocorticoids to signal through the mineralocorticoid receptors (25). This signaling is particularly important in persons with the metabolic syndrome, because they have circulating glucocorticoid concentrations that are several orders of magnitude greater than their aldosterone concentrations. Mineralocorticoid receptor activation by glucocorticoids promotes inflammation, oxidative stress, fibrosis, insulin resistance, and endothelial dysfunction (5, 9, 10). Aldosterone Antagonists 17-Spirolactone steroids, or spirolactones, were developed 50 years ago to antagonize the action of aldosterone and other sodium-retaining hormones on the renal distal tubule (12). Initially, the mineralocorticoid receptor antagonist spironolactone was used widely as a potassium-sparing diuretic in volume-overload states, such as congestive heart failure, cirrhosis, and primary hyperaldosteronism (8, 12). Later, RALES (Randomized Aldactone Evaluation Study) (14) showed that mineralocorticoid receptor antagonists reduced cardiovascular events. This study demonstrated that a low dose of spironolactone improved morbidity and mortality in patients with severe heart failure. Subsequently, EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study) (15) demonstrated that treatment with eplerenone, a selective mineralocorticoid receptor antagonist, reduced mortality after myocardial infarction. These studies refocused attention on aldosterones effects on the mineralocorticoid receptors of nonrenal cells and have allowed investigators to use both spironolactone and eplerenone as pharmacologic probes to delineate the role of aldosterone and mineralocorticoid receptor signaling in various clinical disorders. Eplerenone is a newer, selective mineralocorticoid receptor antagonist that offers the same benefits as generic spironolactone, but it is no longer actively promoted. The protective effects of mineralocorticoid receptor blockade complement the effects of reninangiotensin system blockade (6). Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists act on the angiotensin peptides and receptors, respectively, and also suppress aldosterone secretion by the adrenal glands. Although the clinical effects are not fully elucidated, the complementary actions of these 2 classes of drugs provide a potential framework for treating various disorders, including resistant hypertension, cardiovascular disease, and chronic kidney disease. The Role of Aldosterone in Resistant Hypertension Resistant hypertension is defined as hypertension that requires more than 3 drugs in full doses to adequately control pressure. It is an increasingly common condition in industrialized nations (1623) that parallels the exponential growth in global obesity and the diabetes and chronic kidney disease epidemics (4, 5). Mounting evidence suggests that an elevated aldosterone level, in association with obesity and insulin resistance, contributes not only to salt retention and volume expansion but also to the inflammation and oxidative stress that promote the development of the metabolic syndrome and resistant hypertension (Figure 1) (46). The 17% to 22% prevalence of primary aldosteronism in individuals with resistant hypertension, which is much higher than that in the general population with hypertension, suggests a relationship between elevated aldosterone levels and resistant hypertension (1923). Moreover, individuals with resistant hypertension but without primary hyperaldosteronism have higher aldosterone levels and greater intravascular volume expansion than do control participants (17). The elevated 24-hour urinary levels of both

The effects of fenoldopam, a selective dopamine receptor agonist, on systemic and renal hemodynamics in normotensive subjects

OBJECTIVE Acute renal failure, frequently a consequence of renal vasoconstriction and subsequent renal ischemia, is a common problem for which no proven preventive or therapeutic agents exist. Fenoldopam is a new, selective, dopamine-1 receptor agonist that causes both systemic and renal arteriolar vasodilation. In hypertensive patients, fenoldopam rapidly decreases blood pressure, increases renal blood flow, and maintains or improves the glomerular filtration rate. We sought to determine a dose of fenoldopam that increases renal blood flow without inducing hypotension in normotensive patients and to explore the role of volume status (sodium replete vs. deplete) in these effects. DESIGN Randomized, double-blind, placebo-controlled, cross-over study. SETTING Clinical research unit. PATIENTS Fourteen normal male volunteers. INTERVENTIONS Renal plasma flow (para-aminohippurate clearance) and glomerular filtration rate (inulin clearance) were measured during three fixed, escalating doses of fenoldopam (0.03, 0.1, and 0.3 Lg/kg/min) on both a high-sodium and a low-sodium diet. MEASUREMENTS AND MAIN RESULTS Fenoldopam significantly increased renal plasma flow in a dose-dependent manner compared with placebo: 670 + 148 vs. 576 + 85 mUmin at 0.03 iLg/kg/min; 777 + 172 vs. 579 + 80 mUmin at 0.1 tig/kg/min; and 784 + 170 vs. 592 + 165 mUmin at 0.3 ilg/kg/min (p < .05 fenoldopam vs. placebo at all three doses). Glomerular filtration rate was maintained. At the lowest dose (i.e., 0.03 ILg/kg/min), significant renal blood flow increases occurred without changes in systemic blood pressure or heart rate. At 0.1 and 0.3 Lgl/kg/ min, systolic blood pressure did not change, but diastolic blood pressure was slightly lower in the fenoldopam group than in the placebo group: 62.5 + 6.4 vs. 63.6 + 2.6 mm Hg, respectively, at 0.3 tg/kg/min (p < .05). None of the effects of fenoldopam were altered by volume status. CONCLUSIONS Fenoldopam increased renal blood flow in a dose-dependent manner compared with placebo, and, at the lowest dose, significantly increased renal blood flow occurred without changes in systemic blood pressure or heart rate. These findings will be useful in designing future studies exploring the role of fenoldopam in preventing or treating renal failure in patients who are not hypertensive.

Aldosterone as a mediator of progressive renal disease: Pathogenetic and clinical implications

End-stage renal disease is an enormous public health burden with an increasing incidence and prevalence. This escalating prevalence suggests that newer therapeutic interventions and strategies are needed to complement current antihypertensive approaches. Although much evidence shows that angiotensin II mediates progressive renal disease, recent evidence also implicates aldosterone as an important pathogenetic factor in progressive renal disease. Several lines of experimental evidence show that selective blockade of aldosterone, independent of renin-angiotensin blockade, reduces proteinuria and nephrosclerosis in the spontaneously hypertensive stroke-prone rat model and reduces proteinuria and glomerulosclerosis in the subtotally nephrectomized rat model (ie, remnant kidney). Although pharmacological blockade with angiotensin II-receptor blockers and angiotensin-converting enzyme inhibitors reduces proteinuria and nephrosclerosis and/or glomerulosclerosis, selective reinfusion of aldosterone restores these abnormalities despite continued renin-angiotensin blockade. Based on this theoretic construct, randomized clinical studies will be initiated to delineate the potential renal-protective effects of antihypertensive therapy using aldosterone-receptor blockade. This is a US government work. There are no restrictions on its use.

Ischemic renal disease: an emerging cause of chronic renal failure and end-stage renal disease

Ischemic renal disease (IRD) is defined as a clinically important reduction in glomerular filtration rate or loss of renal parenchyma caused by hemodynamically significant renal artery stenosis. IRD is a common and often overlooked clinical entity that presents itself in the setting of extrarenal arteriosclerotic vascular disease in older individuals with azotemia. Eleven to 14% of end-stage renal disease (ESRD) cases are attributable to chronic IRD. A high percentage of patients entering ESRD programs are hypertensive. Many patients with a presumed diagnosis of hypertensive nephrosclerosis actually have undiagnosed ischemic nephropathy as the etiology of their ESRD. It is important for the clinician to identify IRD, because IRD is a potentially reversible cause of chronic renal failure in a hypertensive patient. Atherosclerotic renal artery disease is common among patients with coronary artery disease and aortic and peripheral vascular disease. Atherosclerotic renal artery disease is a progressive disorder, and its progression is associated with loss of renal mass and functioning. A decrease in glomerular filtration rate sufficient to cause an elevation of the serum creatinine concentration requires injury to both kidneys. Consequently, IRD can arise from one of two main clinical situations: bilateral hemodynamically significant renal artery stenosis leading to bilateral renal ischemia; and hemodynamically significant renal artery stenosis in a solitary functioning kidney, or in a kidney that is providing the majority of a patients glomerular filtration. The primary reason for establishing the diagnosis of IRD is the hope that correction of a renal artery stenosis will lead to improvement of renal function, or a delay in progression to ESRD. There are six major clinical settings in which the clinician could suspect IRD: acute renal failure caused by the treatment of hypertension, especially with angiotensin converting enzyme inhibitors; progressive azotemia in a patient with known renovascular hypertension; acute pulmonary edema superimposed upon poorly controlled hypertension and renal failure; progressive azotemia in an elderly patient with refractory or severe hypertension; progressive azotemia in an elderly patient with evidence of atherosclerotic disease; and unexplained progressive azotemia in an elderly patient. Noninvasive testing modalities that have been used recently include the angiotensin converting enzyme inhibitor renal scan, duplex Doppler sonography, magnetic resonance angiography, and the spiral computed tomography. Treatment methods include percutaneous transluminal angioplasty, endovascular stenting, and surgical revascularization. The results of treatment for preservation of renal function have been encouraging, with stabilization or improvement in renal function observed in a significant proportion of cases.

Combined Therapy with Thiazide-Type and Loop Diuretic Agents for Resistant Sodium Retention

Excerpt True resistance to a loop-type diuretic agent such as furosemide is relatively uncommon, and treatment failures can often be attributed to noncompliance either with medication or diet (1). ...

Pressure-induced vasoconstriction of renal microvessels in normotensive and hypertensive rats. Studies in the isolated perfused hydronephrotic kidney.

The capacity of small arteries to respond to increased intravascular pressure may be altered in hypertension. In the kidney, hypertension is associated with a compensatory shift in the autoregulatory response to pressure. To directly determine the effects of established hypertension on the renal mkrovascular response to changes of perfusion pressure, we evaluated pressure-induced vasoconstriction in hydronephrotic kidneys isolated from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Vessel diameters of interlobular arteries (ILAs) and afferent and efferent arterioles were determined by computerassisted videomicroscopy daring alterations in renal arterial pressure (RAP) from 80 to 180 mm Hg. Increased RAP induced a pressure-dependent vasoconstriction in preglomerular vessels (afferent arterioles and ILAs), but not in postglomerular vessels (efferent arterioles). The calcium antagonist nifedipine prevented pressure-induced afferent arteriolar vasoconstriction with a similar half-maximal inhibitory concentration (IC50) (WKY, 63 ± 27 vs. SHR, 60 ± 32 nM). The pressure-activation curves for ILAs in SHR and WKY were similar. In contrast, the pressure-activation curve for afferent arterioles in SHR kidneys exhibited a rightward shift, which was observed at every segment of the afferent arteriole (i.e., near ILA, at midportion, and near glomerulus). These findings demonstrate that the HA and the afferent arteriole both possess the ability to constrict in response to increased pressure, whereas this property is lacking in the efferent arteriole. Hypertension was associated with a compensatory shift in the pressure response of the afferent arteriole, such that higher RAPs were required to elicit vasoconstriction in this vessel.

Impaired myogenic responsiveness of renal microvessels in Dahl salt-sensitive rats.

The mechanisms mediating abnormal renal autoregulation in Dahl salt-sensitive (DS) rats have not been fully defined. In the present study, we assessed myogenic responsiveness of interlobular arteries (ILAs), afferent arterioles (AAs), and efferent arterioles in isolated perfused hydronephrotic Dahl rat kidneys. Dahl rats were divided into four groups according to strain (Dahl salt-resistant [DR] or DS rats) and dietary sodium manipulation (rats fed low or high salt diets). Systolic blood pressure was elevated only in DS rats fed the high salt diet (202 +/- 4 mm Hg, p less than 0.05). Myogenic responses were obtained by stepwise elevation of renal arterial pressure. Vessel diameters were determined by computer-assisted videomicroscopy. Preglomerular microvessels of DS and DR rats responded differently to changes in renal arterial pressure. AAs and ILAs manifested diminished myogenic responsiveness to increasing renal arterial pressure in DS rats compared with DR rats (p less than 0.05). Both AAs and ILAs in DS rats manifested a higher threshold pressure for eliciting myogenic responses and a decrease in maximal pressure-induced vasoconstriction. The sensitivity of the AA myogenic response to nifedipine was enhanced in DS rats compared with DR rats (p less than 0.05). For rats fed the high salt diet, preglomerular vessels exhibited reduced myogenic responsiveness in both strains. In contrast to preglomerular microvessels, efferent arterioles from all four groups of rats failed to exhibit pressure-induced vasoconstriction. Our data suggest that diminished myogenic responsiveness of AAs and ILAs in DS rats contributes to impaired renal autoregulation in this strain.