Twenty-Four-Hour Ambulatory Blood Pressure Monitoring.

The diagnosis, management, and estimated mortality risk in patients with hypertension have been historically based on clinic or office blood pressure readings. Current evidence indicates that 24-hour ambulatory blood pressure monitoring should be an integral part of hypertension care. The 24-hour ambulatory monitors currently available on the market are small devices connected to the arm cuff with tubing that measure blood pressure every 15 to 30 minutes. After 24 hours, the patient returns, and the data are downloaded, including any information requested by the physician in a diary. The most useful information includes the 24-hour average blood pressure, the average daytime blood pressure, the average nighttime blood pressure, and the calculated percentage drop in blood pressure at night. The most widely used criteria for 24-hour measurements are from the American Heart Association 2017 guidelines and the European Society of Hypertension 2018 guidelines. Two important scenarios described in this document are white coat hypertension, in which patients have normal blood pressures at home but high blood pressures during office visits, and masked hypertension, in which patients are normotensive in the clinic but have high blood pressures outside of the office. The Centers for Medicare and Medicaid Services has made changes in its policy to allow reimbursement for a broader use of 24-hour ambulatory blood pressure monitoring within some specific guidelines. Primary care physicians should make more use of ambulatory blood pressure monitoring, especially in patients with difficult to manage hypertension.

Mechanism of the blood pressure--raising effect of cocaine in humans.

BACKGROUND: Although the sympathomimetic actions and cardiovascular complications of cocaine are ascribed to inhibition of norepinephrine (NE) reuptake, this hypothesis has not been tested in humans. We asked (a) whether cocaine can inhibit NE reuptake in the human peripheral circulation and (b) whether the NE-mediated peripheral vasoconstriction is the main mechanism mediating blood pressure-raising effect of cocaine. METHODS AND RESULTS: In 15 healthy cocaine-naive subjects, we measured blood pressure, forearm blood flow, and forearm venous NE concentration during administration of (a) intrabrachial cocaine (0.15 and 15 mg), which produced no systemic neurohormonal effects, and (b) intranasal cocaine (2 mg/kg). Intrabrachial cocaine (0.15 mg) increased venous forearm NE concentration by 82% and vascular resistance by 71% (P<0.01). Increasing the intrabrachial cocaine dose by 100-fold to match the venous cocaine level of massive cocaine overdose caused a small additional increase in venous forearm NE concentration without causing significant additional vasoconstriction. Although intranasal cocaine (2 mg/kg) matched the venous cocaine concentrations caused by 0.15 mg of intrabrachial cocaine, venous NE concentration was unchanged as sympathetic nerve activity (SNA) decreased reflexively as the result of an increase in blood pressure. When SNA was restored to baseline by blunting the cocaine-induced rise in blood pressure (baroreflex activation) with nitroprusside, venous NE concentration increased to the same level caused by intrabrachial cocaine. CONCLUSIONS: In healthy cocaine-naive individuals, cocaine can inhibit NE reuptake in the human peripheral circulation. However, this mechanism does not contribute importantly to the blood pressure-raising effect of cocaine because activation of baroreceptor reflexes decreases SNA, the neural stimulus for NE release.

Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women.

OBJECTIVES: We investigated whether the route of estrogen replacement therapy (ET) is the major determinant of C-reactive protein (CRP) in postmenopausal women. BACKGROUND: Recent studies demonstrated that oral ET causes a sustained increase in CRP, implicating a proinflammatory effect. Because CRP is synthesized in the liver, we hypothesized that estrogen-induced CRP elevation is related to first-pass hepatic metabolism. METHODS: In 21 postmenopausal women, we conducted a randomized, crossover, placebo-controlled study to compare the effects of transdermal versus oral ET on CRP and inflammatory cytokines. We measured CRP, interleukin (IL)-1-beta, IL-6, and tumor necrosis factor-alpha before and after eight weeks of transdermal estradiol (E(2)) (100 microg/day), oral conjugated estrogen (CEE) (0.625 mg/day), or placebo. Insulin-like growth factor-1 (IGF-1), a hepatic-derived anabolic peptide, was also measured. RESULTS: Transdermal E(2) had no effect on CRP or IGF-1 levels. In contrast, eight weeks of oral conjugated estrogens caused a more than twofold increase in CRP and a significant reduction in IGF-1 (p < 0.01) in the same women. The magnitude of increase in CRP was inversely correlated to the decrease in IGF-1 (r = -0.49, p = 0.008). Neither transdermal E(2) nor oral CEE had any effects on the plasma concentrations of cytokines that promote CRP synthesis. CONCLUSIONS: In postmenopausal women, oral but not transdermal ET increased CRP by a first-pass hepatic effect. An increase in CRP levels is accompanied by a reduction in IGF-1, an anti-inflammatory growth factor. Because CRP is a powerful predictor of an adverse prognosis in otherwise healthy postmenopausal women, the route of administration may be an important consideration in minimizing the adverse effects of ET on cardiovascular outcomes.

Sympathetic overactivity as a cause of hypertension in chronic renal failure.

OBJECTIVE: To review the current literature on sympathetic mediation of hypertension in chronic renal failure. BACKGROUND: Hypertension is present in the vast majority of patients with chronic renal failure and constitutes a major risk factor for the excessive cardiovascular morbidity and mortality in this patient population. Although, traditionally, this hypertension is thought to be largely volume-dependent, an increasing body of literature suggests that there is an important sympathetic neural component. Microneurographic studies have demonstrated sympathetic overactivity without baroreflex impairment in both hypertensive chronic hemodialysis patients as well as in those with less advanced renal insufficiency. Sympathetic nerve activity was found to be normal in hemodialysis patients with bilateral nephrectomy, leading to the hypothesis that sympathetic overactivity in uremia is caused by a neurogenic signal (carried by renal afferents) arising in the failing kidney. This hypothesis is supported by rat studies showing that renal deafferentation abrogates hypertension in the 5/6 nephrectomy model of chronic renal insufficiency. In addition, in patients with chronic renal insufficiency and renin-dependent hypertension, sympathetic overactivity was normalized by chronic angiotensin converting enzyme inhibition but not by calcium channel blockade, implicating a major central neural action of angiotensin II. CONCLUSIONS: Sympathetic overactivity in chronic renal failure is caused by neurohormonal mechanisms arising in the failing kidney. Future clinical studies are needed to determine whether normalization of sympathetic activity should constitute an important therapeutic goal in this high-risk patient population.

Hypertensive emergencies. Etiology and management.

Although systemic hypertension is a common clinical disorder, hypertensive emergencies are unusual in clinical practice. Situations that qualify as hypertensive emergencies include accelerated or malignant hypertension, hypertensive encephalopathy, acute left ventricular failure, acute aortic dissection, pheochromocytoma crisis, interaction between tyramine-containing foods or drugs and monoamine oxidase inhibitors, eclampsia, drug-induced hypertension and possibly intracranial hemorrhage. It is important to recognize these conditions since immediate lowering of systemic blood pressure is indicated. The diagnosis of hypertensive emergencies depends on the clinical manifestations rather than on the absolute level of the blood pressure. Depending on the target organ that is affected, the manifestations of hypertensive emergencies can be quite expressive, yet variable. Thus, the physician has to make the clinical diagnosis urgently in order to render appropriate therapy. Several parenteral drugs can quickly and effectively lower the blood pressure in hypertensive emergencies. Intravenous fenoldopam, a selective dopamine (DA1) receptor agonist, offers the advantage of improving renal blood flow and causing natriuresis. Intravenous nicardipine may be beneficial in reserving tissue perfusion in patients with ischemic disorders. Whereas trimethaphan camsilate is the drug of choice for managing acute aortic dissection, hydralazine remains the drug of choice for the treatment of eclampsia. The alpha-adrenoceptor, phentolamine, is useful in patients with pheochromocytoma crisis. Enalaprilat is the only ACE inhibitor available for parenteral use and may be particularly useful in treating hypertensive emergencies in patients with heart failure. However, ACE inhibitors may cause a precipitous fall in blood pressure in patients who are hypovolemic. Although useful as adjunctive therapy in hypertensive crises, diuretics should be used with caution in these patients because prior volume depletion may be present in some conditions such as malignant hypertension. The treating physician should be familiar with the pharmacological and clinical actions of drugs which are indicated for and useful in the treatment of hypertensive emergencies. Once the patient's situation has stabilized, the patient may be switched to an oral medication and the physician should discuss long term follow up plans. With appropriate clinical diagnosis, hypertensive emergencies can be successfully treated and the complications can be prevented with timely intervention.

Cardiac repolarization abnormalities among patients with various stages of chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease (CKD) are at increased risk of life-threatening cardiovascular arrhythmias. Although these arrhythmias are usually secondary to structural heart diseases that are commonly associated with CKD, a significant proportion of cases with sudden cardiac death have no obvious structural heart disease. This study aims to explore the relationship of cardiac repolarization in patients with CKD and worsening kidney function. HYPOTHESIS: There is cardiac repolarization abnormalities among patients with chronic kidney disease. METHODS: This was a retrospective, chart-review study of admissions or clinic visits to a university hospital between 2005 and 2010 by patients with a diagnosis of CKD. Inclusion criteria selected patients who had 12-lead surface electrocardiography (ECG), renal function tests within 24 hours, and transthoracic echocardiography within 6 months. Cases with a documented etiology for the corrected Qt (Qtc) interval prolongation including structural heart disease, QT prolonging drugs, or relevant disease conditions, were excluded. RESULTS: Our sample size was 154 ECGs. Two-thirds of patients with CKD had QTc interval prolongation, and about 20% had a QTc interval >500 ms. QTc interval was significantly different and increased with each successive stage of CKD using the Bazett (P < 0.006) or Fridericia (P = 0.03) formula. QTc interval correlated significantly with serum creatinine (P = 0.01). These finding were independent of age, gender, potassium, and calcium concentrations. CONCLUSIONS: The progression of CKD resulted in a significant delay of cardiac repolarization, independent of other risk factors. This effect may potentially increase the risk of sudden cardiac death, and may also increase the susceptibility of drug-induced arrhythmia.

Diabetic nephropathy -- a multifaceted target of new therapies.

Diabetic nephropathy (DN) remains the most common cause for end stage renal disease (ESRD) as the burden of diabetes increases worldwide. Nearly one-third of patients with diabetes develop nephropathy making early diagnosis critical in preventing long term kidney loss. Microalbuminuria is the earliest clinical manifestation of DN and is associated with substantial risk for progressive kidney damage. Hyperglycemia activates various inflammatory pathways both directly and via gene transcription to induce oxidative stress, reactive oxygen species, fibrotic factors TGF-ß, renin-angiotensin- aldosterone system (RAAS), and advanced glycation end-products, leading collectively to podocyte injury, malfunction, apoptosis, and protein deposition in extracellular matrix of the nephron with albumin leak. Furthermore elevated glucose may also induce epigenetic metabolic memory with continued complications leading to diabetic complications. In addition, other clinical factors including genetic predisposition, obesity, blood pressure, high lipids, and smoking add to the rate of progression in DN. Thus early diagnosis and normalizing glycemic control in addition to careful blood pressure, weight, lipid control, and smoking cessation remain important in decreasing DN progression particularly for those with higher genetic risk.With evolution in the understanding of mechanistic processes leading to DN, targeted therapies such as RAAS blockers, thiazolidinediones, statins, and fibric acid derivatives are being utilized. However the optimal treatment for DM continues to evolve as newer therapies including inhibitors of sodium glucose transport and preglycated proteins as well as antifibrotic agents are being actively investigated in decreasing DN progression.

Adiposity-independent sympathetic activity in black men.

Obesity is thought to lead to sympathetic overactivity as a compensatory adjustment to weight gain. However, most of the experimental support for the hypothesis has been derived from white cohorts. Our previous study in blacks indicated that sympathetic nerve activity (SNA) is closely correlated with body mass index only in women, whereas, in black men, SNA is elevated and dissociated from adiposity (Abate et al., Hypertension 38: 379-383, 2001). To further determine whether total and regional adiposity are determinants of SNA in blacks, we performed a prospective weight loss study in 12 normotensive obese black men and 9 obese black women. SNA, body mass index, and abdominal fat mass were measured before and 16 wk after hypocaloric diet. The major new findings are that, in obese black men, the dietary-induced weight loss of 11.3+/-0.8 kg resulted in reduction in plasma leptin, insulin, and visceral abdominal fat but had no effect on SNA (from baseline of 26+/-4 to 28+/-3 bursts/min, P=not significant). In contrast, in black women, weight loss of 8.0+/-0.9 kg caused similar reductions in plasma leptin, insulin, and visceral abdominal fat and led to a reduction in SNA by 40% (from baseline of 22+/-2 to 13+/-3 bursts/min, P<0.05). In conclusion, these new data from this prospective study provide strong support for a major adiposity-independent sympathetic activity in black men and adiposity-related sympathetic activity in black women.

Disorders of lipid metabolism and chronic kidney disease in the elderly.

The growing population of elderly with chronic kidney disease (CKD) is at greater risk for cardiovascular disease given an independent risk of CKD, as well as from added dyslipidemia of aging and renal dysfunction. Changes in lipid metabolism with more isodense and high-dense, triglyceride-rich particles, low high-density lipoprotein cholesterol, and increased triglyceride levels occur with CKD and aging, which are noted to have significant atherogenic potential. In addition, lipid abnormalities may lead to the progression of CKD. Cardiovascular mortality in the end-stage renal disease population is more than 10 times higher than the general population. Treatment of dyslipidemia in the general population suggests important benefits both in reducing cardiovascular risk and in the prevention of cardiovascular disease. Secondary analyses of elderly subgroups of various large prospective studies with statins suggest treatment benefit with statin use in the elderly. Similarly limited data from secondary analyses of CKD subgroups of larger prospective trials using statins also suggest a possible benefit in cardiovascular outcomes and the progression of kidney disease. However, randomized trials have yet to confirm similar benefits and targets of treatment for dyslipidemia in the elderly with CKD and end-stage renal disease. Treatment in the elderly with CKD should be individualized and outweigh risks of side effects and drug-drug interactions. There is a need for further specific investigation of dyslipidemia of CKD in the aging population in relation to renal disease progression and cardiovascular outcome.

Sympathetic nervous system function in renal hypertension.

Hypertension is a common complication of chronic renal failure, accelerating the deterioration in renal function and constituting an important risk factor for the excessive cardiovascular morbidity and mortality. However, there are large gaps in our understanding of the pathogenesis and treatment of renal hypertension. Although this hypertension traditionally is thought to be largely volume dependent, an increasing body of literature suggests that there is an important sympathetic neural component. Microneurographic studies have demonstrated sympathetic overactivity without baroreflex impairment in both hypertensive chronic hemodialysis patients as well as in those with less advanced renal insufficiency. In a small group of patients with moderate chronic renal insufficiency and renin-dependent hypertension, sympathetic overactivity was normalized during antihypertensive monotherapy with the angiotensin converting enzyme inhibitor enalapril, but exacerbated by antihypertensive therapy with the dihydropyridine calcium channel blocker amlodipine. These results implicate a potentially important role for the sympathetic nervous system in explaining recent trial data suggesting an added renoprotective effect of antihypertensive agents that block the renin-angiotensin system. Future clinical trials are needed to determine whether normalization of sympathetic activity should constitute an important therapeutic goal to improve renal and cardiovascular outcomes in patients with chronic renal failure.

Reflex sympathetic activation during static exercise is severely impaired in patients with myophosphorylase deficiency.

During static exercise, metabolites accumulate in the muscle interstitium where they stimulate chemosensitive afferent nerves that reflexly increase efferent muscle sympathetic nerve activity (MSNA) and blood pressure. In experimental animals, lactic acid potently stimulates the muscle metaboreflex, but its role in humans is more controversial. To determine if lactic acid is a critical mediator of metaboreflex activation in humans, we performed microelectrode recordings of MSNA in eight patients with myophosphorylase deficiency (McArdle's disease) who cannot metabolize intramuscular glycogen and do not generate lactic acid in exercising muscles. Each patient was matched with three healthy control subjects to maximize statistical power. In controls, 2 min of static handgrip performed at 33 % or 45 % of maximal voluntary contraction (MVC) produced intensity-dependent increases in MSNA (171 +/- 22 % and 379 +/- 95 %, respectively). In the patients, MSNA responses to static handgrip were markedly attenuated (33 +/- 14 % at 33 % MVC; 32 +/- 19 % at 45 % MVC; P < 0.05 vs. controls). Likewise, when static handgrip (30 % MVC) was performed to fatigue, MSNA increased by 366 +/- 73 % in controls but only by 51 +/- 14 % in patients (P < 0.05). Pressor responses to static handgrip were also attenuated in patients compared to controls, whereas heart rate responses were identical. In contrast to exercise, the MSNA responses to other reflex stimuli (the cold pressor test or Valsalva's manoeuvre) were similar in patients and controls. Together these data indicate that appropriate activation of glycogenolytic pathways is obligatory for normal metaboreflex-mediated sympathoexcitation during static exercise in humans.