Renal nerves in the maintenance of hypertension: a potential therapeutic target.

Renal sympathetic efferent and afferent nerves, which lie within and immediately adjacent to the wall of the renal arteries, contribute to the maintenance of hypertension. Because the causative factors of hypertension change over time, denervation of both efferent and afferent renal nerves should result in long-term attenuation of hypertension. The importance of the renal nerves in hypertensive patients can now be defined with the novel development of percutaneous, minimally invasive renal denervation from within the renal artery using radiofrequency energy as a therapeutic strategy. Studies thus far show that catheter-based renal denervation in patients with resistant essential hypertension lowers systolic blood pressure 27 mm Hg by 12 months, with the estimated glomerular filtration rate remaining stable. The decrease in arterial pressure after renal denervation is associated with decreased peripheral sympathetic nervous system activity, suggesting that the kidney is a source of significant central sympathetic outflow via afferent renal nerve activity.

Recently Approved and Under Investigation Drugs for Treating Patients with Heart Failure.

Heart Failure (HF) represents a leading cause of morbidity and mortality worldwide. Despite the recent advances in the treatment of this condition, patients´ prognosis remains unfavorable in most cases. Sacubitril/valsartan and ivabradine have been recently approved to improve clinical outcomes in patients with HF with reduced ejection fraction. Drugs under investigation for treating patients with HF encompass many novel mechanisms including vasoactive peptides, blocking inflammatory- mediators, natriuretic peptides, selective non-steroidal mineralocorticoid-receptor antagonists, myocardial ß3 adrenoreceptor agonists, inhibiting the cytochrome C/cardiolipin peroxidase complex, neuregulin-1/ErbB signaling and inhibiting late inward sodium current. The aim of this manuscript is to review the main drugs under investigation for the treatment of patients with HF and give perspectives for their implementation into clinical practice.

N-Acetylcysteine added to volume expansion with sodium bicarbonate does not further prevent contrast-induced nephropathy: results from the cardiac angiography in renally impaired patients study.

We reviewed data from the multicenter CARE (Cardiac Angiography in Renally Impaired Patients) study to see if benefit could be shown for N-acetylcysteine (NAC) in patients undergoing cardiac angiography who all received intravenous bicarbonate fluid expansion. Four hundred fourteen patients with moderate-to-severe chronic kidney disease were randomized to receive intra-arterial administration of iopamidol-370 or iodixanol-320. All patients were prehydrated with isotonic sodium bicarbonate solution. Each site chose whether or not to administer NAC 1,200 mg twice daily to all patients. Serum creatinine (SCr) levels and estimated glomerular filtration rate were assessed at baseline and 2-5 days after receiving contrast. The primary outcome was a postdose SCr increase 0.5 mg/dL (44.2 mumol/L) over baseline. Secondary outcomes were a postdose SCr increase 25% and the mean peak change in SCr. The NAC group received significantly less hydration (892 +/- 236 mL vs. 1016 +/- 328 mL; P < 0.001) and more contrast volume (146 +/- 74 mL vs. 127 +/- 71 mL; P = 0.009) compared with no-NAC group. SCr increases 0.5 mg/dL occurred in 4.2% (7 of 168 patients) in NAC group and 6.5% (16 of 246 patients) in no-NAC group (P = 0.38); rates of SCr increases 25% were 11.9% and 10.6%, respectively (P = 0.75); mean post-SCr increases were 0.07 mg/dL in NAC group versus 0.11 mg/dL in no-NAC group (P = 0.14). In conclusion, addition of NAC to fluid expansion with sodium bicarbonate failed to reduce the rate of contrast-induced nephropathy (CIN) after the intra-arterial administration of iopamidol or iodixanol to high-risk patients with chronic kidney disease.

Renal Denervation Update From the International Sympathetic Nervous System Summit: JACC State-of-the-Art Review.

Three recent renal denervation studies in both drug-naïve and drug-treated hypertensive patients demonstrated a significant reduction of ambulatory blood pressure compared with respective sham control groups. Improved trial design, selection of relevant patient cohorts, and optimized interventional procedures have likely contributed to these positive findings. However, substantial variability in the blood pressure response to renal denervation can still be observed and remains a challenging and important problem. The International Sympathetic Nervous System Summit was convened to bring together experts in both experimental and clinical medicine to discuss the current evidence base, novel developments in our understanding of neural interplay, procedural aspects, monitoring of technical success, and others. Identification of relevant trends in the field and initiation of tailored and combined experimental and clinical research efforts will help to address remaining questions and provide much-needed evidence to guide clinical use of renal denervation for hypertension treatment and other potential indications.

Cardiac Angiography in Renally Impaired Patients (CARE) study: a randomized double-blind trial of contrast-induced nephropathy in patients with chronic kidney disease.

BACKGROUND: No direct comparisons exist of the renal tolerability of the low-osmolality contrast medium iopamidol with that of the iso-osmolality contrast medium iodixanol in high-risk patients. METHODS AND RESULTS: The present study is a multicenter, randomized, double-blind comparison of iopamidol and iodixanol in patients with chronic kidney disease (estimated glomerular filtration rate, 20 to 59 mL/min) who underwent cardiac angiography or percutaneous coronary interventions. Serum creatinine (SCr) levels and estimated glomerular filtration rate were assessed at baseline and 2 to 5 days after receiving medications. The primary outcome was a postdose SCr increase > or = 0.5 mg/dL (44.2 micromol/L) over baseline. Secondary outcomes were a postdose SCr increase > or = 25%, a postdose estimated glomerular filtration rate decrease of > or = 25%, and the mean peak change in SCr. In 414 patients, contrast volume, presence of diabetes mellitus, use of N-acetylcysteine, mean baseline SCr, and estimated glomerular filtration rate were comparable in the 2 groups. SCr increases > or = 0.5 mg/dL occurred in 4.4% (9 of 204 patients) after iopamidol and 6.7% (14 of 210 patients) after iodixanol (P=0.39), whereas rates of SCr increases > or = 25% were 9.8% and 12.4%, respectively (P=0.44). In patients with diabetes, SCr increases > or = 0.5 mg/dL were 5.1% (4 of 78 patients) with iopamidol and 13.0% (12 of 92 patients) with iodixanol (P=0.11), whereas SCr increases > or = 25% were 10.3% and 15.2%, respectively (P=0.37). Mean post-SCr increases were significantly less with iopamidol (all patients: 0.07 versus 0.12 mg/dL, 6.2 versus 10.6 micromol/L, P=0.03; patients with diabetes: 0.07 versus 0.16 mg/dL, 6.2 versus 14.1 micromol/L, P=0.01). CONCLUSIONS: The rate of contrast-induced nephropathy, defined by multiple end points, is not statistically different after the intraarterial administration of iopamidol or iodixanol to high-risk patients, with or without diabetes mellitus. Any true difference between the agents is small and not likely to be clinically significant.

Renal effects of contrast media in diabetic patients undergoing diagnostic or interventional coronary angiography.

BACKGROUND: The use of safe iodinated contrast media (CM) to prevent contrast-induced nephropathy (CIN) is an important consideration among renally impaired diabetic patients during coronary angiography. HYPOTHESIS: Diabetic patients with normal or mild renal dysfunction are less likely to receive renal protective measures during angiography, yet they may also be at risk for CIN. We compared the renal effects of iopamidol and iodixanol in diabetic patients who were referred for angiography. METHODS: Diabetic patients (N=122) with a serum creatinine (SCr) level of < or = 2 mg/dl were double-blind randomized to receive nonionic CM: iopamidol-370 (low osmolar, monomeric) or iodixanol-320 (iso-osmolar, dimeric). Renal stability was evaluated at baseline and at Days 1, 3, and 7 post-angiography. The primary endpoint was a > or = 25% increase in SCr. RESULTS: Seventeen (10 iopamidol, 7 iodixanol; P=NS) patients had an increase in SCr > or = 25% over baseline. Over all days, analysis revealed nonsignificant differences in the incidence of CIN between the two study groups regardless of how CIN was defined. CONCLUSIONS: Diabetic patients with normal or mild renal dysfunction are at risk for CIN. No significant difference in renal response was observed for these CM in this at-risk population.

Lowering blood pressure with beta-blockers in combination with other renin-angiotensin system blockers in patients with hypertension and type 2 diabetes: results from the GEMINI Trial.

The effects of beta-blockade in addition to more specific renin-angiotensin system (RAS) blockers on blood pressure (BP) in patients with diabetes are described. After washout of medications other than angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, patients were titrated to a BP level <130/80 mm Hg using therapy with carvedilol 6.25 to 25 mg bid (n=498) or metoprolol tartrate 50 to 200 mg bid (n=737). At the end of the beta-blocker titration period, a BP level <130/80 mm Hg was achieved in 37% of carvedilol-treated and 36% of metoprolol-treated participants who continued to receive a renin-angiotensin system blocker. In the approximately 60% of participants in whom a BP level <130/80 mm Hg was not attained with renin-angiotensin system blockade plus beta-blockade, hydrochlorothiazide was added in 43% and 44% of carvedilol and metoprolol groups, respectively; 25% (both arms) also required a calcium channel blocker. Among those in whom goal BP was not achieved, 42% of carvedilol- and 40% of metoprolol-treated participants were not titrated to the highest dose of beta-blocker. The use of carvedilol compared with metoprolol did not effect glycemic control.

Use and side-effect profile of spironolactone in a private cardiologist's practice.

BACKGROUND: The beneficial effects of spironolactone on the treatment of cardiovascular diseases are well known, but translating these benefits into private practice can be difficult because of the drug's side-effect profile. HYPOTHESIS: When patients are monitored over the long term, spironolactone can be used safely with an acceptable side-effect profile. METHODS: We retrospectively studied 762 patients taking spironolactone over a 7-year period in a cardiologist's referral-based practice and monitored them for side effects from the medication. RESULTS: Data were available on 762 patients. The average age of our patients when started on the medication was 67.2 +/- 0.5 years. Of these, 585 (76.8%) patients were treated for heart failure and 155 (20.3%) for hypertension. An average dose of 38.4 +/- 1.4 mg of spironolactone was used for treatment of all conditions. Of the 762 patients, 81 (10.6%) experienced side effects while using the medication; 40 had hyperkalemia (5.3%), 14 had gynecomastia (1.8%), and 15 had gastritis (2%). Of the patients with hyperkalemia, average creatinine clearance decreased from 64.6 +/- 5.8 ml/min at therapy start to 50.3 +/- 5.5 ml/min at the time of onset of side effects. CONCLUSION: Spironolactone can be used with an acceptable side-effect profile as long as patients are monitored long-term while receiving the medication.

Ventricular repolarization markers for predicting malignant arrhythmias in clinical practice.

Malignant cardiac arrhythmias which result in sudden cardiac death may be present in individuals apparently healthy or be associated with other medical conditions. The way to predict their appearance represents a challenge for the medical community due to the tragic outcomes in most cases. In the last two decades some ventricular repolarization (VR) markers have been found to be useful to predict malignant cardiac arrhythmias in several clinical conditions. The corrected QT, QT dispersion, Tpeak-Tend, Tpeak-Tend dispersion and Tp-e/QT have been studied and implemented in clinical practice for this purpose. These markers are obtained from 12 lead surface electrocardiogram. In this review we discuss how these markers have demonstrated to be effective to predict malignant arrhythmias in medical conditions such as long and short QT syndromes, Brugada syndrome, early repolarization syndrome, acute myocardial ischemia, heart failure, hypertension, diabetes mellitus, obesity and highly trained athletes. Also the main pathophysiological mechanisms that explain the arrhythmogenic predisposition in these diseases and the basis for the VR markers are discussed. However, the same results have not been found in all conditions. Further studies are needed to reach a global consensus in order to incorporate these VR parameters in risk stratification of these patients.

Natriuretic peptides, obesity and cardiovascular diseases.

Obesity, hypertension and heart failure are conditions commonly associated with each other. Recent investigations have demonstrated that low plasmatic levels of natriuretic peptides are linked with obesity. Thus, knowing the actions of these hormones in water and salt homeostasis, it is possible to establish that low levels of natriuretic peptides may be the common denominator among obesity, hypertension and heart failure. Knowledge on this topic is crucial to develop further investigation for definitive conclusions.

Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial.

CONTEXT: Beta-blockers have been shown to decrease cardiovascular risk in patients with hypertension and type 2 diabetes mellitus (DM); however, some components of the metabolic syndrome are worsened by some beta-blockers. OBJECTIVE: To compare the effects of beta-blockers with different pharmacological profiles on glycemic and metabolic control in participants with DM and hypertension receiving renin-angiotensin system (RAS) blockade, in the context of cardiovascular risk factors. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, parallel-group trial (The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives [GEMINI]) conducted between June 1, 2001, and April 6, 2004, at 205 US sites that compared the effects of carvedilol and metoprolol tartrate on glycemic control. The 1235 participants were aged 36 to 85 years with hypertension (>130/80 mm Hg) and type 2 DM (glycosylated hemoglobin [HbA1c], 6.5%-8.5%) and were receiving RAS blockers. Participants were followed up for 35 weeks. INTERVENTIONS: Participants were randomized to receive a 6.25- to 25-mg dose of carvedilol (n = 498) or 50- to 200-mg dose of metoprolol tartrate (n = 737), each twice daily. Open-label hydrochlorothiazide and a dihydropyridine calcium antagonist were added, if needed, to achieve blood pressure target. MAIN OUTCOME MEASURES: Difference between groups in mean change from baseline HbA1c following 5 months of maintenance therapy. Additional prespecified comparisons included change from baseline HbA1c in individual treatment groups, treatment effect on insulin sensitivity, and microalbuminuria. RESULTS: The 2 groups differed in mean change in HbA1c from baseline (0.13%; 95% confidence interval [CI], -0.22% to -0.04%; P = .004; modified intention-to-treat analysis). The mean (SD) HbA1c increased with metoprolol (0.15% [0.04%]; P<.001) but not carvedilol (0.02% [0.04%]; P = .65). Insulin sensitivity improved with carvedilol (-9.1%; P = .004) but not metoprolol (-2.0%; P = .48); the between-group difference was -7.2% (95% CI, -13.8% to -0.2%; P = .004). Blood pressure was similar between groups. Progression to microalbuminuria was less frequent with carvedilol than with metoprolol (6.4% vs 10.3%; odds ratio, 0.60; 95% CI, 0.36-0.97; P = .04). CONCLUSIONS: Both beta-blockers were well tolerated; use of carvedilol in the presence of RAS blockade did not affect glycemic control and improved some components of the metabolic syndrome relative to metoprolol in participants with DM and hypertension. The effects of the 2 beta-blockers on clinical outcomes need to be compared in long-term clinical trials.

Novel treatment approaches in hypertensive type 2 diabetic patients.

Type 2 diabetes mellitus (T2DM) and hypertension represent two common conditions worldwide. Their frequent association with cardiovascular diseases makes management of hypertensive patients with T2DM an important clinical priority. Carvedilol and renal denervation are two promising choices to reduce plasma glucose levels and blood pressure in hypertensive patients with T2DM to reduce future complications and improve clinical outcomes and prognosis. Pathophysiological mechanisms of both options are under investigation, but one of the most accepted is an attenuation in sympathetic nervous system activity which lowers blood pressure and improves insulin sensitivity. Choice of these therapeutic approaches should be individualized based on specific characteristics of each patient. Further investigations are needed to determine when to consider their use in clinical practice.

Renal denervation for treating resistant hypertension: current evidence and future insights from a global perspective.

Adequate blood pressure control represents an important goal for all physicians due to the complications of hypertension which reduce patients' quality of life. A new interventional strategy to reduce blood pressure has been developed for patients with resistant hypertension. Catheter-based renal denervation has demonstrated excellent results in recent investigations associated with few side effects. With the growing diffusion of this technique worldwide, some medical societies have published consensus statements to guide physicians how to best apply this procedure. Questions remain to be answered such as the long-term durability of renal denervation, the efficacy in patients with other sympathetically mediated diseases, and whether renal denervation would benefit patients with stage 1 hypertension.

Left ventricular hypertrophy: major risk factor in patients with hypertension: update and practical clinical applications.

Left ventricular hypertrophy is a maladaptive response to chronic pressure overload and an important risk factor for atrial fibrillation, diastolic heart failure, systolic heart failure, and sudden death in patients with hypertension. Since not all patients with hypertension develop left ventricular hypertrophy, there are clinical findings that should be kept in mind that may alert the physician to the presence of left ventricular hypertrophy so a more definitive evaluation can be performed using an echocardiogram or cardiovascular magnetic resonance. Controlling arterial pressure, sodium restriction, and weight loss independently facilitate the regression of left ventricular hypertrophy. Choice of antihypertensive agents may be important when treating a patient with hypertensive left ventricular hypertrophy. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers followed by calcium channel antagonists most rapidly facilitate the regression of left ventricular hypertrophy. With the regression of left ventricular hypertrophy, diastolic function and coronary flow reserve usually improve, and cardiovascular risk decreases.

Natriuretic peptides, obesity and cardiovascular diseases / Peptídeos natriuréticos, obesidade e doenças cardiovasculares

Obesity, hypertension and heart failure are conditions commonly associated with each other. Recent investigations have demonstrated that low plasmatic levels of natriuretic peptides are linked with obesity. Thus, knowing the actions of these hormones in water and salt homeostasis, it is possible to establish that low levels of natriuretic peptides may be the common denominator among obesity, hypertension and heart failure. Knowledge on this topic is crucial to develop further investigation for definitive conclusions.

Contrast-induced nephropathy-choice of contrast agents to reduce renal risk.

Contrast-induced nephropathy (CIN) represents an increasing healthcare burden and challenge as the frequency of diagnostic imaging and interventional procedures increases, particularly among patients at risk for developing CIN. Universally accepted strategies to reduce the risk for CIN include careful patient screening and selection, adequate patient hydration, limiting the volume of contrast medium administered, and choosing a safe, non-ionic, low-osmolar contrast agent. For both intra-arterial and intravenous use, all ionic and non-ionic iodinated contrast agents may further impair renal function in high-risk patients. Based on comparisons of contrast media in proximal renal tubular cell culture and in recent robust head-to-head prospective clinical trials in high-risk patients, however, iso-osmolar iodixanol and low-osmolar iopamidol are comparable and appear to be the contrast agents of choice to reduce renal risk for CIN.