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.

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.

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.

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.

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.

Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study.

BACKGROUND: Renal denervation (RDN) with radiofrequency ablation substantially reduces blood pressure in patients with treatment-resistant hypertension. We assessed the long-term antihypertensive effects and safety. METHODS: Symplicity HTN-1 is an open-label study that enrolled 153 patients, of whom 111 consented to follow-up for 36 months. Eligible patients had a systolic blood pressure of at least 160 mm Hg and were taking at least three antihypertensive drugs, including a diuretic, at the optimum doses. Changes in office systolic blood pressure and safety were assessed every 6 months and reported every 12 months. This study is registered with ClinicalTrials.gov, numbers NCT00483808, NCT00664638, and NCT00753285. FINDINGS: 88 patients had complete data at 36 months. At baseline the mean age was 57 (SD 11) years, 37 (42%) patients were women, 25 (28%) had type 2 diabetes mellitus, the mean estimated glomerular filtration rate was 85 (SD 19) mL/min per 1·73 m(2), and mean blood pressure was 175/98 (SD 16/14) mm Hg. At 36 months significant changes were seen in systolic (-32·0 mm Hg, 95% CI -35·7 to -28·2) and diastolic blood pressure (-14·4 mm Hg, -16·9 to -11·9). Drops of 10 mm Hg or more in systolic blood pressure were seen in 69% of patients at 1 month, 81% at 6 months, 85% at 12 months, 83% at 24 months, and 93% at 36 months. One new renal artery stenosis requiring stenting and three deaths unrelated to RDN occurred during follow-up. INTERPRETATION: Changes in blood pressure after RDN persist long term in patients with treatment-resistant hypertension, with good safety. FUNDING: Ardian LLC/Medtronic Inc.

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.

International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension.

Catheter-based radiofrequency ablation technology to disrupt both efferent and afferent renal nerves has recently been introduced to clinical medicine after the demonstration of significant systolic and diastolic blood pressure reductions. Clinical trial data available thus far have been obtained primarily in patients with resistant hypertension, defined as standardized systolic clinic blood pressure ≥ 160 mm Hg (or ≥ 150 mm Hg in patients with type 2 diabetes) despite appropriate pharmacologic treatment with at least 3 antihypertensive drugs, including a diuretic agent. Accordingly, these criteria and blood pressure thresholds should be borne in mind when selecting patients for renal nerve ablation. Secondary forms of hypertension and pseudoresistance, such as nonadherence to medication, intolerance of medication, and white coat hypertension, should have been ruled out, and 24-h ambulatory blood pressure monitoring is mandatory in this context. Because there are theoretical concerns with regard to renal safety, selected patients should have preserved renal function, with an estimated glomerular filtration rate ≥ 45 ml/min/1.73 m(2). Optimal periprocedural management of volume status and medication regimens at specialized and experienced centers equipped with adequate infrastructure to cope with potential procedural complications will minimize potential patient risks. Long-term safety and efficacy data are limited to 3 years of follow-up in small patient cohorts, so efforts to monitor treated patients are crucial to define the long-term performance of the procedure. Although renal nerve ablation could have beneficial effects in other conditions characterized by elevated renal sympathetic nerve activity, its potential use for such indications should currently be limited to formal research studies of its safety and efficacy.

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.

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.

The role of renal sympathetic nerves in hypertension: has percutaneous renal denervation refocused attention on their clinical significance?

Renal sympathetic efferent and afferent nerves, which lie within and immediately adjacent to the wall of the renal artery, contribute to the pathogenesis of hypertension. Because the causative factors of hypertension change over time, denervation of both efferent and afferent nerves should result in long-term attenuation of the hypertension. The importance of the renal nerves in patients with hypertension 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 refractory hypertension lowers systolic blood pressure 27 mm Hg by 12 months with estimated glomerular filtration rate remaining stable. An attenuation of hypertension of this magnitude by catheter-based renal sympathetic denervation in combination with pharmacologic therapy is likely to be valuable in decreasing the risks of stroke, left ventricular hypertrophy, heart failure, and chronic renal failure.

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.

Contrast-induced nephropathy and long-term adverse events: cause and effect?

BACKGROUND AND OBJECTIVES: The relationship of contrast-induced nephropathy (CIN) to long-term adverse events (AEs) is controversial. Although an association with AEs has been previously reported, it is unclear whether CIN is causally related to these AEs. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We obtained long-term (> or =1 yr) follow-up on 294 patients who participated in a randomized, double-blind comparison of two prevention strategies for CIN (iopamidol versus iodixanol). A difference in the incidence of AEs between patients who had developed CIN and those who had not was performed using a chi(2) test and Poisson regression analysis. A similar statistical approach was used for the differences in AEs between those who received iopamidol or iodixanol. Multiple definitions of CIN were used to strengthen and validate the results and conclusions. RESULTS: The rate of long-term AEs was higher in individuals with CIN (all definitions of CIN). After adjustment for baseline comorbidities and risk factors, the adjusted incidence rate ratio for AEs was twice as high in those with CIN. Randomization to iopamidol reduced both the incidence of CIN and AEs. CONCLUSIONS: The parallel decrease in the incidence of CIN and AEs in one arm of this randomized trial supports a causal role for CIN.

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.