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Margaret M Redfield,
Horng H Chen,
Barry A Borlaug,
Marc J Semigran,
Kerry L Lee,
Gregory Lewis,
Martin M Lewinter,
Jean L Rouleau,
David A Bull,
Douglas L Mann, [......],
Grace Lin,
Jae K Oh,
Manesh R Patel,
Raymond J Kim,
Russell P Tracy,
Eric J Velazquez,
Kevin J Anstrom,
Adrian F Hernandez,
Alice M Mascette,
Eugene Braunwald
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ABSTRACT: IMPORTANCE Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction (HFPEF). OBJECTIVE To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF. DESIGN Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial of 216 stable outpatients with HF, ejection fraction ≥50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Follow-up was through August 30, 2012. INTERVENTIONS Sildenafil (n = 113) or placebo (n = 103) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks. MAIN OUTCOME MEASURES Primary end point was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score (range, 1-n, a higher value indicates better status; expected value with no treatment effect, 95) based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks. RESULTS Median age was 69 years, and 48% of patients were women. At baseline, median peak oxygen consumption (11.7 mL/kg/min) and 6-minute walk distance (308 m) were reduced. The median E/e' (16), left atrial volume index (44 mL/m2), and pulmonary artery systolic pressure (41 mm Hg) were consistent with chronically elevated left ventricular filling pressures. At 24 weeks, median (IQR) changes in peak oxygen consumption (mL/kg/min) in patients who received placebo (-0.20 [IQR, -0.70 to 1.00]) or sildenafil (-0.20 [IQR, -1.70 to 1.11]) were not significantly different (P = .90) in analyses in which patients with missing week-24 data were excluded, and in sensitivity analysis based on intention to treat with multiple imputation for missing values (mean between-group difference, 0.01 mL/kg/min, [95% CI, -0.60 to 0.61]). The mean clinical status rank score was not significantly different at 24 weeks between placebo (95.8) and sildenafil (94.2) (P = .85). Changes in 6-minute walk distance at 24 weeks in patients who received placebo (15.0 m [IQR, -26.0 to 45.0]) or sildenafil (5.0 m [IQR, -37.0 to 55.0]; P = .92) were also not significantly different. Adverse events occurred in 78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%). CONCLUSION AND RELEVANCE Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00763867.
JAMA The Journal of the American Medical Association 03/2013; · 30.03 Impact Factor
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Bradley A Bart, Steven R Goldsmith,
Kerry L Lee,
Michael M Givertz,
Christopher M O'Connor,
David A Bull,
Margaret M Redfield,
Anita Deswal,
Jean L Rouleau,
Martin M Lewinter, [......],
Marc J Semigran,
G Michael Felker,
Horng H Chen,
Adrian F Hernandez,
Kevin J Anstrom,
Steven E McNulty,
Eric J Velazquez,
Jenny C Ibarra,
Alice M Mascette,
Eugene Braunwald
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ABSTRACT: Background Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the efficacy and safety of ultrafiltration in patients with acute decompensated heart failure complicated by persistent congestion and worsened renal function. Methods We randomly assigned a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients). The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after random assignment. Patients were followed for 60 days. Results Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of the change in the serum creatinine level and body weight 96 hours after enrollment (P=0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level was -0.04±0.53 mg per deciliter (-3.5±46.9 μmol per liter) in the pharmacologic-therapy group, as compared with +0.23±0.70 mg per deciliter (20.3±61.9 μmol per liter) in the ultrafiltration group (P=0.003). There was no significant difference in weight loss 96 hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5±5.1 kg [12.1±11.3 lb] and 5.7±3.9 kg [12.6±8.5 lb], respectively; P=0.58). A higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P=0.03). Conclusions In a randomized trial involving patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches. Ultrafiltration was associated with a higher rate of adverse events. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00608491 .).
New England Journal of Medicine 11/2012; · 53.30 Impact Factor
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Achal Gupta,
Eugene Braunwald,
Steven McNulty,
G Michael Felker,
E Michael Gilbert,
Rami Alharethi,
Kerry L Lee,
Kevin J Anstrom,
Margaret M Redfield, Steven R Goldsmith,
Christopher M O'Connor,
David A Bull,
Josef Stehlik,
Sheldon E Litwin
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ABSTRACT: Obesity could attenuate diuretic effectiveness in treatment of acute decompensated heart failure (HF).
The DOSE trial randomized 308 subjects with acute HF to low- versus high-intensification intravenous diuretic therapy. We tested for statistical interactions between obesity and dosing strategy across clinical end points. After 72 hours of treatment, obese subjects (body mass index >30 kg/m(2); n = 173) had greater volume loss than nonobese subjects (n = 119) but similar improvements in dyspnea and freedom from congestion. Both groups had greater fluid loss with high-intensification treatment. Obese subjects had a higher incidence of worsening renal function (WRF) at 72 hours with low-intensification treatment, compared with nonobese subjects. In contrast, nonobese and obese subjects had similar incidence of WRF with high-intensification treatment. There were no differences between obese and nonobese subjects in time to discharge and 60-day freedom from death, emergency department visit, or rehospitalization.
The incidence of WRF was greater in obese than in nonobese subjects with low-intensification treatment. However, the frequency of WRF was equivalent in obese and nonobese subjects with high-intensification treatment. Additional studies are needed to assess whether obese patients with acute HF benefit from an initial high-intensification treatment strategy.
Journal of cardiac failure 11/2012; 18(11):837-44. · 3.25 Impact Factor
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ABSTRACT: Numerous studies over the last decade have demonstrated that renal dysfunction and worsening renal function (WRF) are common in patients hospitalized for heart failure (HHF) and appear to be associated with poor in-hospital and post-discharge outcomes. Unfortunately, its etiology has not been completely understood, and its prediction during hospitalization remains challenging. The evaluation of renal impairment during hospitalization should take into consideration the underlying renal substrate (e.g., predisposing clinical comorbidities such as diabetes and hypertension), initiating mechanisms (e.g., in-hospital therapies such as diuretics), and amplifying factors (neurohormonal and hemodynamic profile changes). Various patterns of WRF may have different prognostic implications and may require different therapeutic approaches. WRF may be initially classified by duration (transient vs. persistent) and by etiology (elevated venous pressures vs. arterial underfilling). Other critical contributing factors during hospitalization include progressive left ventricular dysfunction, neurohormonal activation, and medications. Transient WRF as a result of aggressive therapy targeting congestion may not be associated with poor outcomes. Persistent WRF seen in patients with severe hemodynamic derangements may be associated with poor post-discharge prognosis. Future investigations must clarify the pathophysiological correlates of various patterns of WRF. To date, there is an unmet clinical need to achieve adequate control over congestion while preserving renal function in HHF patients. Thus, the aim of this review is to provide an in-depth and critical interpretation of the available data on the prognostic importance of RD and WRF during hospitalization in an effort to improve HF management.
Heart Failure Reviews 05/2012; · 3.20 Impact Factor
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Bradley A Bart, Steven R Goldsmith,
Kerry L Lee,
Margaret M Redfield,
G Michael Felker,
Christopher M O'Connor,
Horng H Chen,
Jean L Rouleau,
Michael M Givertz,
Marc J Semigran,
Douglas Mann,
Anita Deswal,
David A Bull,
Martin M Lewinter,
Eugene Braunwald
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ABSTRACT: Worsening renal function is common among patients hospitalized for acute decompensated heart failure (ADHF). When this occurs, subsequent management decisions often pit the desire for effective decongestion against concerns about further worsening renal function. There are no evidence-based treatments or guidelines to assist in these difficult management decisions. Ultrafiltration is a potentially attractive alternative to loop diuretics for the management of fluid overload in patients with ADHF and worsening renal function.
The National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network designed a clinical trial to determine if ultrafiltration results in improved renal function and relief of congestion compared with stepped pharmacologic care when assessed 96 hours after randomization in patients with ADHF and cardiorenal syndrome. Enrollment began in June 2008. This paper describes the rationale and design of the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF).
Treating the signs and symptoms of congestion in ADHF is often complicated by worsening renal function. CARRESS-HF compares treatment strategies (ultrafiltration vs stepped pharmacologic care) for the management of worsening renal function in patients with ADHF. The results of the CARRESS-HF trial are expected to provide information and evidence as to the most appropriate approaches for treating this challenging patient population.
Journal of cardiac failure 03/2012; 18(3):176-82. · 3.25 Impact Factor
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ABSTRACT: Loop diuretics, though often effective for treating congestion, have significant limitations. Discovering ways to limit exposure to loop diuretics while achieving effective decongestion is an important goal of current clinical research in heart failure (HF). Vasopressin antagonists are effective in removing large amounts of water, but not salt, in HF. Few data exist about the detailed renal and hormonal effects of these agents compared with or in combination with loop diuretics. This study investigated the renal and neurohormonal effects of loop diuretics, the mixed vasopressin antagonist conivaptan, and the combination in patients with chronic stable HF.
In 8 patients with chronic stable HF on standard medical treatment, heart rate, arterial pressure, systemic vascular resistance, and cardiac output (the latter 2 by using impedance cardiography), as well as glomerular filtration rate (iothalamate clearance), renal blood flow (para-aminohippurate clearance), urinary volumes and urinary sodium, plasma catecholamines, renin activity, arginine vasopressin, and B-type natriuretic peptide were assessed before and at hourly intervals for 4 hours after receiving furosemide, conivaptan, or the combination on 3 different study days at a minimum of 1-week intervals. There were no significant effects of conivaptan, furosemide, or the combination on any hemodynamic variable, neurohormonal level, renal blood flow, or glomerular filtration rate. Conivaptan and furosemide similarly increased urine volumes; the effect of the combination was significantly greater. Furosemide, but not conivaptan, increased urinary sodium excretion, and the combination was significantly greater than after furosemide alone.
Without adversely affecting important hemodynamic variables, neurohormones, renal blood flow, or glomerular filtration rate, conivaptan significantly augmented both the diuretic and the natriuretic response to furosemide in patients with chronic HF. These results may have implications for the design of furosemide-sparing regimens in the treatment of acute HF.
Journal of cardiac failure 12/2011; 17(12):982-9. · 3.25 Impact Factor
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Journal of cardiac failure 10/2011; 17(10):804-5. · 3.25 Impact Factor
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G Michael Felker,
Kerry L Lee,
David A Bull,
Margaret M Redfield,
Lynne W Stevenson, Steven R Goldsmith,
Martin M LeWinter,
Anita Deswal,
Jean L Rouleau,
Elizabeth O Ofili, [......],
Steven E McNulty,
Eric J Velazquez,
Abdallah G Kfoury,
Horng H Chen,
Michael M Givertz,
Marc J Semigran,
Bradley A Bart,
Alice M Mascette,
Eugene Braunwald,
Christopher M O'Connor
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ABSTRACT: Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use.
In a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient's previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The coprimary end points were patients' global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours.
In the comparison of bolus with continuous infusion, there was no significant difference in patients' global assessment of symptoms (mean AUC, 4236±1440 and 4373±1404, respectively; P=0.47) or in the mean change in the creatinine level (0.05±0.3 mg per deciliter [4.4±26.5 μmol per liter] and 0.07±0.3 mg per deciliter [6.2±26.5 μmol per liter], respectively; P=0.45). In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients' global assessment of symptoms in the high-dose group (mean AUC, 4430±1401 vs. 4171±1436; P=0.06). There was no significant difference between these groups in the mean change in the creatinine level (0.08±0.3 mg per deciliter [7.1±26.5 μmol per liter] with the high-dose strategy and 0.04±0.3 mg per deciliter [3.5±26.5 μmol per liter] with the low-dose strategy, P=0.21). The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function.
Among patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00577135.).
New England Journal of Medicine 03/2011; 364(9):797-805. · 53.30 Impact Factor
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ABSTRACT: INTRODUCTION: It has been > 25 years since it was first discovered that arginine vasopressin levels are elevated in heart failure and this elevation is proportional to the severity of heart failure. Tolvaptan is an oral nonpeptide V₂-selective antagonist and has been shown to induce free water excretion without increasing urine sodium, an effect termed 'aquaresis'. AREAS COVERED: This paper aims to review the physiology, chemistry, pharmacokinetics, clinical efficacy and safety of tolvaptan in HF. A PubMed literature search was performed using 'tolvaptan' and the MeSH term 'heart failure', yielding 89 references. EXPERT OPINION: Clinical trials conducted in ambulatory and hospitalized patients with HF have found treatment with tolvaptan causes rapid and sustained body weight reductions concurrent with increases in urine output, improves and/or normalizes serum sodium in hyponatremic patients, reduces signs and symptoms of congestion and increases thirst. However, tolvaptan has not been shown to decrease HF re-hospitalization or mortality. As an adjunct to standard therapy, tolvaptan is unique in that it is virtually the only novel agent tested in patients hospitalized for acute heart failure syndrome (AHFS) to reach its primary end point for short-term efficacy without causing deleterious side effects. There is theoretical concern that chronic V₂ receptor blockade may cause harmful long-term side effects via enhanced V(1a) receptor activation, potentially offsetting any favorable effects on congestion and hyponatremia. The 'vaptan' class of drugs is an active and promising area for clinical investigation and future research is necessary to clarify the therapeutic role of selective and nonselective vasopressin inhibition in chronic HF and AHFS.
Expert Opinion on Pharmacotherapy 03/2011; 12(6):961-76. · 3.20 Impact Factor
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Steven R Goldsmith
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ABSTRACT: Hyponatremia is independently associated with adverse outcomes in patients with congestive heart failure (CHF). The primary cause of hyponatremia in CHF is the inappropriate secretion of the antidiuretic hormone arginine vasopressin (AVP). The binding of AVP to V(2) receptors in the renal collecting duct promotes water retention, a process that can lead to dilutional hyponatremia as well as increased ventricular preload. Conventional treatment of hyponatremia in CHF is largely based on water restriction, which is neither effective nor well-tolerated. V(2)- and dual V(1a)/V(2)-receptor antagonists offer physiologically based treatment for dilutional hyponatremia. Clinical trials in patients with hyponatremia including those with CHF using both selective and nonselective vasopressin antagonists have demonstrated the effectiveness and safety of these agents in correcting this common electrolyte abnormality.
Congestive Heart Failure 07/2010; 16 Suppl 1:S15-8.
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ABSTRACT: Excessive sympathetic drive is undoubtedly a major contributing factor to the pathophysiology of hypertension and heart failure. Much of the excessive sympathetic drive in these conditions is directed to the kidney, where it leads to inappropriate sodium retention, renin stimulation, and diminished renal function. Less well appreciated is the role the kidney itself plays in the generation of increased sympathetic activity by way of the renal somatic afferent nerves. The kidney therefore is both target and contributor to increased sympathetic activity in these conditions. Although some current pharmacotherapy indirectly targets this "sympathorenal axis," resistant hypertension remains a common problem, and the prognosis in heart failure remains poor, especially in more severe cases. It is now possible to directly target this axis via procedures, which directly interrupt renal sympathetic efferent and afferent signaling. Other procedures involving chronic carotid nerve stimulation may indirectly influence renal sympathetic tone and so improve renal sodium handling. These techniques have demonstrated early promise in hypertension and offer significant potential in heart failure as well. Should their early promise be borne out in controlled studies, the "sympathorenal axis" will have been proven to be a key element in the pathophysiology of these 2 very common, and dangerous, conditions.
Journal of cardiac failure 05/2010; 16(5):369-73. · 3.25 Impact Factor
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Alan J Bank,
Christopher L Kaufman,
Aaron S Kelly,
Kevin V Burns,
Stuart W Adler,
Tom S Rector, Steven R Goldsmith,
Maria-Teresa P Olivari,
Chuen Tang,
Linda Nelson,
Andrea Metzig
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ABSTRACT: Retrospective single-center studies have shown that measures of mechanical dyssynchrony before cardiac resynchronization therapy (CRT), or acute changes after CRT, predict response better than QRS duration. The Prospective Minnesota Study of Echocardiographic/TDI in Cardiac Resynchronization Therapy (PROMISE-CRT) study was a prospective multicenter study designed to determine whether acute (1 week) changes in mechanical dyssynchrony were associated with response to CRT.
Nine Minnesota Heart Failure Consortium centers enrolled 71 patients with standard indications for CRT. Left ventricular (LV) size, function, and mechanical dyssynchrony (echocardiography [ECHO], tissue Doppler imaging [TDI], speckle-tracking echocardiography [STE]) as well as 6-minute walk distance and Minnesota Living with Heart Failure Questionnaire scores were measured at baseline and 3 and 6 months after CRT. Acute change in mechanical dyssynchrony was not associated with clinical response to CRT. Acute change in STE radial dyssynchrony explained 73% of the individual variation in reverse remodeling. Baseline measures of mechanical dyssynchrony were associated with reverse remodeling (but not clinical) response, with 4 measures each explaining 12% to 30% of individual variation.
Acute changes in radial mechanical dyssynchrony, as measured by STE, and other baseline mechanical dyssynchrony measures were associated with CRT reverse remodeling. These data support the hypothesis that acute improvement in LV mechanical dyssynchrony is an important mechanism contributing to LV reverse remodeling with CRT.
Journal of cardiac failure 07/2009; 15(5):401-9. · 3.25 Impact Factor
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ABSTRACT: Hospitalization for acute decompensated heart failure (ADHF) involves substantial morbidity and mortality. Current management strategies have major limitations, and there has been little progress in the development of newer therapies. Arginine vasopressin-receptor antagonists may have promise in the treatment of ADHF in view of their ability to facilitate diuresis. This pilot study was designed to evaluate the efficacy and safety of intravenous conivaptan, a dual arginine vasopressin V(1A)/V(2)-receptor antagonist, in treating ADHF.
In a double-blind, multicenter trial, 170 patients hospitalized for worsening heart failure and given standard therapy were randomly assigned to treatment with conivaptan (20-mg loading dose followed by 2 successive 24-hour continuous infusions of 40, 80, or 120 mg/d) or placebo. The conivaptan and placebo groups did not differ significantly in patient or clinician assessments of global and respiratory status at 48 hours. There was no evidence of worsening heart failure in any group. Conivaptan at each dosage increased urine output significantly more than placebo at 24 hours (P <or= .02), with the difference averaging 1.0 to 1.5 L. Decreases in mean body weight with conivaptan 40 and 80 mg/d ( approximately 1-2 kg) paralleled the increases in urine output but did not reach statistical significance. Conivaptan was well tolerated and not associated with clinically important changes in vital signs, electrolyte disturbances, or cardiac rhythm. The most common adverse events were infusion-site reactions.
When added to standard therapy for ADHF, conivaptan safely improves urine output. Further study of this compound in ADHF may be warranted, especially in view of the limitations of current treatment for this syndrome.
Journal of cardiac failure 10/2008; 14(8):641-7. · 3.25 Impact Factor
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Journal of cardiac failure 09/2008; 14(6):533-4; author reply 534. · 3.25 Impact Factor
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Journal of cardiac failure 09/2008; 14(6):531-2; author reply 532-3. · 3.25 Impact Factor
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Steven R Goldsmith
American Journal of Cardiovascular Drugs 02/2008; 8(5):349. · 1.77 Impact Factor
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Steven R Goldsmith
Journal of the American College of Cardiology 12/2007; 50(22):2145-7. · 14.16 Impact Factor
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Steven R Goldsmith
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ABSTRACT: Neurohormonal abnormalities contribute to the pathophysiology of congestive heart failure (CHF). Successful approaches to improving the prognosis of patients with CHF are based largely on therapeutic interruption of activated neurohormonal systems. The use of antagonists and inhibitors of the renin-angiotensin-aldosterone and sympathetic nervous systems has significantly improved clinical outcomes in CHF. Excessive secretion of arginine vasopressin (AVP) has the potential for deleterious effects on various physiologic processes in CHF Inhibition of AVP through vasopressin receptor antagonist therapy is a potentially beneficial new therapeutic approach to CHF
Cleveland Clinic Journal of Medicine 10/2006; 73 Suppl 3:S19-23. · 3.77 Impact Factor
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Steven R Goldsmith
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ABSTRACT: Arginine vasopressin (AVP) signals predominantly through the V1a receptor, which subserves vasoconstriction in the peripheral circulation, and is linked directly to stimulation of myocardial hypertrophic growth factors, and the V2 receptor, the main function of which is to alter the expression of aquaporin channels in the renal collecting ducts, which leads to water retention. Agents that antagonize or block these receptors could be expected to reduce vascular tone (assuming sufficient V1a signaling is present to be causing an effect), reduce direct mitogenic signaling in the myocardium (again assuming sufficient V1a effect is present), and increase water excretion (assuming sufficient V2 signaling is present). The case for antagonizing both sets of receptors depends on the clinical situation. Pure V1a antagonists might be useful in treatment of hypertension or heart failure, but they are of little use in hyponatremia unless it is caused by heart failure. V2 antagonists would be useful in any euvolemic or hypervolemic condition associated with hyponatremia and may help produce an effective and safe diuresis independent of serum sodium when used in conjunction with loop diuretics in patients with heart failure. Selective blockade of either receptor could lead to increased signaling at the unblocked receptor sites, potentially a problematic result, especially in heart failure where disease progression is affected by increased afterload, preload, and the direct myocardial effects of neurohormonal imbalance. Therefore, a strong rationale exists for the use of combined vasopressin antagonists in patients with heart failure, particularly if the agents are used on a chronic basis.
The American journal of medicine 08/2006; 119(7 Suppl 1):S93-6. · 4.47 Impact Factor
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Steven R Goldsmith
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ABSTRACT: Increased arginine vasopressin (AVP) secretion in heart failure may lead to vasoconstriction, left ventricular remodeling, and water retention-actions that promote afterload, preload, and hyponatremia and thereby cause disease progression. Interfering with AVP-mediated signaling pharmacologically may be beneficial in heart failure. Selective antagonism of the vasopressin 2 (V2) receptor may facilitate a safe diuresis and normalize low serum sodium levels, as demonstrated in preliminary clinical trials. Pure V2 antagonism, however, may stimulate AVP secretion and enhance V1a signaling, while pure V1a receptor antagonism may lead to unwanted V2 stimulation and secondary water retention and volume expansion. Combined V1a and V2 receptor antagonism could potentially prove advantageous as a therapy for heart failure by acting synergistically to facilitate diuresis and improve hemodynamics.
Cleveland Clinic Journal of Medicine 07/2006; 73 Suppl 2:S20-3; discussion S30-3. · 3.77 Impact Factor
