Rethinking Parkinson's disease: could dopamine reduction therapy have clinical utility?

Following reports of low striatal dopamine content in Parkinson's disease, levodopa was shown to rapidly reverse hypokinesis, establishing the model of disease as one of dopamine deficiency. Dopaminergic therapy became standard of care, yet it failed to reverse the disease, suggesting the understanding of disease was incomplete. The literature suggests the potential for toxicity of dopamine and its metabolites, perhaps more relevant given the recent evidence for elevated cytosolic dopamine levels in the dopaminergic neurons of people with Parkinson's.

Transurethral Renal Pelvic Denervation: A Feasibility Trial in Patients with Uncontrolled Hypertension.

Background: Endovascular renal denervation reduces blood pressure (BP). We explored an alternative approach to renal denervation using radiofrequency energy delivered across the renal pelvis utilizing the natural orifice of the urethra and the ureters.

Methods: This open-label, single-arm feasibility study enrolled patients with uncontrolled hypertension despite antihypertensive drug therapy.

Estimates of Intracellular Dopamine in Parkinson's Disease: A Systematic Review and Meta-Analysis.

Background: The hallmark of Parkinson's disease is depletion of dopamine in the basal ganglia. Models of Parkinson's disease include dopamine as a contributor to disease progression. However, intraneuronal levels of dopamine have not been reported.

Design of Hack-Resistant Diabetes Devices and Disclosure of Their Cyber Safety.

The focus of the medical device industry and regulatory bodies on cyber security parallels that in other industries, primarily on risk assessment and user education as well as the recognition and response to infiltration. However, transparency of the safety of marketed devices is lacking and developers are not embracing optimal design practices with new devices. Achieving cyber safe diabetes devices: To improve understanding of cyber safety by clinicians and patients, and inform decision making on use practices of medical devices requires disclosure by device manufacturers of the results of their cyber security testing.

Dietary Intervention for Overweight and Obese Adults: Comparison of Low-Carbohydrate and Low-Fat Diets. A Meta-Analysis.

Background: Reduced calorie, low fat diet is currently recommended diet for overweight and obese adults. Prior data suggest that low carbohydrate diets may also be a viable option for those who are overweight and obese.

Purpose: Compare the effects of low carbohydrate versus low fats diet on weight and atherosclerotic cardiovascular disease risk in overweight and obese patients.

What is the greatest regulatory challenge in the translation of biomaterials to the clinic?

Leaders in the field comment on what they perceive to be the greatest barriers to biomaterial translation.

Causes of death and rehospitalization in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction: results from Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) program.

Background: The postdischarge rehospitalization and death rates are high in patients with acute heart failure (HF) syndromes despite optimization of standard therapy for chronic HF. To the best of our knowledge, there has been no systematic analysis of the causes of death and rehospitalization in this patient population.

Methods: This was a prespecified analysis of adjudicated cause-specific all-cause mortality and cardiovascular (CV) hospitalization in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, a randomized, double-blind, placebo-controlled study in patients hospitalized with worsening HF and left ventricular ejection fraction < or =40% comparing tolvaptan, an oral vasopressin receptor antagonist to placebo, in addition to standard care.

Mechanisms underlying improvements in ejection fraction with carvedilol in heart failure.

Background: Reductions in heart rate (HR) with beta-blocker therapy have been associated with improvements in ejection fraction (EF). However, the relative contributions of HR reduction, positive inotropism, afterload reduction, and reverse remodeling to improvements in EF are unknown.

Methods And Results: Twenty-nine patients (63+/-12 years old) with New York Heart Association class II-III heart failure underwent serial measurements of left ventricular volumes using 3-dimensional echocardiography and blood pressures by sphygmomanometry at baseline, 2 weeks, 2, 6, and 12 months after initiation of carvedilol.

Adherence with once daily versus twice daily carvedilol in patients with heart failure: the Compliance And Quality of Life Study Comparing Once-Daily Controlled-Release Carvedilol CR and Twice-Daily Immediate-Release Carvedilol IR in Patients with Heart Failure (CASPER) Trial.

Background: Suboptimal compliance in taking guideline-based pharmacotherapy in patients with chronic heart failure (HF) potentially increases the burden of hospitalizations and diminishes quality of life. By simplifying the medical regimen, once-daily dosing can potentially improve compliance. The Compliance And Quality of Life Study Comparing Once-Daily Controlled-Release Carvedilol CR and Twice-Daily Immediate-Release Carvedilol IR in Patients with Heart Failure (CASPER) Trial was designed to measure differential compliance, satisfaction, and quality of life in chronic HF patients taking carvedilol immediate release (IR) twice daily versus the bioequivalent carvedilol controlled-release (CR) once daily.

Nesiritide for acute decompensated heart failure: does the benefit justify the risk?

Nesiritide is US Food and Drug Administration-approved for the treatment of patients with acutely decompensated heart failure who suffer from symptoms at rest or with minimal exertion. Its approval was based on a clinical development program that focused on surrogates and short-term effects on symptoms rather than clinical outcomes. The association between its use and subsequent risk of death raises the question of whether the endpoints assessed in the clinical development program were adequate, and provides the opportunity to evaluate the process of weighing risks with benefits.

Rationale and design of CASPER: compliance and quality of life study comparing once-daily carvedilol CR and twice-daily carvedilol IR in patients with heart failure.

Adherence to a complex medical regimen in patients with chronic heart failure is an important problem. In the Medicare population, patients with heart failure take an average of 7-8 distinct medications that require >11 separate doses on a daily basis. Nonadherence to these regimens accounts for a significant proportion of hospital admissions.

Reducing the risks of sudden death and heart failure post myocardial infarction: utility of optimized pharmacotherapy.

Current guidelines define the standard of care for patients after myocardial infarction (MI), with particular focus on patients with significant ventricular dysfunction. Inherent in these recommendations are assumptions about the relative risks and benefits, as well as the costs, of the available options. This review will consider strategies to prevent sudden death and heart failure post-MI by utilization of pharmacologic therapies--angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), aldosterone antagonists, statins, and beta-blockers--in parallel with the approaches reviewed elsewhere in this supplement.

Management of diuretic-refractory, volume-overloaded patients with acutely decompensated heart failure.

Fluid overload is a common presentation for decompensated heart failure, yet management strategies are poorly defined because of relatively few randomized clinical trials that delineate an optimal strategy. Patients refractory to diuretic therapy may be considered for treatment with inotropes or vasodilators, and others may be considered for venovenous ultrafiltration. The rationale for use of each therapy is reviewed.

Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials.

Context: Nesiritide improves symptoms in patients with acutely decompensated heart failure compared with placebo and appears to be safer than dobutamine. Its short-term safety relative to standard diuretic and vasodilator therapies is less clear.

Objective: To investigate the safety of nesiritide relative to noninotrope-based control therapies, primarily consisting of diuretics or vasodilators.

Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure.

Background: Renal function is an important prognostic factor for patients with acutely decompensated heart failure (ADHF). We investigated the renal effects of nesiritide as treatment for ADHF.

Methods And Results: Randomized clinical trials comparing nesiritide with either placebo or active control for ADHF were identified by electronic and manual searches and thorough review of US Food and Drug Administration files available via the website.

Practical guidelines to optimize effectiveness of beta-blockade in patients postinfarction and in those with chronic heart failure.

Antiadrenergic therapy reduces the risks of death and major morbidity in patients postinfarction and in those with chronic heart failure. Despite the common perception, these benefits are not attributable to a class effect, and clinical trials reveal evidence of specific agents that provide clinical advantages. To optimize patient outcome in the postinfarction setting, propranolol or timolol should be used in the setting of preserved ventricular function, and carvedilol should be used in patients with impaired ventricular function, with or without clinical evidence of heart failure.

Eprosartan improves cardiac performance, reduces cardiac hypertrophy and mortality and downregulates myocardial monocyte chemoattractant protein-1 and inflammation in hypertensive heart disease.

Objective: The purpose of this investigation was to determine whether angiotensin II receptor (AII1R) antagonism interferes with cardiac monocyte chemoattractant protein-1 (MCP-1) expression in hypertrophic cardiomyopathy and failure.

Design: We studied the effects of the AII1R antagonist eprosartan on MCP-1 expression, and on the recruitment of macrophages into the myocardium in a model of cardiac hypertrophy and morbidity/mortality.

Methods: Stroke-prone spontaneously hypertensive rats fed a high-salt, high-fat diet (SFD) developed heart failure characterized by left ventricular (LV) hypertrophy/pathology and hypocontractility.

Neurohormonal antagonism in heart failure: what is the optimal strategy?

Pharmacologic management of chronic heart failure rests on appropriate volume management followed by neurohormonal antagonism. Despite the rationale for neurohormonal antagonists, their use remains low. Definitive studies establish that neurohormonal antagonists are effective across the spectrum of disease, from the early Stage A patient at risk of developing structural heart disease and symptomatic heart failure to the Stage D patient with symptoms at rest.

Increasing organ transplantation--fairly.

Ten to 30 times as many people die as a result of end-organ failure than are fortunate enough to undergo transplantation. To date, efforts to increase the donor pool or establish an alternative to transplant have failed. The authors' goal was to define a revision to the transplant system that can use innate human motivators to lead to an increase in organ donation.