Pathological sympathoexcitation: how is it achieved?

AIM: Congestive heart failure (CHF) and obstructive sleep apnoea syndrome (OSAS) are both associated with an intense sympathoexcitation, including an increased muscle sympathetic nerve activity (MSNA). We have studied the firing characteristics of single vasoconstrictor fibres to the muscle vascular bed in CHF and OSAS patients, at rest and during transient sympathoexcitatory stimuli, to elucidate the mechanisms by which vasoconstrictor output is augmented in these conditions. RESULTS: The main alternatives for augmenting sympathetic output are an increased firing frequency of individual nerve fibres and an increased recruitment of nerve fibres. Starting with the frequency alternative, the inherent bursting character of MSNA provides two possibilities to increase the firing of individual fibres: (1) by increasing the proportion of neural bursts in which the fibre is active (increased firing probability) and (2) by increasing the number of spikes a fibre generates per burst (increased multiple within-burst firing). At rest and in cardiac sinus rhythm, an increased firing probability is seen in both CHF and OSAS patients, whereas increased multiple within-burst firing is found in OSAS but not in CHF. In response to transient sympathoexcitatory stimuli (such as pre-mature heart beats), both patient groups show marked shifts towards multiple within-burst firing. Thus, both mechanisms for augmenting discharge frequency are operating in these two pathological conditions, but the firing characteristics at rest differ significantly. During recording sessions in sympathoexcited patients, we have encountered vasoconstrictor fibres that are active almost exclusively during periods of transient sympathoexcitation, while being virtually silent at rest. This suggests that recruitment of previously inactive vasoconstrictor fibres, the second main alternative for increasing vasoconstrictor output, contributes to transient sympathoexcitatory responses in these patients. Although it seems reasonable to assume that recruitment may also contribute to the resting level of MSNA in CHF and OSAS, this issue is difficult to resolve in microneurographic studies. CONCLUSION: In conclusion, pathological sympathoexcitation appears to depend on both recruitment and increased firing frequency. A shift towards multiple within-burst firing, at rest or in response to transient stimuli, may constitute a risk factor per se as it entails neural volleys with high instantaneous firing frequencies and consequently higher release of neurotransmitters.     

Pathological sympathoexcitation: how is it achieved?

Aim: Congestive heart failure (CHF) and obstructive sleep apnoea syndrome (OSAS) are both associated with an intense sympathoexcitation, including an increased muscle sympathetic nerve activity (MSNA). We have studied the firing characteristics of single vasoconstrictor fibres to the muscle vascular bed in CHF and OSAS patients, at rest and during transient sympathoexcitatory stimuli, to elucidate the mechanisms by which vasoconstrictor output is augmented in these conditions. Results: The main alternatives for augmenting sympathetic output are an increased firing frequency of individual nerve fibres and an increased recruitment of nerve fibres. Starting with the frequency alternative, the inherent bursting character of MSNA provides two possibilities to increase the firing of individual fibres: (1) by increasing the proportion of neural bursts in which the fibre is active (increased firing probability) and (2) by increasing the number of spikes a fibre generates per burst (increased multiple within‐burst firing). At rest and in cardiac sinus rhythm, an increased firing probability is seen in both CHF and OSAS patients, whereas increased multiple within‐burst firing is found in OSAS but not in CHF. In response to transient sympathoexcitatory stimuli (such as pre‐mature heart beats), both patient groups show marked shifts towards multiple within‐burst firing. Thus, both mechanisms for augmenting discharge frequency are operating in these two pathological conditions, but the firing characteristics at rest differ significantly. During recording sessions in sympathoexcited patients, we have encountered vasoconstrictor fibres that are active almost exclusively during periods of transient sympathoexcitation, while being virtually silent at rest. This suggests that recruitment of previously inactive vasoconstrictor fibres, the second main alternative for increasing vasoconstrictor output, contributes to transient sympathoexcitatory responses in these patients. Although it seems reasonable to assume that recruitment may also contribute to the resting level of MSNA in CHF and OSAS, this issue is difficult to resolve in microneurographic studies. Conclusion: In conclusion, pathological sympathoexcitation appears to depend on both recruitment and increased firing frequency. A shift towards multiple within‐burst firing, at rest or in response to transient stimuli, may constitute a risk factor per se as it entails neural volleys with high instantaneous firing frequencies and consequently higher release of neurotransmitters.     

The 6-min walk test in heart failure: is it a max or sub-maximum exercise test?

The aim of the study is to compare the cardiorespiratory response during the 6-min walk test (6MWT) with a symptom-limited cardiopulmonary exercise test (CPET) in patients with varying degrees of heart failure. Thirty-seven patients with heart failure (New York Heart Association I–III) were asked to complete a 6MWT and a CPET on a cycle ergometer. Respiratory gases were measured during both the tests and patients were grouped into tertiles according to their VO_2peak reached during the CPET prior to performing statistical analysis of all other respiratory parameters. Patients were grouped into the following tertiles: Group 1 (VO_2peak >25.2 ml/kg per min, N = 13), Group 2 (VO_2peak >17.5–25.2 ml/kg per min), and Group 3 (VO_2peak ≤17.5 ml/kg per min). Despite the good overall correlation between 6MWT VO₂ and CPET VO_2peak (r = 0.72, P < 0.001), significant differences were seen within Groups 1 and 3 (P < 0.05). In Group 1, 6MWT VO₂ was significantly lower compared with CPET VO_2peak, whereas Group 3 showed significantly higher 6MWT VO₂ compared with CPET VO_2peak. In conclusion, the use of the 6MWT to evaluate exercise capacity in patients with heart failure is highly dependent on the degree of functional impairment. In patients with advanced heart failure, the 6MWT elicits a maximum exercise response, whereas it only constitutes a sub-maximal exercise test in patients with mild heart failure and no functional limitations. This must be taken into consideration when using the 6MWT in large epidemiological studies to evaluate therapy outcome and clinical prognosis in patients with varying degrees of clinical disabilities.     

Proteomics in heart failure: top-down or bottom-up?

The pathophysiology of heart failure (HF) is diverse, owing to multiple etiologies and aberrations in a number of cellular processes. Therefore, it is essential to understand how defects in the molecular pathways that mediate cellular responses to internal and external stressors function as a system to drive the HF phenotype. Mass spectrometry (MS)-based proteomics strategies have great potential for advancing our understanding of disease mechanisms at the systems level because proteins are the effector molecules for all cell functions and, thus, are directly responsible for determining cell phenotype. Two MS-based proteomics strategies exist: peptide-based bottom-up and protein-based top-down proteomics—each with its own unique strengths and weaknesses for interrogating the proteome. In this review, we will discuss the advantages and disadvantages of bottom-up and top-down MS for protein identification, quantification, and analysis of post-translational modifications, as well as highlight how both of these strategies have contributed to our understanding of the molecular and cellular mechanisms underlying HF. Additionally, the challenges associated with both proteomics approaches will be discussed and insights will be offered regarding the future of MS-based proteomics in HF research.     

Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency: When is it indicated,what is the goal and how to do it?

Pancreatic exocrine insufficiency with steatorrhea is a major consequence of pancreatic diseases (e.g. chronic pancreatitis, cystic fibrosis, severe acute necrotizing pancreatitis, pancreatic cancer), extrapancreatic diseases like celiac disease and Crohn's disease, and gastrointestinal and pancreatic surgical resections. Recognition of this entity is highly relevant to avoid malnutrition-related morbidity and mortality. Therapy of pancreatic exocrine insufficiency is based on the oral administration of pancreatic enzymes aiming at providing the duodenal lumen with sufficient amount of active lipase at the time of gastric emptying of nutrients. Administration of enzymes in form of enteric-coated minimicrospheres avoids acid-mediated lipase inactivation and ensures gastric emptying of enzymes in parallel with nutrients. Despite that, factors like an acidic intestinal pH and bacterial overgrowth may prevent normalization of fat digestion even in compliant patients. The present article critically reviews current therapeutic approaches to pancreatic exocrine insufficiency.     

In vivo testing of a right heart mini-pump during a 24 hour period: is it safe?

A coaxial atrial cannula connected to a mini-centrifugal pump was developed to bypass the right heart during extreme exposures in off-pump coronary artery bypass surgery. This study was designed to test the effect of this pump, running during 24 hours, on blood elements to evaluate its use as a prolonged right heart support. In a calf model (body weight 68+/-5 kg), the pump was inserted and set to its maximal motor speed of 7000 rpm. Blood samples were drawn every 6 hours for blood gas analyses, as well as for hematology and chemistry. The right heart mini-pump performed perfectly at its maximal speed over the 24 hour period. Blood gas parameters and blood lactate levels reflected adequate tissue perfusion (baseline: 2.2+/-0.5 mmol/L vs. 24 h: 2+/-0.3 mmol/L; p = 0.64). Red blood cell count was stable (baseline: 9.8+/-1.4 x 10(12)/L vs. 24 h: 9.6+/-1.1 x 10(12)/L; p = 0.83). Free plasma hemoglobin remained below 100 mg/L throughout the experiment. Platelet count was stable during the first 6 hours and exhibited a tendency to drop thereafter (baseline: 749+/-104 x 10(9)/L vs. 24 h: 486+/-20 x 10(9)/L; p = 0.01). This right heart mini-pump appears to provide sufficient blood flow during a 24 hour period with minimal impact on red cell and moderate platelet damage after 6 hours. These results suggest a potential application of this system for postcardiotomy right heart support.     

Is there any connection between angiotensin converting enzyme activity and liver cirrhosis of alcoholic genesis?

The objective of this study was to assess the serum angiotensin converting enzyme (ACE) activity in patients with liver cirrhosis caused by chronic alcohol consumption, in order to get better insight into the function of the renin-angiotensin system. PATIENTS AND METHODS: Serum level of ACE activity was measured by Neels spectrophotometry in 35 alcoholic liver cirrhosis patients classified according to Child-Pugh-Turcotte criteria and 35 dyspeptic patients with any liver disease excluded (control group). RESULTS: Serum values of ACE were statistically significantly higher (p < 0.00001) in the group of liver cirrhosis patients (x = 250.16 +/- 85.5 nmol) than in the control group (x = 115.88 +/- 58.19 nmol). The highest levels of ACE were measured in class B group of liver cirrhosis patients vs. class A and class B groups (p < 0.013). CONCLUSION: It is concluded that liver cirrhosis patients have elevated ACE levels, which coud be useful in the diagnosis and follow up of these patients.     

Dialysis in acute renal failure: is more better?

An increasing body of evidence indicates therapy dose and intensity influence the outcome of dialyzed ARF patients. However, a number of unanswered questions remain on this issue. These questions need to be addressed in future prospective, controlled trials that assess the effect of dose and intensity on outcome both within and between the various ARF renal replacement therapies, with appropriate and clinically relevant control arms. Such investigations should provide guidelines ultimately for the dialytic management of critically ill patients with ARF.     

Survival of rats with experimental chronic heart failure depending on pharmacodynamic and pharmacokinetic parameters of angiotensin-converting enzyme inhibitors and β-adrenoceptor blockers

Lipophilic inhibitors of angiotensin-converting enzyme increased 6-month survival and/or lifetime of rats with experimental chronic heart failure. These drugs had no effect on the mortality rate of animals with acute decompensation of the disease. β-Adrenoceptor blockers without intrinsic sympathomimetic activity not only prolonged 6-month survival and lifetime, but also decreased the mortality rate of rats with decompensation of chronic heart failure. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 141, No. 1, pp. 45–48, January, 2006     

Postmortem diagnosis of chronic granulomatous disease: how worthwhile is it?

A previously healthy 11 year old boy died unexpectedly after a rapid course of progressive pneumonia. Postmortem microbiology and histopathology suggested an underlying diagnosis of chronic granulomatous disease. This was confirmed by neutrophil oxidative burst and gene mutation analysis of other family members, one of whom benefited from early bone marrow transplantation.     

Aberrant P-cadherin expression: is it associated with estrogen-independent growth in breast cancer?

Breast carcinomas represent a heterogeneous group of tumors, with a diverse biologic behavior, outcome, and response to therapy. Recent studies have demonstrated that alterations in the expression of adhesion molecules in cancer cells are related to aggressiveness and poor prognosis. The aim of our study was to investigate the expression of P-cadherin in breast carcinomas and correlate it with estrogen receptor (ER) status. We selected 73 ductal carcinomas in situ (DCIS) and 149 invasive carcinomas of the breast, and assessed the expression of P-cadherin as well as other biologic markers. P-cadherin expression showed a strong inverse correlation with ER expression in both types of breast carcinoma (in situ and invasive). P-cadherin-positive and ER-negative tumors were related to a higher histologic grade, a high proliferation rate, and expression of c-erbB-2. We demonstrated that P-cadherin identifies a subgroup of breast carcinomas that lacks ER expression, and correlates with higher proliferation rates and other predictors of aggressive behavior. We believe that these tumors represent an advanced step in cancer progression, and our data support the hypothesis that an estrogen-independent pathway regulates P-cadherin expression.     

Provision of palliative care for chronic heart failure inpatients: how much do we need?

Background  

The dissemination of palliative care for patients presenting complex chronic diseases at various stages has become an important matter of public health. A death census in Swiss long-term care facilities (LTC) was set up with the aim of monitoring the frequency of selected indicators of palliative care.     

Rheumatoid arthritis: what is refractory disease and how to manage it?

Despite the enthusiastic progresses in the field of rheumatoid arthritis pharmacotherapy the presence of prognostic factors associated with an unfavorable outcome and the inappropriate and/or delayed initiation of DMARDs can diminish the likelihood of achieving remission and increase the probability of refractoriness to treatment. During the last decade we have experience exciting developments regarding the approval of new treatment options but few patients are reaching sustained remission and refractory patients continue to be a problem. Thus, it is critical to understand how clinicians can decrease the risk of refractoriness by close monitoring disease activity, using well defined and accepted composite measures, and by early and optimized use of DMARDs, including biologics. The goal of this review paper is to offer an evidence based roadmap to prevent and to deal with refractory RA.