The role of circadian phase in sleep and performance during Antarctic winter expeditions.

The Antarctic environment presents an extreme variation in the natural light-dark cycle which can cause variability in the alignment of the circadian pacemaker with the timing of sleep, causing sleep disruption, and impaired mood and performance. This study assessed the incidence of circadian misalignment and the consequences for sleep, cognition, and psychological health in 51 over-wintering Antarctic expeditioners (45.6 ± 11.9 years) who completed daily sleep diaries, and monthly performance tests and psychological health questionnaires for 6 months. Circadian phase was assessed via monthly 48-h urine collections to assess the 6-sulphatoxymelatonin (aMT6s) rhythm. Although the average individual sleep duration was 7.2 ± 0.8 h, there was substantial sleep deficiency with 41.4% of sleep episodes <7 h and 19.1% <6 h. Circadian phase was highly variable and 34/50 expeditioners had sleep episodes that occurred at an abnormal circadian phase (acrophase outside of the sleep episode), accounting for 18.8% (295/1565) of sleep episodes. Expeditioners slept significantly less when misaligned (6.1 ± 1.3 h), compared with when aligned (7.3 ± 1.0 h; p < .0001). Performance and mood were worse when awake closer to the aMT6s peak and with increased time awake (all p < .0005). This research highlights the high incidence of circadian misalignment in Antarctic over-wintering expeditioners. Similar incidence has been observed in long-duration space flight, reinforcing the fidelity of Antarctica as a space analog. Circadian misalignment has considerable safety implications, and potentially longer term health risks for other circadian-controlled physiological systems. This increased risk highlights the need for preventative interventions, such as proactively planned lighting solutions, to ensure circadian alignment during long-duration Antarctic and space missions.

Challenges for the future: the gastroenterology specialist workforce in New Zealand.

AIM: New Zealand has among the highest rates of colorectal cancer and inflammatory bowel disease in the world. With the imminent rollout of the National Bowel Screening Programme, we sought to determine the capacity of and demand faced by the current gastroenterology specialist workforce, and to compare it with other countries. METHOD: Specialists in gastroenterology were asked to complete a questionnaire on their education, number of FTE in the public and private sectors, number of colonoscopies performed, anticipated years to retirement and other associated information. Additional statistics were obtained from personal communication, visits to endoscopy units throughout the country and government datasets. RESULTS: In November 2017 there were 93 gastroenterologists in New Zealand, equating to 1.96 gastroenterologist specialists/100,000 population. The response rate was 55%. One quarter of gastroenterologists spent time working in general internal medicine additionally to gastroenterology in public hospitals. Fifty-one percent of gastroenterologists were older than 50 years and 42% aimed to retire within the next 10 years. Four of the 20 district health boards had no gastroenterologists in post. CONCLUSIONS: New Zealand has a lower specialist gastroenterologist ratio and older workforce compared with other comparable western countries and may struggle to meet the growing gastroenterology healthcare needs of the population. Substantial regional gastroenterology service inequities exist across the country.

Complete esophageal obstruction following endoscopic variceal ligation: a case report and literature review.

Endoscopic variceal ligation (EVL) is an important treatment modality in managing complications of portal hypertension. Since its advent 30 years ago, the procedural complications have decreased significantly, especially when compared with variceal sclerotherapy. With the current widespread use of EVL, rare complications are now becoming increasingly recognized. We present a case of complete esophageal obstruction, its management, and clinical course. Our literature review identified only eight reported cases. We compare the varied treatment approaches and outcomes in the cited articles.

A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure.

AIMS: Although active-controlled trials with renin­angiotensin inhibitors are ethically mandated in heart failure with reduced ejection fraction, clinicians and regulators often want to know how the experimental therapy would perform compared with placebo. The angiotensin receptor-neprilysin inhibitor LCZ696 was compared with enalapril in PARADIGM-HF. We made indirect comparisons of the effects of LCZ696 with putative placebos. METHODS AND RESULTS: We used the treatment-arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an ACE inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alternative) as the reference trial for comparison of an ARB to placebo. The hazard ratio of LCZ696 vs. a putative placebo was estimated through the product of the hazard ratio of LCZ696 vs. enalapril (active-control) and that of the historical active-control (enalapril or candesartan) vs. placebo. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 34­50%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 21­44%; P < 0.0001) and heart failure hospitalization (49%, 39­58%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 15­39%; P < 0.0001). Putative placebo analyses based on CHARM-Alternative gave relative risk reductions of 39% (95%CI 27­48%; P < 0.0001) for the composite outcome of cardiovascular death or heart failure hospitalization, 32% (95%CI 16­45%; P < 0.0001) for cardiovascular death, 46% (33­56%; P < 0.0001) for heart failure hospitalization, and 26% (95%CI 11­39%; P < 0.0001) for all-cause mortality. CONCLUSION: These indirect comparisons of LCZ696 with a putative placebo show that the strategy of combined angiotensin receptor blockade and neprilysin inhibition led to striking reductions in cardiovascular and all-cause mortality, as well as heart failure hospitalization. These benefits were obtained even though LCZ696 was added to comprehensive background beta-blocker and mineralocorticoid receptor antagonist therapy.

Left ventricular lead position and outcomes in the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT).

BACKGROUND: Conflicting data exist regarding the association between left ventricular (LV) lead position and benefit from cardiac resynchronization therapy. We evaluated the relationships between LV lead positions and the risk of death or hospitalization for heart failure (HF) in the cardiac resynchronization therapy arm of the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT). METHODS: LV lead position was categorized by site investigator (MD) and in a chest radiograph core laboratory (CXR) as "anterior," "lateral," or "posterior" in the short axis, and "basal," "mid," or "apical" in the long axis. Agreement between MD and CXR LV lead position classification was evaluated and the independent relationship between LV lead position and clinical outcome was assessed using Cox multivariable models. RESULTS: Agreement between MD and CXR LV lead position was poor (κ ≤ 0.26). Over 39 ± 20 months, 140 of 447 (31.3%) patients met the RAFT primary end point (death or HF hospitalization). In adjusted analyses, neither MD-determined nor CXR-determined anterior or apical LV lead position was significantly associated with the primary outcome. However, CXR-defined apical LV lead position was associated with a higher risk of HF hospitalization (hazard ratio, 1.99; P = 0.004). CONCLUSIONS: Poor agreement between implanting physician and core lab CXR-based categorizations of LV lead position was observed. Neither categorization method resulted in significant associations between apical or anterior LV lead position and the risk of the composite primary outcome of death or heart failure hospitalization. However, CXR-defined apical lead position was associated with increased risk of HF hospitalization.

Site selection in global clinical trials in patients hospitalized for heart failure: perceived problems and potential solutions.

There are over 1 million hospitalizations for heart failure (HF) annually in the United States alone, and a similar number has been reported in Europe. Recent clinical trials investigating novel therapies in patients with hospitalized HF (HHF) have been negative, and the post-discharge event rate remains unacceptably high. The lack of success with HHF trials stem from problems with understanding the study drug, matching the drug to the appropriate HF subgroup, and study execution. Related to the concept of study execution is the importance of including appropriate study sites in HHF trials. Often overlooked issues include consideration of the geographic region and the number of patients enrolled at each study center. Marked differences in baseline patient co-morbidities, serum biomarkers, treatment utilization and outcomes have been demonstrated across geographic regions. Furthermore, patients from sites with low recruitment may have worse outcomes compared to sites with higher enrollment patterns. Consequently, sites with poor trial enrollment may influence key patient end points and likely do not justify the costs of site training and maintenance. Accordingly, there is an unmet need to develop strategies to identify the right study sites that have acceptable patient quantity and quality. Potential approaches include, but are not limited to, establishing a pre-trial registry, developing site performance metrics, identifying a local regionally involved leader and bolstering recruitment incentives. This manuscript summarizes the roundtable discussion hosted by the Food and Drug Administration between members of academia, the National Institutes of Health, industry partners, contract research organizations and academic research organizations on the importance of selecting optimal sites for successful trials in HHF.

Routine versus selective cardiac magnetic resonance in non-ischemic heart failure - OUTSMART-HF: study protocol for a randomized controlled trial (IMAGE-HF (heart failure) project 1-B).

BACKGROUND: Imaging has become a routine part of heart failure (HF) investigation. Echocardiography is a first-line test in HF given its availability and it provides valuable diagnostic and prognostic information. Cardiac magnetic resonance (CMR) is an emerging clinical tool in the management of patients with non-ischemic heart failure. Current ACC/AHA/CCS/ESC guidelines advocate its role in the detection of a variety of cardiomyopathies but there is a paucity of high quality evidence to support these recommendations.The primary objective of this study is to compare the diagnostic yield of routine cardiac magnetic resonance versus standard care (that is, echocardiography with only selective use of CMR) in patients with non-ischemic heart failure. The primary hypothesisis that the routine use of CMR will lead to a more specific diagnostic characterization of the underlying etiology of non-ischemic heart failure. This will lead to a reduction in the non-specific diagnoses of idiopathic dilated cardiomyopathy and HF with preserved ejection fraction. DESIGN: Tertiary care sites in Canada and Finland, with dedicated HF and CMR programs, will randomize consecutive patients with new or deteriorating HF to routine CMR or selective CMR. All patients will undergo a standard clinical echocardiogram and the interpreter will assign the most likely HF etiology. Those undergoing CMR will also have a standard examination and will be assigned a HF etiology based upon the findings. The treating physician's impression about non-ischemic HF etiology will be collected following all baseline testing (including echo ± CMR). Patients will be followed annually for 4 years to ascertain clinical outcomes, quality of life and cost. The expected outcome is that the routine CMR arm will have a significantly higher rate of infiltrative, inflammatory, hypertrophic, ischemic and 'other' cardiomyopathy than the selective CMR group. DISCUSSION: This study will be the first multicenter randomized, controlled trial evaluating the role of CMR in non-ischemic HF. Non-ischemic HF patients will be randomized to routine CMR in order to determine whether there are any gains over management strategies employing selective CMR utilization. The insight gained from this study should improve appropriate CMR use in HF. TRIAL REGISTRATION: NCT01281384.

Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) IMAGE HF Project I-A: study protocol for a randomized controlled trial.

BACKGROUND: Ischemic heart disease (IHD) is the most common cause of heart failure (HF); however, the role of revascularization in these patients is still unclear. Consensus on proper use of cardiac imaging to help determine which candidates should be considered for revascularization has been hindered by the absence of clinical studies that objectively and prospectively compare the prognostic information of each test obtained using both standard and advanced imaging. METHODS/DESIGN: This paper describes the design and methods to be used in the Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) multi-center trial. The primary objective is to compare the effect of HF imaging strategies on the composite clinical endpoint of cardiac death, myocardial infarction (MI), cardiac arrest and re-hospitalization for cardiac causes.In AIMI-HF, patients with HF of ischemic etiology (n = 1,261) will follow HF imaging strategy algorithms according to the question(s) asked by the physicians (for example, Is there ischemia and/or viability?), in agreement with local practices. Patients will be randomized to either standard (SPECT, Single photon emission computed tomography) imaging modalities for ischemia and/or viability or advanced imaging modalities: cardiac magnetic resonance imaging (CMR) or positron emission tomography (PET). In addition, eligible and consenting patients who could not be randomized, but were allocated to standard or advanced imaging based on clinical decisions, will be included in a registry. DISCUSSION: AIMI-HF will be the largest randomized trial evaluating the role of standard and advanced imaging modalities in the management of ischemic cardiomyopathy and heart failure. This trial will complement the results of the Surgical Treatment for Ischemic Heart Failure (STICH) viability substudy and the PET and Recovery Following Revascularization (PARR-2) trial. The results will provide policy makers with data to support (or not) further investment in and wider dissemination of alternative 'advanced' imaging technologies. TRIAL REGISTRATION: NCT01288560.

Benefit of exercise therapy for systolic heart failure in relation to disease severity and etiology-findings from the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training study.

BACKGROUND: This post hoc analysis of the HF-ACTION cohort explores the primary and secondary results of the HF-ACTION study by etiology and severity of illness. METHODS: HF-ACTION randomized stable outpatients with reduced left ventricular (LV) function and heart failure (HF) symptoms to either supervised exercise training plus usual care or to usual care alone. The primary outcome was all-cause mortality or all-cause hospitalization; secondary outcomes included all-cause mortality, cardiovascular mortality or cardiovascular hospitalization, and cardiovascular mortality or HF hospitalization. The interaction between treatment and risk variable, etiology or severity as determined by risk score, New York Heart Association class, and duration of cardiopulmonary exercise test was examined in a Cox proportional hazards model for all clinical end points. RESULTS: There was no interaction between etiology and treatment for the primary outcome (P = .73), cardiovascular (CV) mortality or CV hospitalization (P = .59), or CV mortality or HF hospitalization (P = .07). There was a significant interaction between etiology and treatment for the outcome of mortality (P = .03), but the interaction was no longer significant when adjusted for HF-ACTION adjustment model predictors (P = .08). There was no significant interaction between treatment effect and severity, except a significant interaction between cardiopulmonary exercise duration and training was identified for the primary outcome of all-cause mortality or all-cause hospitalization. CONCLUSION: Consideration of symptomatic (New York Heart Association classes II to IV) patients with HF with reduced LV function for participation in an exercise training program should be made independent of the cause of HF or the severity of the symptoms.

Cardiac-resynchronization therapy for mild-to-moderate heart failure.

BACKGROUND: Cardiac-resynchronization therapy (CRT) benefits patients with left ventricular systolic dysfunction and a wide QRS complex. Most of these patients are candidates for an implantable cardioverter-defibrillator (ICD). We evaluated whether adding CRT to an ICD and optimal medical therapy might reduce mortality and morbidity among such patients. METHODS: We randomly assigned patients with New York Heart Association (NYHA) class II or III heart failure, a left ventricular ejection fraction of 30% or less, and an intrinsic QRS duration of 120 msec or more or a paced QRS duration of 200 msec or more to receive either an ICD alone or an ICD plus CRT. The primary outcome was death from any cause or hospitalization for heart failure. RESULTS: We followed 1798 patients for a mean of 40 months. The primary outcome occurred in 297 of 894 patients (33.2%) in the ICD-CRT group and 364 of 904 patients (40.3%) in the ICD group (hazard ratio in the ICD-CRT group, 0.75; 95% confidence interval [CI], 0.64 to 0.87; P<0.001). In the ICD-CRT group, 186 patients died, as compared with 236 in the ICD group (hazard ratio, 0.75; 95% CI, 0.62 to 0.91; P = 0.003), and 174 patients were hospitalized for heart failure, as compared with 236 in the ICD group (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). However, at 30 days after device implantation, adverse events had occurred in 124 patients in the ICD-CRT group, as compared with 58 in the ICD group (P<0.001). CONCLUSIONS: Among patients with NYHA class II or III heart failure, a wide QRS complex, and left ventricular systolic dysfunction, the addition of CRT to an ICD reduced rates of death and hospitalization for heart failure. This improvement was accompanied by more adverse events. (Funded by the Canadian Institutes of Health Research and Medtronic of Canada; ClinicalTrials.gov number, NCT00251251.).

Calpain activation contributes to hyperglycaemia-induced apoptosis in cardiomyocytes.

AIMS: Cardiomyocyte apoptosis contributes to cardiac complications of diabetes. The aim of this study was to investigate the role of calpain in cardiomyocyte apoptosis induced by hyperglycaemia. METHODS AND RESULTS: In cultured adult rat ventricular cardiomyocytes, high glucose (33 mM) increased calpain activity and induced apoptosis, concomitant with the impairment of Na+/K+ ATPase activity. These effects of high glucose on cardiomyocytes were abolished by various pharmacological calpain inhibitors, knockdown of calpain-1 but not calpain-2 using siRNA, or over-expression of calpastatin, a specific endogenous calpain inhibitor. The effect of calpain inhibition on cardiomyocyte apoptosis was abrogated by ouabain, a selective inhibitor of Na+/K+ ATPase. Furthermore, blocking gp91(phox)-NADPH oxidase activation, L-type calcium channels, or ryanodine receptors prevented calpain activation and apoptosis in high glucose-stimulated cardiomyocytes. In a mouse model of streptozotocin-induced diabetes, administration of different calpain inhibitors blocked calpain activation, increased the Na+/K+ ATPase activity, and decreased apoptosis in the heart. CONCLUSION: Calpain-1 activation induces apoptosis through down-regulation of the Na+/K+ ATPase activity in high glucose-stimulated cardiomyocytes and in vivo hyperglycaemic hearts. High glucose-induced calpain-1 activation is mediated through the NADPH oxidase-dependent pathway and associated with activation of L-type calcium channels and ryanodine receptors. Our data suggest that calpain activation may be important in the development of diabetic cardiomyopathy and thus may represent a potential therapeutic target for diabetic heart diseases.

The 2009 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2--therapy.

OBJECTIVE: To update the evidence-based recommendations for the prevention and management of hypertension in adults for 2009. OPTIONS AND OUTCOMES: For lifestyle and pharmacological interventions, evidence from randomized controlled trials and systematic reviews of trials was preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field. Progression of kidney dysfunction was also accepted as a clinically relevant primary outcome among patients with chronic kidney disease. EVIDENCE: A Cochrane collaboration librarian conducted an independent MEDLINE search from 2007 to August 2008 to update the 2008 recommendations. To identify additional published studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence. RECOMMENDATIONS: For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium to less than 2300 mg (100 mmol)/day (and 1500 mg to 2300 mg [65 mmol to 100 mmol]/day in hypertensive patients); perform 30 min to 60 min of aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index 18.5 kg/m(2) to 24.9 kg/m(2)) and waist circumference (smaller than 102 cm for men and smaller than 88 cm for women); limit alcohol consumption to no more than 14 units per week in men or nine units per week in women; follow a diet that is reduced in saturated fat and cholesterol, and that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources; and consider stress management in selected individuals with hypertension. For the pharmacological management of hypertension, treatment thresholds and targets should be predicated on by the patient's global atherosclerotic risk, target organ damage and comorbid conditions. Blood pressure should be decreased to lower than 140/90 mmHg in all patients, and to lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease. Most patients will require more than one agent to achieve these target blood pressures. Antihypertensive therapy should be considered in all adult patients regardless of age (caution should be exercised in elderly patients who are frail). For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic and/or systolic hypertension include angiotensin- converting enzyme (ACE) inhibitors (in patients who are not black), long-acting calcium channel blockers (CCBs), angiotensin receptor antagonists (ARBs) or beta-blockers (in those younger than 60 years of age). A combination of two first-line agents may also be considered as the initial treatment of hypertension if the systolic blood pressure is 20 mmHg above the target or if the diastolic blood pressure is 10 mmHg above the target. The combination of ACE inhibitors and ARBs should not be used. Other agents appropriate for first-line therapy for isolated systolic hypertension include long- acting dihydropyridine CCBs or ARBs. In patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor/diuretic combination is preferred; in patients with proteinuric nondiabetic chronic kidney disease, ACE inhibitors or ARBs (if intolerant to ACE inhibitors) are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian Cardiovascular Society position statement (recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease). Selected high-risk patients with hypertension who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy. Once blood pressure is controlled, acetylsalicylic acid therapy should be considered. VALIDATION: All recommendations were graded according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.

Resynchronization/defibrillation for ambulatory heart failure trial: rationale and trial design.

PURPOSE OF REVIEW: This paper reviews the effect of cardiac resynchronization therapy (CRT) on patients with heart failure symptoms, in particular, in patients with mild symptoms of heart failure. It provides the rationale and design of a randomized controlled trial to determine if CRT, when added to implantable cardioverter defibrillator, will be beneficial in patients with left ventricular dysfunction, ventricular conduction delay and mild heart failure symptoms. RECENT FINDINGS: CRT has been demonstrated to improve functional capacity, quality of life, and reduce heart failure hospitalization in patients with advanced symptomatic heart failure, and evidence of a ventricular conduction abnormality on ECG. In patients with milder heart failure symptoms, three randomized controlled trials and observational studies failed to convincingly show improvement of functional status, but demonstrated improved ventricular reverse remodelling with more advanced heart failure patients. SUMMARY: Two large randomized clinical trials are currently ongoing (RAFT and MADIT-CRT). The results of these trials will determine the efficacy of CRT in patients with systolic heart failure, ventricular conduction abnormality and milder symptoms.

The 2008 Canadian Hypertension Education Program recommendations for the management of hypertension: part 2 - therapy.

OBJECTIVE: To update the evidence-based recommendations for the prevention and management of hypertension in adults. OPTIONS AND OUTCOMES: For lifestyle and pharmacological interventions, evidence was preferentially reviewed from randomized controlled trials and systematic reviews of trials. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field. Progression of kidney dysfunction was also accepted as a clinically relevant primary outcome among patients with chronic kidney disease. EVIDENCE: A Cochrane collaboration librarian conducted an independent MEDLINE search from 2006 to August 2007 to update the 2007 recommendations. To identify additional published studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by content and methodological experts using prespecified levels of evidence. RECOMMENDATIONS: For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium intake to less than 100 mmol/day (and 65 mmol/day to 100 mmol/day in hypertensive patients); perform 30 min to 60 min of aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index 18.5 kg/m(2) to 24.9 kg/m(2)) and waist circumference (smaller than 102 cm for men and smaller than 88 cm for women); limit alcohol consumption to no more than 14 units per week in men or nine units per week in women; follow a diet that is reduced in saturated fat and cholesterol, and one that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources; and consider stress management in selected individuals with hypertension. For the pharmacological management of hypertension, treatment thresholds and targets should be predicated on by the patient's global atherosclerotic risk, target organ damage and comorbid conditions. Blood pressure should be decreased to lower than 140/90 mmHg in all patients, and to lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease. Most patients will require more than one agent to achieve these target blood pressures. For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic and/or systolic hypertension include angiotensin-converting enzyme (ACE) inhibitors (in nonblack patients), long-acting calcium channel blockers (CCBs), angiotensin receptor antagonists (ARBs) or beta-blockers (in those younger than 60 years of age). A combination of two first-line agents may also be considered for initial treatment of hypertension if systolic blood pressure is 20 mmHg above target or if diastolic blood pressure is 10 mmHg above target. Other agents appropriate for first-line therapy for isolated systolic hypertension include long-acting dihydropyridine CCBs or ARBs. In patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor/diuretic combination is preferred; in patients with proteinuric nondiabetic chronic kidney disease, ACE inhibitors are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian Cardiovascular Society position statement (recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease). Selected high-risk patients with hypertension but who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy. Once blood pressure is controlled, acetylsalicylic acid therapy should be considered. VALIDATION: All recommendations were graded according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.

Relation Between Red Blood Cell Distribution Width and Cardiovascular Event Rate in People With Coronary Disease.

BACKGROUND: Higher levels of red blood cell distribution width (RDW) may be associated with adverse outcomes in patients with heart failure. We examined the association between RDW and the risk of all-cause mortality and adverse cardiovascular outcomes in a population of people with coronary disease who were free of heart failure at baseline. METHODS AND RESULTS: We performed a post hoc analysis of data from the Cholesterol and Recurrent Events study. Baseline RDW was measured in 4111 participants who were randomized to receive pravastatin 40 mg daily or placebo and followed for a median of 59.7 months. We used Cox proportional hazards models to examine the association between RDW and adverse clinical outcomes. During nearly 60 months of follow-up, 376 participants died. A significant association was noted between baseline RDW level and the adjusted risk of all-cause mortality (hazard ratio per percent increase in RDW, 1.14; 95% confidence interval, 1.05 to 1.24). After categorization based on quartile of baseline RDW and further adjustment for hematocrit and other cardiovascular risk factors, a graded independent relation between RDW and death was observed (P for trend=0.001). For instance, participants with RDW in the highest quartile had an adjusted hazard ratio for death of 1.78 (95% confidence interval, 1.28 to 2.47) compared with those in the lowest quartile. Higher levels of RDW were also associated with increased risk of coronary death/nonfatal myocardial infarction, new symptomatic heart failure, and stroke. CONCLUSIONS: We found a graded independent relation between higher levels of RDW and the risk of death and cardiovascular events in people with prior myocardial infarction but no symptomatic heart failure at baseline.

The 2007 Canadian Hypertension Education Program recommendations for the management of hypertension: part 2 - therapy.

OBJECTIVE: To provide updated, evidence-based recommendations for the prevention and management of hypertension in adults. OPTIONS AND OUTCOMES: For lifestyle and pharmacological interventions, evidence was reviewed from randomized controlled trials and systematic reviews of trials. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field. For treatment of patients with kidney disease, the progression of kidney dysfunction was also accepted as a clinically relevant primary outcome. EVIDENCE: A Cochrane collaboration librarian conducted an independent MEDLINE search from 2005 to August 2006 to update the 2006 Canadian Hypertension Education Program recommendations. In addition, reference lists were scanned and experts were contacted to identify additional published studies. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence. RECOMMENDATIONS: Dietary lifestyle modifications for prevention of hypertension, in addition to a well-balanced diet, include a dietary sodium intake of less than 100 mmol/day. In hypertensive patients, the dietary sodium intake should be limited to 65 mmol/day to 100 mmol/day. Other lifestyle modifications for both normotensive and hypertensive patients include: performing 30 min to 60 min of aerobic exercise four to seven days per week; maintaining a healthy body weight (body mass index of 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm in men and less than 88 cm in women); limiting alcohol consumption to no more than 14 units per week in men or nine units per week in women; following a diet reduced in saturated fat and cholesterol, and one that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources; and considering stress management in selected individuals with hypertension. For the pharmacological management of hypertension, treatment thresholds and targets should take into account each individual's global atherosclerotic risk, target organ damage and any comorbid conditions: blood pressure should be lowered to lower than 140/90 mmHg in all patients and lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease. Most patients require more than one agent to achieve these blood pressure targets. In adults without compelling indications for other agents, initial therapy should include thiazide diuretics; other agents appropriate for first-line therapy for diastolic and/or systolic hypertension include angiotensin-converting enzyme (ACE) inhibitors (except in black patients), long-acting calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs) or beta-blockers (in those younger than 60 years of age). First-line therapy for isolated systolic hypertension includes long-acting dihydropyridine CCBs or ARBs. Certain comorbid conditions provide compelling indications for first-line use of other agents: in patients with angina, recent myocardial infarction, or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor plus diuretic combination is preferred; in patients with nondiabetic chronic kidney disease, ACE inhibitors are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian Cardiovascular Society position statement (recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease). Selected high-risk patients with hypertension who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy. Once blood pressure is controlled, acetylsalicylic acid therapy should be considered. VALIDATION: All recommendations were graded according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.

Tumor necrosis factor-alpha mediates cardiac remodeling and ventricular dysfunction after pressure overload state.

BACKGROUND: Pressure overload is accompanied by cardiac myocyte apoptosis, hypertrophy, and inflammatory/fibrogenic responses that lead to ventricular remodeling and heart failure. Despite incomplete understanding of how this process is regulated, the upregulation of tumor necrosis factor (TNF)-alpha after aortic banding in the myocardium is known. In the present study, we tested our hypothesis that TNF-alpha regulates the cardiac inflammatory response, extracellular matrix homeostasis, and ventricular hypertrophy in response to mechanical overload and contributes to ventricular dysfunction. METHODS AND RESULTS: C57/BL wild-type mice and TNF-knockout (TNF-/-) mice underwent descending aortic banding or sham operation. Compared with sham-operated mice, wild-type mice with aortic banding showed a significant increase in cardiac TNF-alpha levels, which coincided with myocyte apoptosis, inflammatory response, and cardiac hypertrophy in week 2 and a significant elevation in matrix metalloproteinase-9 activity and impaired cardiac function in weeks 2 and 6. Compared with wild-type mice with aortic banding, TNF-/- mice with aortic banding showed attenuated cardiac apoptosis, hypertrophy, inflammatory response, and reparative fibrosis. These mice also showed reduced cardiac matrix metalloproteinase-9 activity and improved cardiac function. CONCLUSIONS: Findings from the present study have suggested that TNF-alpha contributes to adverse left ventricular remodeling during pressure overload through regulation of cardiac repair and remodeling, leading to ventricular dysfunction.

Plasma matrix metalloproteinase-9 level is correlated with left ventricular volumes and ejection fraction in patients with heart failure.

BACKGROUND: Matrix metalloproteinases (MMPs) can alter myocardial extracellular matrix and thereby contribute to adverse ventricular remodeling in progressive heart failure (HF). We hypothesized that increased plasma MMP levels correlate with increased left ventricular (LV) volumes and reduced LV ejection fraction (LVEF) in patients with HF. METHODS AND RESULTS: In the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, patients with symptomatic HF and LVEF <0.40 were randomized to receive various combinations of therapies with candesartan, enalapril, and metoprolol CR. Left ventricular end-diastolic volume (EDV), end-systolic volume (ESV), and LVEF were determined by radionuclide angiography at baseline and at Week 43. Baseline and Week 43 plasma MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured by enzyme-linked immunosorbent assay in 184 patients in this substudy. At baseline, plasma MMP-9 correlated positively with ESV (Spearman's rank correlation coefficient rho = 0.17, P = .02) and negatively with LVEF (rho = -0.18, P = .01). After 43 weeks, LVEF, EDV, and ESV increased significantly (all P < .01); MMP-2 level increased (P = .01), but MMP-9 and TIMP-1 levels did not change significantly overall in the study population. Temporal changes in MMP-9 level were inversely correlated with changes in LVEF (rho = -0.16, P = .04). In multivariable analysis adjusting for clinical characteristics and treatment, a smaller proportional change in MMP-9 level after 43 weeks (below versus above median) predicted a concurrent improvement in LVEF (odds ratio = 2.35, 95% CI 1.24-4.46; P < .01). Similar relationships for MMP-2 and TIMP-1 were not observed. CONCLUSIONS: Elevated plasma MMP-9 levels correlated with lower LVEF and higher ESV, whereas increasing MMP-9 levels are associated with a concurrent deterioration of LV function. These findings suggest that monitoring of plasma markers of myocardial matrix remodeling may provide important prognostic information with respect to ongoing adverse LV remodeling in HF patients.