Heart failure: when form fails to follow function.

Cardiac performance is normally determined by architectural, cellular, and molecular structures that determine the heart's form, and by physiological and biochemical mechanisms that regulate the function of these structures. Impaired adaptation of form to function in failing hearts contributes to two syndromes initially called systolic heart failure (SHF) and diastolic heart failure (DHF). In SHF, characterized by high end-diastolic volume (EDV), the left ventricle (LV) cannot eject a normal stroke volume (SV); in DHF, with normal or low EDV, the LV cannot accept a normal venous return. These syndromes are now generally defined in terms of ejection fraction (EF): SHF became 'heart failure with reduced ejection fraction' (HFrEF) while DHF became 'heart failure with normal or preserved ejection fraction' (HFnEF or HFpEF). However, EF is a chimeric index because it is the ratio between SV--which measures function, and EDV--which measures form. In SHF the LV dilates when sarcomere addition in series increases cardiac myocyte length, whereas sarcomere addition in parallel can cause concentric hypertrophy in DHF by increasing myocyte thickness. Although dilatation in SHF allows the LV to accept a greater venous return, it increases the energy cost of ejection and initiates a vicious cycle that contributes to progressive dilatation. In contrast, concentric hypertrophy in DHF facilitates ejection but impairs filling and can cause heart muscle to deteriorate. Differences in the molecular signals that initiate dilatation and concentric hypertrophy can explain why many drugs that improve prognosis in SHF have little if any benefit in DHF.

Lung cancer incidence in Canadian petroleum workers.

OBJECTIVES: This study's purpose was to conduct a more in-depth analysis of the potential association between lung cancer, occupational exposures and smoking using data on cohort members from a Canadian petroleum company and refined statistical analyses. METHODS: Information on various exposures including asbestos and petroleum coke dust, as well as job type and operating segment were collected via manual and computerised company records. We performed life-table analyses, Poisson regression and restricted cubic splines to model exposure-response patterns while controlling for smoking status and age. Model diagnostics included the assessment of dispersion and offset parameters. RESULTS: These analyses show that lung cancer risk is strongly related to age and smoking, and to a lesser extent to province of last residence. When controlling for these covariates, there is suggestive evidence that maintenance work may also be related to lung cancer risk. Some analyses also indicate that asbestos exposure may be associated with lung cancer risk, although a clear exposure-response trend is not seen. Other exposures, including petroleum coke dust, were not strongly related to lung cancer risk, particularly when expressed as a continuous measure. CONCLUSIONS: These data suggest that maintenance work may be associated with lung cancer incidence, although exposures to the single agents studied did not emerge as strong predictors of lung cancer incidence. Maintenance work may be a surrogate for general exposures to several agents (eg, polycyclic aromatic hydrocarbons, metals, welding fumes, radiation, etc), although these results may be affected by residual confounding due to smoking or other socio-demographic factors.

The pain of nasal tampon removal after nasal surgery: a randomized control trial.

OBJECTIVE: The purpose of this study was to compare the pain and discomfort associated with the removal of two commercially available nasal tampons after nasal surgery. STUDY DESIGN: Prospective, paired, randomized clinical trial. SUBJECTS: Consecutive, consenting, adult patients undergoing nasal surgery. INTERVENTIONS: The nose was packed with a Rapid Rhino tampon (Applied Therapeutics, Tampa, FL) on one side and a Rhino Rocket tampon (Shippert Medical Technologies Corporation, Centennial, CO) on the other. OUTCOMES: The pain of packing removal was assessed with a validated 100-mm visual analog scale. Patient satisfaction was measured on a Likert scale from 1 to 5. RESULTS: In all 13 patients, the pain of removal was greater with the Rhino Rocket Tampon (82.7 +/- 20.9 mm) than with the Rapid Rhino tampon (12.0 +/- 11.9 mm); the mean difference was 70.7 mm (95% confidence interval [CI], 47.1-78.2 mm; P < 0.0001). Patient satisfaction was significantly higher with the Rapid Rhino nasal tampon (4.6 +/- 1.1 vs 1.5 +/- 0.7; mean difference 3.1 [95% CI, 2.6-3.6]; P < 0.001). CONCLUSIONS: Removal of the Rapid Rhino nasal tampon was significantly less painful and was associated with higher patient satisfaction than the removal of the Rhino Rocket nasal tampon.

Should trans fatty acids be viewed as membrane-active drugs?

Trans fatty acids (TFA) can modify cellular function by interacting with hydrophobic regions of membrane proteins. Because these interactions resemble those of pharmacological agents, it might be appropriate to view TFA as drugs.

Comparison of nasal tampons for the treatment of epistaxis in the emergency department: a randomized controlled trial.

STUDY OBJECTIVE: Nasal tampons are commonly used to stop bleeding, yet their insertion is painful. We compare the pain of insertion and removal of 2 commonly used nasal tampons. METHODS: This was a prospective randomized controlled trial in 1 urban and 1 suburban emergency department (ED). Subjects were a convenience sample of adult ED patients with active epistaxis requiring insertion of a nasal tampon, regardless of coagulation status. Pretreatment of the nasal mucosa was performed using an aerosolized lidocaine-Neo-Synephrine combination. Patients were randomized to tamponade with a single Rapid Rhino or Rhino Rocket nasal tampon. The pain and ease of insertion and success of tamponade were recorded. Tampon removal was performed after 1 to 3 days, and the pain and ease of removal, as well as the presence of any bleeding, were noted. Patients rated pain of insertion and removal on a previously validated 100-mm visual analogue pain scale (100=worst pain). Physician ease of insertion and removal was recorded on a 5-point Likert scale. Continuous data are presented as means and 95% confidence intervals (CIs). RESULTS: We evaluated 40 patients evenly distributed between study groups and sites. Median patient age was 61 years (interquartile range 48 to 79 years), and 33% were female patients. Coagulopathy was present in 10 (25%) patients. Baseline characteristics were similar in both treatment groups. The mean pain of insertion of the Rapid Rhino (30 mm, 95% CI 18 to 41 mm) was significantly less than with the Rhino Rocket (48 mm, 95% CI 34 to 61 mm; mean difference 18 mm, 95% CI 1 to 35 mm). The mean pain of removal of the Rapid Rhino (11 mm, 95% CI 1 to 21 mm) was also lower than with the Rhino Rocket (23 mm, 95% CI 13 to 33 mm; mean difference 12 mm, 95% CI -1 to 25 mm). The Rapid Rhino was also easier to insert and remove and had a lower incidence of recurrent bleeding after removal than the Rhino Rocket. Rates of successful tamponade were similar in the 2 groups. CONCLUSION: The Rapid Rhino nasal tampon is less painful to insert and easier to remove than the Rhino Rocket, whereas both are similarly effective at stopping nosebleeds.

Left ventricular function in atrial fibrillation during overdrive pacing.

OBJECTIVE: Our purpose was to measure the effect of ventricular pacing in patients with atrial fibrillation (AF) on stroke volume and cardiac output. BACKGROUND: Unceasing variation in cycle length in AF decreases stroke volume and cardiac output. Because ventricular-inhibited pacing after atrioventricular node ablation has been reported to improve left ventricular performance, we tested the hypothesis that overdrive pacing would produce a similar benefit by regularizing cycle length. METHODS AND RESULTS: We studied 18 patients with chronic AF and permanent pacemakers. The aortic time velocity integral (TVI) was measured with continuous-wave Doppler and was used as a surrogate measure of stroke volume (stroke volume = TVI x aortic valve area, and aortic valve area is constant whether in AF or during pacing). For each patient, the linear relation between preceding cycle length and TVI in AF was used to estimate relative stroke volume (TVI compared within each patient) at a preceding cycle length of 666 ms in AF, and a similar comparison between AF and pacing was made at the minimum allowable pacing rate. Relative stroke volume in AF was then compared with relative stroke volume at both the fixed cycle (666 ms) and the minimum allowable rate. During pacing at 666 ms, relative stroke volume increased significantly by 18% (t = 2.8, P =.048), but there was no difference in cardiac output during pacing at the minimum possible rate and the corresponding preceding cycle length in AF. CONCLUSION: Our data suggest that regularization of ventricular rhythm by overdrive pacing in patients with AF only improves stroke volume (and by extension, cardiac output) at pacing rates at the outer limit of and above the normal physiologic range.

Pathophysiology of heart failure: identifying targets for pharmacotherapy.

Recent advances in our understanding of the pathophysiology of heart failure have greatly increased the number of potential targets for therapy. The most important of these advances was the recognition that a major goal of therapy should be to modify long-term proliferative responses, as well as to achieve short-term functional improvement. This conclusion emerged from several clinical trials which showed that correction of functional abnormalities in these patients, although often of immediate clinical value, can worsen long-term prognosis. Although vasodilators alleviate the disability that is caused by excessive afterload, most increase long-term mortality: similarly, although inotropic drugs provide immediate relief of symptoms and are useful as temporary support in patients with damaged hearts, most inotropes also shorten long-term survival. Treatment of chronic heart failure should not be targeted simply at the signs and symptoms noted by Withering. Instead, a major goal of therapy should be to slow progression by modifying maladaptive growth responses in the failing heart, which were unknown when Withering discovered that digitalis can alleviate the signs and symptoms of heart failure. New targets for treatment, therefore, include the maladaptive proliferative signaling cascades that cause progressive ventricular dilatation (remodeling) and hastens cardiac cell death. The ability to inhibit maladaptive proliferative signaling in patients with heart failure was greatly enhanced by the rapid pace of discovery in molecular biology. New understanding of the ability of neurohumoral mediators, such as norepinephrine and angiotensin II, to stimulate remodeling, apoptosis, and other deleterious features of the hypertrophic response has opened important areas for research into the causes and therapy of heart failure. Similarly, potential roles for cell adhesion molecules, cytokines, and peptide growth factors in activating maladaptive proliferative responses suggests additional targets for therapy. This and other new information regarding signal transduction pathways, notably the many crossovers between functional and proliferative signaling, provide promising opportunities in this rapidly advancing area of study.

A porcine epistaxis model: hemostatic effects of octylcyanoacrylate.

OBJECTIVE: To develop a standardized porcine epistaxis model and evaluate the hemostatic effects of octyl-cyanoacrylate (OCA). STUDY DESIGN AND SETTING: Twenty-four standardized full-thickness wounds were created on the nasal septae of 7 pigs with a 4-mm surgical punch. Wounds were randomized to no treatment or topical OCA before and after full heparinization. The rate of hemostasis, time to hemostasis, and number of applicators of OCA required to achieve complete hemostasis were determined and groups were compared with t tests and chi2 tests. RESULTS: Complete and sustained hemostasis was achieved in all wounds treated with OCA. The time to hemostasis was significantly shorter in the wounds treated with OCA vs those left to clot on their own (mean difference, 150 seconds; 95% CI, 92 to 209 seconds, P<0.001). None of the wounds required more than 3 applications of OCA. CONCLUSIONS: We describe a simple and reproducible animal epistaxis model and demonstrate that OCA is effective in achieving hemostasis in this model.

Maladaptive growth in the failing heart: the cardiomyopathy of overload.

The hypertrophic response to overload plays an important role in the progressive deterioration of the failing heart--the "Cardiomyopathy of Overload"--and so contributes to the poor prognosis in patients with heart failure. Although increased myocyte size reduces the load on individual sarcomeres, hypertrophy also has maladaptive features. The latter include molecular changes that weaken and impair relaxation in the overloaded heart, and accelerate cardiac myocyte death. Different types of overload lead to concentric and eccentric hypertrophy; as the latter tends to progress ("remodeling"), dilatation is associated with an especially poor prognosis. Concentric hypertrophy is due largely to cardiac myocyte thickening, while eccentric hypertrophy is caused by cell elongation. These differences, along with evidence that concentric hypertrophy is initiated by increased diastolic stretch while eccentric hypertrophy results from increased systolic stress, indicate that these growth responses are mediated by different signal transudation pathways. The beneficial effects of neurohumoral blockers in patients with heart failure are due partly to their ability to inhibit maladaptive features of overload-induced proliferative signaling. The molecular complexity of the hypertrophic response now being uncovered offers opportunities for the development of new therapy to inhibit remodeling and cell death in the failing heart.

Proliferative signaling and disease progression in heart failure.

Therapy for heart failure has traditionally been directed to such short-term functional abnormalities as low cardiac output, high filling pressures, and fluid retention. More recently, it has become clear that therapy must also inhibit the proliferative responses that contribute to the progressive deterioration of the failing heart. That heart failure is more than a hemodynamic disorder became apparent when clinical trials showed that drugs that improve such functional abnormalities as high venous pressure and low cardiac output failed to improve long-term prognosis. Most vasodilators, in spite of alleviating short-term problems caused by excessive afterload, increase long-term mortality; the notable exceptions are ACE inhibitors, the ability of which to prolong survival and inhibit remodeling can be attributed to inhibition of proliferative signaling. Other clinical trials showed that inotropic drugs, while providing immediate relief of symptoms, generally shorten long-term survival, whereas beta-adrenergic receptor blockers, which inhibit proliferative signaling by norepinephrine, improve prognosis. These findings can be explained by crossovers between functional and proliferative signaling, among the most important of which is the ability of neurohumoral mediators, such as norepinephrine and angiotensin II, to stimulate maladaptive hypertrophy, remodeling, apoptosis and other deleterious proliferative responses in the failing heart. The emerging understanding of the role of cytoskeletal and cell adhesion molecules in activating maladaptive proliferative responses suggests additional targets for therapy, and the rapid pace of discovery in molecular biology promises additional opportunities to inhibit this abnormal signaling, which causes progressive ventricular dilatation (remodeling) and cardiac cell death, now recognized to be major problems in this syndrome.