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Background Sacubitril/valsartan is an angiotensin receptor–neprilysin inhibitor indicated for the treatment of patients with chronic heart failure (HF) with reduced ejection fraction; however, its mechanism of benefit remains unclear. Biomarkers that are linked to ventricular remodeling, myocardial injury, and fibrosis may provide mechanistic insight and important clinical guidance regarding sacubitril/valsartan use. Methods This 52-week, multicenter, open-label, single-arm study is designed to (1) correlate biomarker changes with cardiac remodeling parameters, cardiovascular outcomes, and patient-reported outcome data and (2) determine short- and long-term changes in concentrations of biomarkers related to potential mechanisms of action and effects of sacubitril/valsartan therapy. Approximately 830 patients with HF with reduced ejection fraction will be initiated and titrated on sacubitril/valsartan according to United States prescribing information. Primary efficacy end points include the changes in N-terminal pro–B-type natriuretic peptide concentrations and cardiac remodeling from baseline to 1 year. Secondary end points include changes in concentrations of N-terminal pro–B-type natriuretic peptide and remodeling to 6 months, and changes in patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire-23 from baseline to 1 year. In addition, several other relevant biomarkers will be measured. Biomarker changes relative to the number of cardiovascular events in 12 months will also be assessed as exploratory end points. Conclusions Results from the Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF) will help establish a mechanistic understanding of angiotensin receptor–neprilysin inhibitor therapeutic benefits and provide clinicians with clarity on how to interpret information on biomarkers during treatment (PROVE-HF ClinicalTrials.gov identifier: NCT02887183 ).

Background: Therapy with sacubitril/valsartan improves outcome in those with heart failure with reduced ejection fraction (HFrEF). Questions remain regarding effect of sacubitril/valsartan on left ventricular (LV) remodeling as well as its effects on circulating biomarkers (including B-type

Background. There is increasing interest in the use of continuous arteriovenous hemofiltration/dialysis for treatment of profound renal failure after cardiovascular operations. Vascular access for this is usually accomplished by percutaneous cannulation of the femoral artery and vein, with the inherent risks of vascular trauma, patient immobilization, hemorrhage, or infectious complications. Methods. Fifteen (0.36%) of 4,166 patients receiving cardiovascular surgical procedures sustained postoperative renal failure requiring treatment with continuous arteriovenous hemofiltration/dialysis. Each patient had creation of acute arteriovenous forearm access using a modified Allen-Brown shunt. Shunts were monitored continuously for hemorrhage, malfunction, infection, and thrombus, and were explanted when no longer required. Results. Sixteen shunts were implanted in 15 patients over the 41-month period. All shunts functioned satisfactorily, with the duration of implantation ranging from 1 to 64 days. There were no infectious or hemorrhagic complications. Conclusions. The acute creation of a simple forearm shunt for postoperative continuous arteriovenous hemofiltration/dialysis is preferred over femoral arterial and venous cannulation because it can be constructed rapidly and easily in the operating room or at the bedside, has a low complication rate, is available for immediate use, may be left in place indefinitely, does not interfere with patient mobilization or ambulation, and is easily removed.

Aprotinin has recently been shown to reduce postoperative bleeding and transfusion requirements associated with coronary artery bypass grafting. One concern with its use, however, is that it may have a deleterious effect on graft patency because it promotes hemostasis. Forty-seven patients undergoing coronary artery bypass. Forty-seven patients undergoing coronary artery bypass grafting were enrolled in a prospective, randomized double-blind trial of aprotinin to determine the effect of this agent on postoperative bleeding, transfusion requirements, renal function, and graft patency. The study group was comprised of the 32 patients who underwent technically adequate ultrafast CT scans 6 to 8 weeks postoperatively to determine graft patency. Sixteen patients received aprotinin (aprotinin group) and 16 received placebo (control group).Demographic and operative descriptors were comparable between groups. Postoperative mediastinal and chest tube drainage in the aprotinin group was significantly less than that in the control group (722 vs 1,540 mL; p = 0.0006) and the mean blood transfusion requirements were less, but this did not reach significance (125 vs 297 mL; p = 0.42). Analysis of graft patency by patients revealed that 5 patients in the aprotinin group (31%) had at least one occluded graft, while none of the patients in the control group had an occluded graft (p = 0.04). Analysis by graft revealed that 38 of 43 grafts placed in the aprotinin group were patent, while all 38 grafts placed in the placebo group were patent (88.4 vs 100%; p = 0.057). There was no difference in the incidence of myocardial infarction, renal dysfunction or hematologic indexes at discharge between the groups, or evidence of other thrombotic complications.We conclude that high-dose aprotinin is effective in reducing hemorrhage after coronary artery bypass grafting. However, its routine use should be approached cautiously due to its possible adverse effects on graft patency.

The effect of intraoperative autotransfusion during coronary artery bypass grafting was studied in a randomized double-blind trial involving 38 patients. Nineteen patients had the collected RBCs washed and autotransfused (autotransfusion group), while the remaining patients had their washed cells discarded (control group). Postoperative hemoglobin and hematocrit values were similar. Exposure to banked blood was markedly decreased in the autotransfusion group compared with the control group. In addition, the mean volume of banked packed RBCs transfused per patient was significantly less in the autotransfusion group compared with the control group. Platelet utilization also was markedly decreased in the autotransfusion group. Cryopredpitate and fresh frozen plasma utilization also was less in the autotransfusion group than in the control group, but this did not reach statistical significance. We conclude that the intraoperative use of autotransfusion decreases the volume of homologous blood products transfused, which results in reduced exposure of the patients to banked blood products.

This review traces both the progress and the scope of mechanical devices developed to assist or substitute the functions of a failing heart. The present states of art, particularly the clinical results of their application, are briefly summarized. Physiological and engineering issues confronting us today and a number of newer concepts in mechanical cardiac assist are then discussed in perspective.

The sinuses of Valsalva are 3 distinct outpouchings of the aortic wall associated with the 3 cusps of the aortic valve that may develop aneurysmal dilation because of weakness of or injury to the sinus wall. Rupture of a sinus aneurysm can create an aortocardiac fistula. Ruptured sinuses of Valsalva aneurysms (RSVAs) may present a diagnostic dilemma because of their varied clinical presentations. However, if included on a differential, they are easily diagnosed and surgically treated. In our article we detail 4 RSVA cases, each demonstrating a manner in which an RSVA may present clinically. Our first case involves a 68-year-old patient with an RSVA diagnosis after presenting with cardiac arrest and congestive heart failure. Our second case involves a 42-year-old patient with an RSVA diagnosis in the context of acute chest pain, ischemic electrocardiographic changes, and hypotension. Our third RSVA case involves a 60-year-old patient who presented solely with a sudden onset of lower-extremity edema. Our fourth case involves a 46-year-old asymptomatic patient with RSVA diagnosed during a routine physical exam. Comparisons of reported case series from around the world illustrate RSVA epidemiology, concomitant lesions, clinical presentations, and repair techniques. Comparisons of Eastern and Western series reveal that the incidence of RSVAs is higher in Eastern than in Western countries, with a 4:1 male preponderance across ethnic lines. Among the Eastern series reporting RSVAs, ventricular septal defects and aortic valve incompetence were the only frequently associated concomitant lesions. In contrast, Western series of RSVAs showed a wide range of concomitant lesions. The difficulty in diagnosing RSVAs is mainly due to the variability of their clinical impact and presentation. These factors largely depend on the cardiac chamber into which the aortocardiac fistula forms. However, once RSVA is on a differential, the advent of transesophageal and transthoracic radiography has made RSVA diagnosis relatively easy. Surgical repairs of RSVAs are of low risk and generally have an excellent long-term prognosis. As a result, many authors believe that early surgical intervention in patients with an RSVA is justified. Among the series studied, there is evidence that the patch technique is the safest approach because of its lower association with fistula recurrence. This article highlights for the clinician the diversity of clinical presentations of this often overlooked disorder.

The repair of calcified stenotic aortic valves may be a viable alternative to current valve treatments for early-stage aortic valve disease. To date, evaluation of valve repair feasibility on the benchtop has not been performed. A pulsatile flow system for testing intact human aortic valves was developed to perform quantitative hemodynamic and mechanical assessment of a new aortic valve repair approach.Intact calcified human aortic valves were divided into two groups with effective orifice area (EOA)or =2.0 cm2 (group I, n = 6) or2.0 cm2 (group II, n = 6). All valves were chemically debrided in stages for up to 60 min. A subset of valves in each group was also surgically debrided. At each stage, pre- and post-treatment hemodynamic assessment and video motion analysis were performed in the pulsatile flow system at multiple levels of physiological loading. Mineral removed was quantified using atomic absorption spectroscopy.Progressive removal of mineral with both mechanical and chemical debridement was associated with improved hemodynamic function of calcified human aortic valves. Improvements in EOA of up to 40% and decreases in transvalvular pressure gradient (deltaP) of up to 46% were seen. No clinically relevant increases in regurgitation were observed.Repair of stenotic calcified aortic valves using surgical and chemical debridement showed that removal of calcific deposits was directly associated with improvements in valve hemodynamic function. The level of improvement was proportional to the degree of aortic valve stenosis, to the use of surgical debridement, and to the duration of chemical debridement treatment. The study results suggested that aortic valve repair warrants further investigation as an alternative to current valve treatments in patients with early to mid-stage calcific aortic valve disease.

Objective To evaluate the effect of prophylactic procainamide on the frequency of postoperative atrial fibrillation in patients undergoing myocardial revascularization. Design Prospective, randomized, double-blind, placebo-controlled pilot study. Setting Surgical intensive care unit and wards at a university hospital affiliate. Patients A total of 46 patients undergoing myocardial revascularization. Interventions Twenty-two patients received procainamide (procainamide group) and 24 patients received placebo (control group). Procainamide was administered to the procainamide group within 1 hr of the patient's arrival in the intensive care unit and consisted of an intravenous loading dose (12 mg/kg) followed by a maintenance dose (2 mg/min) of procainamide. The control group received a similar volume of placebo. When the patient was able to take oral medication, the study drug was administered orally in a weight-adjusted dosage. Measurements Electrocardiograms (EKGs) were continuously monitored. Procainamide and N-acetyl procainamide serum concentrations were measured, and the dosages in the procainamide group were adjusted by an independent observer. The study drug was continued for 5 days or until an event occurred that resulted in dismissal from the study. Main results The procainamide group and control group had similar preoperative demographic descriptors and operative variables, except for the mean left ventricular ejection fraction, which was lower in the control group than in the procainamide group (60% vs. 68%, p = .03 [Wilcoxon rank-sum test]). There were no hospital deaths. The number of episodes of postoperative atrial fibrillation was significantly reduced in the procainamide group (5 episodes in 129 patient days at risk [3.9%/day at risk]) compared with the control group (17 episodes in 161 patient days at risk [10.6%/day at risk], p = .04 [Fisher's exact test]). Complication rates were similar in both groups. Conclusions In a pilot trial, prophylactic procainamide reduced the number of episodes of atrial fibrillation in patients after coronary artery bypass grafting. Procainamide also decreased the number of patients who experienced postoperative atrial fibrillation. However, due to the small sample size, this latter difference was not statistically significant. Further studies are needed to confirm this encouraging trend.

Pineal serotonin N-acetyltransferase activity and melatonin content exhibit marked daily rhythms in chickens: Peak values occur during the period of low locomotor activity which coincides with dark in a 24-hr light-dark regimen. Manipulation of the light-dark ratio (photoperiod) in 24-hr light-dark schedules modifies the shape of the oscillation in N-acetyltransferase activity so that the enzyme activity is always low in the light; total dark-time enzyme activity increases (17%) while average dark-time activity decreases linearly (35%) in response to a doubling of the length of the dark period. Dark-time pineal N-acetyltransferase activity decreases rapidly in response to a light signal during the dark; sensitivity of the dark-time enzyme activity to 10-min light signals is higher during the first half of the dark period and lower during the second half of the dark period in a light-dark cycle (LD12:12). N-acetyltransferase activity is regulated by light in such a way as to keep account of photoperiod and changes in photoperiod which could be of physiological utility. Photoperiod has a long-term effect on the N-acetyltransferase activity rhythm; it modifies the shape of the oscillation. Changes in photoperiod are also translated into modifications of the N-acetyltransferase activity rhythm: Rapid responses to light during the dark-time permit detection of an instantaneous change in the daily light-dark ratio.

1. In vivo pineal gland N -acetyltransferase activity (NAT) exhibits a 27-fold circadian rhythm (peak in the subjective dark-time) that can be controlled with environmental lighting. 2. In vitro , 6–7 day organ cultures if pineal glands from chickens (killed in the light-time) display changes in NAT. During the first 24 hr of culture there is a rise to a peak during the projected dark-time and a dip follows during the ensuing projected light-time. 3. In vitro there is a spontaneous decline of NAT which occurs in organ cultures of pineal glands from chickens (killed in the dark-time) at approximately the time of projected lights-on; the decline in enzyme activity occurs earlier if prior photoperiod was LD 16:8 than if prior photoperiod was LD 12:12. 4. In vitro NAT in pineal glands from chickens (killed in their light-time and organ cultured for 6 hr) are inhibited by norepinephrine, pargyline and cycloheximide. 5. In vitro NAT in pineal glands from chickens (killed in their dark-time and organ cultured for 8 hr) are inhibited by isoproterenol and cycloheximide and are stimulated (1.7–2.2 fold) by theophylline and dibutyryl cAMP.

1. The high dark-time level of the rhythm (27-fld, circadian) in pineal gland N -acetyltransferase activity in chickens ( in vivo ) is regulated by light, requires continuous protein synthesis, and can be inhibited by beta-agonists, pargyline, ethanol, serotonin and histamine. 2. The first dark-time peak can be delayed (2–4 hr) with light. 3. Cycloheximide is inhibitory throughout the dark-time (83–97%). 4. Isoproterenol, epinephrine, L -dopa, ethanol, pargyline, serotonin or histamine injections inhibit the dark-time rise (61–83%). 5. Melatonin, caffeine, theophylline, Lorazepam, phenoxybenzamine, Benadryl, PMS, progesterone, testosterone, estrogen, reserpine, arginine vasotocin, dopamine, Equithesin, mersalyl acid, carbachol, pilocarpine, cysteamine, taurine, penicillamine, atropine sulfate, immobilization stress or low temperature stress did not affect the dark-time rise.

In the pineal gland N-acetyltransferase activity (NAT) exhibits a circadian rhythm that can be controlled by environmental lighting. Dark-time NAT is 27 times the levels in the light-time. We studied the properties of NAT of pineal glands of chicks killed in the dark and found: 1. 1. NAT is linear for the first 30 min under assay conditions then levels off. 2. 2. NAT is unstable at 37°C; activity of the enzymes drops to 13–45% (of its value 0°C) in 20 min. Variability in the amount of enzyme activity lost in 20 min can be accounted for by variation in the initial activity. 3. 3. NAT is relatively stable at 0°C over a period of 24 hr. 4. 4. NAT can be protected at 37°C by one of its substrates, acetyl coenzyme A (4 mM). It is also protected by some structural analogs of acetyl coenzyme A (cysteamine, 4 mM; penicillamine, 4 mM) and by some sulfhydryl protecting agents (dithiothreitol, 4 mM; EDTA, 5 mM). The amount of protection by cysteamine is variable over a concentration range of 0.08–800 mM; 8 mM solutions of cysteamine reduce enzyme activity. NAT was lowered by iodoacetate, N-ethylmaleimide and pituitary extract. 5. 5. NAT is protected by dilution.

N-Acetyltransferase, an enzyme involved in melatonin production in the pineal gland, exhibits a circadian rhythm in chickens with peak values in the dark-time and low values during the light-time, commencing at lights-on. When pineal glands of chickens killed during the dark-time (with high N-acetyltransferase activity) were organ-cultured, there was a decline in enzyme activity to light-time values. Regardless of the time of the dark at which the chickens were killed, the enzyme activity reached light-time levels at precisely the same time.

Circadian rhythmicity was studied by following the course of N-acetyl-transferase activity in the pineal glands of chickens in vitro. The results indicate (i) a daily change during day 1 of organ culture in constant dark that was dependent on the time the chickens were killed, (ii) equivocal persistence of the daily change in constant dark during 6 to 7 days of organ culture, (iii) an effect of light, (iv) inhibition by adrenergic agents and cycloheximide, and (v) stimulation by dibutyryl adenosine 3',5'-monophosphate and related compounds.