Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Mechanically Unloading the Left Ventricle Before Coronary Reperfusion Reduces Left Ventricular Wall Stress and Myocardial Infarct Size
- Prospective Study of Breakfast Eating and Incident Coronary Heart Disease in a Cohort of Male US Health Professionals
- Long-term Survival of Dialysis Patients With Bacterial Endocarditis Undergoing Valvular Replacement Surgery in the United States
- Emergency Department Bypass for ST-Segment–Elevation Myocardial Infarction Patients Identified With a Prehospital Electrocardiogram: A Report From the American Heart Association Mission: Lifeline Program
- Outcomes of Urgent Warfarin Reversal With Frozen Plasma Versus Prothrombin Complex Concentrate in the Emergency Department
- Protein Kinase G Positively Regulates Proteasome-Mediated Degradation of Misfolded Proteins
- Gβγ-Independent Recruitment of G-Protein Coupled Receptor Kinase 2 Drives Tumor Necrosis Factor α–Induced Cardiac β-Adrenergic Receptor Dysfunction
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Mechanically Unloading the Left Ventricle Before Coronary Reperfusion Reduces Left Ventricular Wall Stress and Myocardial Infarct Size
Each year, nearly 8 million people worldwide suffer a heart attack, which is commonly caused by a blocked coronary artery leading to reduced oxygen supply to the heart, known as ischemia. Every minute of occlusion directly correlates with ongoing heart muscle damage. Treatment focuses on quickly re-establishing blood flow to the heart, known as reperfusion. However, despite timely reperfusion, ≈5% to 10% of patients die in the hospital, and 25% develop chronic heart failure. Using a porcine model of an acute heart attack, we studied whether first reducing the workload of the heart with a mechanical pump despite delaying coronary reperfusion would reduce myocardial damage. We identified that a percutaneously delivered left atrial–to–femoral artery circuit driven by a centrifugal pump reduces left ventricular wall stress, work, and strain while maintaining systemic arterial pressure. Next, we observed that mechanically unloading the heart despite delaying reperfusion promotes phosphorylation of proteins involved in myocardial salvage. Finally, we showed that compared with controls, myocardial damage was reduced with initiation of mechanical support in the setting of a heart attack. These findings suggest that initially reducing the workload of the heart despite delaying coronary reperfusion reduces myocardial injury. The clinical implications of these findings require further study. See p 328.
Prospective Study of Breakfast Eating and Incident Coronary Heart Disease in a Cohort of Male US Health Professionals
Among adults, skipping meals is associated with many cardiometabolic risk factors, including excess body weight, hypertension, insulin resistance, and elevated fasting lipid concentrations. However, no formal evidence-based dietary guidelines exist for adults concerning eating habits such as breakfast eating, and it has remained unknown whether specific eating habits regardless of dietary composition influence the risk of major cardiovascular health outcomes such as coronary heart disease (CHD). In this first large, prospective analysis of eating habits and CHD (defined as nonfatal myocardial infarction or fatal CHD), we studied a well-characterized cohort of 26 902 male American dentists, veterinarians, pharmacists, optometrists, osteopaths, and podiatrists for 16 years, taking into account comprehensive adjustment for demographic, diet, and lifestyle factors. We found that men who skipped breakfast had an increased risk of CHD compared with men who ate breakfast, an association that was potentially a result of a combination of the mechanistic pathways of obesity, hypertension, hypercholesterolemia, and diabetes mellitus. We did not detect an association between eating frequency (the number of meals and snacks per day) and risk of CHD. Our study provides novel evidence of the benefit of breakfast consumption for the prevention of coronary events and, to the best of our knowledge, is the first study to investigate this topic. If confirmed in future studies of different populations, our findings support a recommendation of daily breakfast eating by clinicians and health authorities to prevent CHD and to improve health at both the individual and population levels. See p 337.
Long-term Survival of Dialysis Patients With Bacterial Endocarditis Undergoing Valvular Replacement Surgery in the United States
Bacterial endocarditis in dialysis patients is associated with high mortality rates. Prior studies have dealt with long-term survival related to the choice of prosthesis type in valvular replacement surgery in dialysis patients, but no studies have addressed this issue in patients with bacterial endocarditis. Dialysis patients hospitalized for bacterial endocarditis from 2004 to 2007 were studied retrospectively using data from the United States Renal Data System. During the study period, 11 156 dialysis patients were hospitalized for bacterial endocarditis and 1267 (11.4%) underwent valvular replacement surgery (tissue valve, 44.3%; nontissue valve, 55.7%). Estimated survival with tissue and nontissue valves at 0.5, 1, 2, and 3 years was 59% and 60%, 48% and 50%, 35% and 37%, and 25% and 30%, respectively. Staphylococcus was the predominant organism (66% of identified organisms). Independent predictors of mortality in patients undergoing valve replacement surgery included older age, diabetes mellitus as the cause of end-stage renal disease, surgery during index hospitalization, staphylococcus as the causative organism, and dysrhythmias as a comorbid condition. Valve replacement surgery is appropriate for well-selected dialysis patients with bacterial endocarditis but is associated with high mortality rates. Survival does not differ with tissue or nontissue prosthesis. See p 344.
Emergency Department Bypass for ST-Segment–Elevation Myocardial Infarction Patients Identified With a Prehospital Electrocardiogram: A Report From the American Heart Association Mission: Lifeline Program
Several strategies are recommended to optimize and shorten reperfusion times for patients with ST-segment–elevation myocardial infarction. These include the use of prehospital ECGs and direct transport to a percutaneous coronary intervention–capable hospital while bypassing a hospital without percutaneous coronary intervention capabilities. Along this spectrum, the European Society of Cardiology guidelines recommend that in the optimal situation, ST-segment–elevation myocardial infarction patients diagnosed with a prehospital ECG should be directly transported to the catheterization laboratory of the percutaneous coronary intervention–capable hospital, thereby bypassing the emergency department (ED). This strategy of bypassing the ED, however, was not endorsed in the updated 2013 American College of Cardiology Foundation/American Heart Association guidelines, likely reflecting the lack of feasibility, efficacy, and safety data for this practice in the United States. We evaluated hospitals participating in the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With The Guidelines, including those participating in the American Heart Association Mission: Lifeline program to determine the contemporary use of ED bypass in the United States and to investigate the association of this strategy with reperfusion times and in-hospital mortality. We found that among ST-segment–elevation myocardial infarction patients identified with a prehospital ECG, the rate of ED bypass varied significantly across US hospitals. Overall, ED bypass occurred infrequently in ≈11% of patients and was mostly isolated to working hours. Compared with evaluation in the ED before transport to the catheterization laboratory, bypassing the ED was associated with significantly faster reperfusion times with no adverse effect on in-hospital mortality. We believe that this strategy is feasible, safe, and efficacious and that it warrants widespread implementation in the United States. See p 352.
Outcomes of Urgent Warfarin Reversal With Frozen Plasma Versus Prothrombin Complex Concentrate in the Emergency Department
This study is the first, to the best of our knowledge, to compare prothrombin complex concentrate with frozen plasma in anticoagulated emergency department patients. Prothrombin complex concentrate is safer and more efficacious for patients with critical bleeding. It is now also used routinely to reverse patients’ warfarin anticoagulation preoperatively, leading to shorter wait times to surgery. Although a cost-benefit analysis was beyond the scope of our study, the baseline cost of a therapeutic dose of prothrombin complex concentrate at our center is lower than that of an appropriate dose of frozen plasma. Centers that currently reverse warfarin anticoagulation routinely with frozen plasma should consider prothrombin complex concentrate as a superior first-line therapy. See p 360.
Protein Kinase G Positively Regulates Proteasome-Mediated Degradation of Misfolded Proteins
Proteasome functional insufficiency plays an important role in bona fide proteinopathy (eg, desmin-related cardiomyopathy) and is implicated in the pathogenesis of many other heart diseases with increased production of misfolded proteins. Benign enhancement of proteasome function can be achieved by genetic approaches and protects against desmin-related cardiomyopathy and acute myocardial ischemia/reperfusion injury in mice; however, no pharmaceutics are currently available to do so. Here, we have shown that enhancement of proteasomal degradation of misfolded proteins can be achieved by protein kinase G gain of function. We have demonstrated that sildenafil activates protein kinase G, stimulates proteasome function, and reduces aberrant protein aggregation in intact mice. Food and Drug Administration–approved drugs are readily available to stimulate protein kinase G (eg, sildenafil). Hence, our results suggest that strategies to increase protein kinase G activities may be used to treat desmin-related cardiomyopathy and other proteinopathy. Currently, no treatment is available for these debilitating diseases. Moreover, this study provides a potentially new mechanism for phosphodiesterase 5 inhibition in treating heart disease. Many recent studies have shown the beneficial effects of phosphodiesterase 5 inhibition in treating heart diseases. Proteasome functional insufficiency is suggested as a common pathogenic factor in the progression of most heart diseases. Accumulation of misfolded proteins, including preamyloid oligomers in cardiomyocytes as observed in failing human hearts, is sufficient to cause cardiomyopathy in mice, and conversely, improving proteasome function slows the progression of the cardiomyopathy. Therefore, it is highly possible that improving proteasomal removal of misfolded proteins in cardiomyocytes of diseased hearts is a benefit of protein kinase G stimulation. See p 365.
Gβγ-Independent Recruitment of G-Protein Coupled Receptor Kinase 2 Drives Tumor Necrosis Factor α–Induced Cardiac β-Adrenergic Receptor Dysfunction
It is well known that proinflammatory cytokine tumor necrosis factor-α (TNFα) is elevated in congestive heart failure and contributes to pathological left ventricular remodeling. The surprising failure of clinical trials on TNF blockade indicates that more needs to be understood about the role of TNFα in cardiac signaling/function to develop better therapeutic approaches. Although TNFα mediates negative inotropy potentially through β-adrenergic receptors (βARs), mechanisms underlying this process are not well understood. Our current studies show the presence of a direct cross-talk between TNFα receptor signaling and βAR function. TNFα treatment results in nonclassical recruitment of G-protein coupled receptor kinase 2 to βARs that results in βAR phosphorylation inhibiting βAR function. Most surprisingly, TNFα mediates βAR desensitization in a βAR agonist/antagonist–independent manner contrary to the current paradigm of βAR activation and signaling. This finding has significant implications because it suggests that just the presence of TNFα is sufficient to predispose βARs toward dysfunction independent of the sympathetic inputs from epinephrine/norepinephrine. Importantly, TNFα may reduce the number of responsive βARs accounting for reduced myocyte contractility and deleterious remodeling. Therefore, our findings suggest that novel strategies for targeting βARs may be required to overcome the TNFα-mediated βAR dysfunction because TNFα is elevated in comorbid conditions like hypertension, dyslipidemia, diabetes mellitus, and obesity that may underlie deleterious cardiac remodeling and heart failure. See p 377.
- © 2013 American Heart Association, Inc.
- Protein Kinase G Positively Regulates Proteasome-Mediated Degradation of Misfolded Proteins
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