Re: Be Careful With My Heart - EP 251-255 - July 1-5, 2013
Filis Cianciotta
The combination of goal-directed therapy and point-of-care testing was associated with a marked decrease in mortality for patients undergoing congenital heart surgery. Improvement was greatest in the highest risk patients.
The operative risk for all patients undergoing heart surgery was determined according to the RACHS-1 (Risk Adjustment for Congenital Heart Surgery [8]) scoring system. RACHS-1 divides the surgeries into six categories, with category 1 being the lowest mortality operations and category 6 being the surgeries associated with the highest mortality.
As POCT technology improves, smaller and more portable instruments are devised to perform multiple tests in a short amount of time while requiring minimal or no calibration [6, 7, 27]. While POCT has shown to affect the outcome in disease states such as diabetes indirectly [28], improvement in outcomes has only occasionally been shown in critical care areas. Recently, newer near-patient devices which evaluate coagulation profiles after heart surgery have been shown to reduce transfusion requirements, but not mortality. [29, 30]. This, despite the intuitive concept that rapid TAT associated with POCT devices should allow clinicians to make critical decisions promptly in patients with rapidly developing clinical problems.
In conclusion, critically ill patients represent a unique challenge to both laboratory and clinical services. Rapidly changing physiologic conditions warrant careful and prompt evaluation and treatment. For patients recovering after congenital heart operations, the combination of POCT and a GDT protocol based on serial blood lactate values was associated with a marked reduction in mortality. The reduction in mortality was greatest in both the youngest patients and those patients undergoing the highest risk procedures. It is possible that GDT protocols aimed at normalizing other objective indicators of cardiovascular well being may result in similar improvements in outcomes.
Apart from overt heart failure, FRDA patients can have several other cardiac symptoms. Many develop chest pain sounding like classical angina, though not always linked to exertion. It is usually not associated with changes in ECG or troponin levels, though troponin levels are confounded by elevated troponin values at baseline.46 Anecdotally, we have seen individuals in whom this chest pain has responded to quinone containing neutriceutical (CoQ, idebenone), beta-blockers, calcium channel blockers, or nitrates. While early-onset coronary artery disease does not appear to be a common feature of FRDA, medications such as beta-blockers, calcium channel blockers, or nitrates may alleviate symptoms, presumably by decreasing myocardial oxygen demand or increasing microvascular blood supply to the hypertrophied heart.
With respect to therapies, insulin remains the cornerstone of therapy for individuals with clinical evidence of significant insulin deficiency (eg, ketoacidosis, hyperglycemia with weight loss), especially in children.84 There may be a role for other glucose-lowering therapies with careful consideration of individualized risk-benefit assessment in light of comorbidities. In contrast to other forms of diabetes related to mitochondrial impairment, most individuals with FRDA do not have a personal history of lactic acidosis, so metformin is not strictly contraindicated and may be helpful, though its use should be monitored closely, and as with all individuals, discontinued with illness.85 Novel glucose lowering medications may have a role not only in the management of FRDA-related diabetes, but also for other problems, such as glucagon-like peptide 1 receptor (GLP1R) agonists for neurologic and/or cardiac benefits, eg, exenatide and sodium-glucose co-transporter 2 (SGLT2) inhibitors for heart failure with or without diabetes.67,86 These exciting potential benefits warrant additional study in FRDA, with attention to risk for associated adverse effects. Particularly relevant for individuals with FRDA is the increased incidence of euglycemic diabetic ketoacidosis with SGLT2 inhibitor use.87 Finally, in FRDA related diabetes, glycemic targets should be individualized, and screening for complications as in other forms of diabetes, although with attention to the overlap with complications of FRDA itself.
Linear growth and weight gain should be monitored closely in children with FRDA, as in any child with a chronic, multi-system disorder. Specifically, in FRDA, scoliosis is expected to impact height measurements, in particular during and after the pubertal growth spurt. Also, more severe cardiac disease could also adversely impact growth, as in other pediatric heart disorders.88 Many children with FRDA have low body mass index (BMI) when commonly used thresholds for assessing nutritional status are applied.89 However, it is not clear the extent to which BMI truly reflects body composition in FRDA, and whether more nutrition would produce clinical benefit as low BMI values most likely do not directly lead to neurological or cardiac dysfunction. Indeed, in adults with FRDA, BMI may underestimate the degree of excess visceral adiposity that predisposes to diabetes.81 In both children and adults, height and weight are frequently not recorded at clinical visits, likely due to difficulties obtaining measurements in individuals with limited mobility.28 We recommend that increasing attention be paid to making these measurements, and using alternate assessments (eg, recumbent length, arm span, or tibial length) be considered where needed.
Left ventricular (LV) dysfunction caused by various heart diseases, such as idiopathic dilated cardiomyopathy, ischemic heart diseases, valvular diseases, and myocarditis, leads to heart failure, a major cause of mortality in developed countries1. The mortality of heart failure remains high, although it has gradually improved for decades owing to modern treatment for this disease based on evidence obtained from a large number of clinical trials. Furthermore, because heart failure morbidity is high among the elderly2, the growing numbers of heart failure patients, along with high rehospitalization rates, will pose major social issues in aging societies. Thus, the identification of therapeutic targets and the development of novel therapies for heart failure constitute urgent priorities. Because cell death is known to be involved in the development and progression of LV dysfunction3, the regulation of cell death may be one of the best options for a novel heart failure therapy. However, a therapy suppressing cell death has not yet been established as a heart failure treatment.
The membrane-associated iPLA2γ has been shown to be the predominant isoform activated with myocardial injury8. We showed pressure overload increased the level of iPLA2β protein in the heart, while it had no effect on that of iPLA2γ. In addition, our lipidomics data showed reported mediators involved in iPLA2γ-mediated cardiac injury were not significantly increased in Pla2g6+/+ hearts after TAC8. These results suggest no potential contribution of iPLA2γ to pressure overload-induced cardiac remodeling.
In summary, we show that iPLA2β plays a detrimental role in the pathogenesis of pressure-overloaded cardiac dysfunction. iPLA2β produces 18:0 lysophosphatidylserine, resulting in GPR34-mediated necrotic cell death and cardiac dysfunction. The inhibition of the GPR34 signaling pathway reduces cardiac cell death. Thus, iPLA2β, as well as GPR34, may constitute therapeutic targets for patients with heart failure.
There is no clear definition of early tracheostomy, with many studies defining this from within 48 h to within 10 days after the initiation of mechanical ventilation, and early tracheostomy could be considered if the general condition of the patient is stable. Meanwhile, there are concerns with early tracheostomy that it may be conducted on patients who did not require it in the first place. Additionally, the tracheostomy itself may involve high levels of risk in patients with ARDS with high oxygen concentrations, airway pressure, or PEEP; therefore, careful consideration is needed for adaptation to the patient in this recommendation.
The heme oxygenase-1 (HO-1; Hmox1) enzyme system is among the most important inducible mechanisms for cell protection against oxidative damage in the cardiovascular system. During oxidative stress, HO-1 eliminates cellular free heme (1), a powerful oxidant (2, 3), and produces the physiological gas carbon monoxide (CO) (4), which has potent antiinflammatory and antiapoptotic effects and stimulates mitochondrial biogenesis (5, 6). Moreover, administration of low-level CO gas or CO-releasing molecules mitigates many pathological injuries that affect energy metabolism in cells and tissues of experimental animals (7, 8). Hmox1-deficient heart cells accumulate lethal molecular oxidant damage, and embryonic Hmox1 deletion in mice has a high prenatal mortality, with survivors showing growth retardation, iron overload, organ fibrosis, and inflammatory tissue damage (9). Hmox1-deficient mice are highly susceptible to ischemia/reperfusion (I/R) injury and, after hypoxia, show evidence of right ventricular infarction (10, 11). This enzyme system has thus been a focus of attention in several cardiovascular diseases, including heart failure (HF) (12, 13), which is accompanied by oxidant-mediated hypertrophy, dilation, fibrosis, and metabolic disturbances that reduce contractile function (14, 15). The rare human HO-1 deficiency state and certain polymorphisms of the human HO-1 gene promoter are also associated with the development of cardiovascular disease (16, 17).
Oxidative stress also contributes to adaptation to myocardial ischemia and can be induced by pretreatment with hyperoxia (>95% O2), a potentially valuable means of clinical preconditioning (43). O2 preconditioning attenuates I/R injury in rat hearts by decreasing infarct size and improving postischemic heart function (44, 45). This suggests that oxidative stress may not only induce antioxidant protection, but may also generate a protective mitochondrial status through HO-1 induction and downstream support of mitochondrial quality control (25, 46). However, O2 is also toxic at high concentrations over prolonged periods of time, which sets limits on its therapeutic use.
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