Role of phospholipase C in catecholamine-induced increase in myocardial protein synthesis.

The activation of the α1-adrenoceptor-(α1-AR) by norepinephrine results in the G-protein (Gqα) mediated increase in the phosphoinositide-specific phospholipase C (PLC) activity. The byproducts of PLC hydrolytic activity, namely, 1,2-diacylglycerol and inositol-1,4,5-trisphosphate, are important downstream signal transducers for increased protein synthesis in the cardiomyocyte and the subsequent hypertrophic response. In this article, evidence was outlined to demonstrate the role of cardiomyocyte PLC isozymes in the catecholamine-induced increase in protein synthesis by using a blocker of α1-AR and an inhibitor of PLC. The discussion was focused on the α1-AR-Gqα-PLC-mediated hypertrophic signalling pathway from the viewpoint that it may compliment the other ß1-AR-Gs protein-adenylyl cyclase signal transduction mechanisms in the early stages of cardiac hypertrophy development, but may become more relevant at the late stage of cardiac hypertrophy. From the information provided here, it is suggested that some specific PLC isozymes may potentially serve as important targets for the attenuation of cardiac hypertrophy in the vulnerable patient population at-risk for heart failure.

Autopsy Histopathologic Cardiac Findings in 2 Adolescents Following the Second COVID-19 Vaccine Dose.

CONTEXT.­: Myocarditis in adolescents has been diagnosed clinically following the administration of the second dose of an mRNA vaccine for coronavirus disease 2019 (COVID-19). OBJECTIVE.­: To examine the autopsy microscopic cardiac findings in adolescent deaths that occurred shortly following administration of the second Pfizer-BioNTech COVID-19 dose to determine if the myocarditis described in these instances has the typical histopathology of myocarditis. DESIGN.­: Clinical and autopsy investigation of 2 teenage boys who died shortly following administration of the second Pfizer-BioNTech COVID-19 dose. RESULTS.­: The microscopic examination revealed features resembling a catecholamine-induced injury, not typical myocarditis pathology. CONCLUSIONS.­: The myocardial injury seen in these postvaccine hearts is different from typical myocarditis and has an appearance most closely resembling a catecholamine-mediated stress (toxic) cardiomyopathy. Understanding that these instances are different from typical myocarditis and that cytokine storm has a known feedback loop with catecholamines may help guide screening and therapy.

Increased risk of catheter-related infection in critically ill patients given catecholamine inotropes during continuous renal replacement therapy.

INTRODUCTION: Previous in vitro studies have shown that catecholamine inotropes are potent stimulators of bacterial growth and biofilm formation on catheter surfaces. This study aimed to investigate the effects of administering catecholamine inotropes during continuous renal replacement therapy (CRRT) on catheter-related infections in critically ill patients. METHODS: This single-center retrospective cohort study included patients requiring CRRT in an intensive care unit from 2016 to 2017, who were divided into those who received and did not receive catecholamine inotropes for ≥24 h (catecholamine and control groups, respectively). The primary endpoint was catheter-related infection, including catheter-related colonization (CRCOL) and catheter-related bloodstream infection (CRBSI). FINDINGS: We included 235 patients with 297 dialysis catheters. The catecholamine group had higher proportions of cardiovascular disease (p = 0.002), shock (p < 0.001), mechanical ventilation (p < 0.001), and antibiotic use (p = 0.013). There was no significant between-group difference in the CRBSI incidence (5.742 vs. 3.143 events/1000 catheter-days; p = 0.205). However, the CRCOL incidence was significantly higher in the catecholamine group than in the control group (6.221 vs. 0.898 events/1000 catheter-days; p = 0.006). The prominent pathogenic bacteria were gram-negative bacteria. After adjusting for confounding factors in multivariate logistic models, catecholamine inotropes (OR: 3.575, 95% CI: 1.422-9.912, p = 0.008) and immunosuppression (OR: 2.980, 95% CI: 1.137-7.812, p = 0.026) were independently associated with a higher risk of catheter-related infections. DISCUSSION: We observed a similar incidence of catheter-related infection with that in other CRRT patients. Using catecholamine inotropes in those patients increased CRCOL risk, which is consistent with previous in vitro studies. Our findings suggest that catecholamine inotropes is an independent risk factor for catheter-related infections in critically ill patients undergoing CRRT.

The impact of catecholamines on skeletal muscle following massive burns: Friend or foe?

Profound skeletal muscle wasting in the setting of total body hypermetabolism is a defining characteristic of massive burns, compromising the patient's recovery and necessitating a protracted period of rehabilitation. In recent years, the prolonged use of the non-selective beta-blocker, propranolol, has gained prominence as an effective tool to assist with suppressing epinephrine-dependent burn-induced hypermetabolism and by extension, blunting muscle catabolism. However, synthetic ß-adrenergic agonists, such as clenbuterol, are widely associated with the promotion of muscle growth in both animals and humans. Moreover, experimental adrenodemedullation is known to result in muscle catabolism. Therefore, the blunting of muscle ß-adrenergic signaling via the use of propranolol would be expected to negatively impair muscle protein homeostasis. This review explores these paradoxical observations and identifies the manner by which propranolol is thought to exert its anti-catabolic effects in burn patients. Moreover, we identify potential avenues by which the use of beta-blocker therapy in the treatment of massive burns could potentially be further refined to promote the recovery of muscle mass in these critically ill patients while continuing to ameliorate total body hypermetabolism.

Bcl-2-associated athanogene 5 overexpression attenuates catecholamine-induced vascular endothelial cell apoptosis.

Bcl-2 associated athanogene 5 (Bag5) is a novel endoplasmic reticulum (ER) regulator. However, its role in catecholamine-induced endothelial cells damage has not been fully understood. In our study, catecholamine was used to mimic hypertension-related endothelial cell damage. Then, western blots, enzyme-linked immunosorbent assay, immunofluorescence, quantitative polymerase chain reaction and pathway analysis were conducted to analyze the role of Bag5 in endothelial cell damage in response to catecholamine. Our results indicated that the endothelial cell viability was impaired by catecholamine. Interestingly, Bag5 overexpression significantly reversed endothelial cell viability. Mechanistically, Bag5 overexpression inhibited ER stress, attenuated oxidative stress and repressed inflammation in catecholamine-treated endothelial cells. These beneficial effects finally contributed to endothelial cell survival under catecholamine treatment. Pathway analysis demonstrated that Bag5 was under the control of the mitogen-activated protein kinase (MAPK)-extracellular-signal-regulated kinase (ERK) signaling pathway. Reactivation of the MAPK-ERK pathway could upregulate Bag5 expression and thus promote endothelial cell survival through inhibiting oxidative stress, ER stress, and inflammation. Altogether, our results illustrate that Bag5 overexpression sustains endothelial cell survival in response to catecholamine treatment. This finding identifies Bag5 downregulation and the inactivated MAPK-ERK pathway as potential mechanisms underlying catecholamine-induced endothelial cell damage.

Angiotensin II and Vasopressin for Vasodilatory Shock: A Critical Appraisal of Catecholamine-Sparing Strategies.

Vasodilatory shock is a serious medical condition that increases the morbidity and mortality of perioperative and critically ill patients. Norepinephrine is an established first-line therapy for this condition, but at high doses, it may lead to diminishing returns. Oftentimes, secondary noncatecholamine agents are required in those whose hypotension persists. Angiotensin II and vasopressin are both noncatecholamine agents available for the treatment of hypotension in vasodilatory shock. They have distinct modes of action and unique pharmacologic properties when compared to norepinephrine. Angiotensin II and vasopressin have shown promise in certain subsets of the population, such as those with acute kidney injury, high Acute Physiology and Chronic Health Evaluation II scores, or those receiving cardiac surgery. Any benefit from these drugs must be weighed against the risks, as overall mortality has not been shown to decrease mortality in the general population. The aims of this narrative review are to provide insight into the historical use of noncatecholamine vasopressors and to compare and contrast their unique modes of action, physiologic rationale for administration, efficacy, and safety profiles.

Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial.

Rationale: Exogenous angiotensin II increases mean arterial pressure in patients with catecholamine-resistant vasodilatory shock (CRVS). We hypothesized that renin concentrations may identify patients most likely to benefit from such therapy.Objectives: To test the kinetic changes in renin concentrations and their prognostic value in patients with CRVS.Methods: We analyzed serum samples from patients enrolled in the ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) trial for renin, angiotensin I, and angiotensin II concentrations before the start of administration of angiotensin II or placebo and after 3 hours.Measurements and Main Results: Baseline serum renin concentration (normal range, 2.13-58.78 pg/ml) was above the upper limits of normal in 194 of 255 (76%) study patients with a median renin concentration of 172.7 pg/ml (interquartile range [IQR], 60.7 to 440.6 pg/ml), approximately threefold higher than the upper limit of normal. Renin concentrations correlated positively with angiotensin I/II ratios (r = 0.39; P < 0.001). At 3 hours after initiation of angiotensin II therapy, there was a 54.3% reduction (IQR, 37.9% to 66.5% reduction) in renin concentration compared with a 14.1% reduction (IQR, 37.6% reduction to 5.1% increase) with placebo (P < 0.0001). In patients with renin concentrations above the study population median, angiotensin II significantly reduced 28-day mortality to 28 of 55 (50.9%) patients compared with 51 of 73 patients (69.9%) treated with placebo (unstratified hazard ratio, 0.56; 95% confidence interval, 0.35 to 0.88; P = 0.012) (P = 0.048 for the interaction).Conclusions: The serum renin concentration is markedly elevated in CRVS and may identify patients for whom treatment with angiotensin II has a beneficial effect on clinical outcomes.Clinical trial registered with www.clinicaltrials.gov (NCT02338843).

Association between high dose catecholamine support and liver dysfunction following cardiac surgery.

BACKGROUND: Cardiac surgery using cardiopulmonary bypass is a well-established procedure. However, up to 20% to 30% of patients require high dose vasopressor or inotropic support following surgery, enhancing the risk of organ dysfunction and impacting mortality. Nonalcoholic fatty liver disease (NAFLD) is a frequent finding in these patients and may be involved in the pathophysiology of vasoplegia and cardiac failure. METHODS: Retrospective analysis of 463 patients undergoing elective cardiac surgery in 2014 at our institution. NAFLD was defined using the NAFLD fibrosis score and the vasoactive-inotropy score was used to determine postoperative vasopressor and inotropic dependency. RESULTS: Patients with NAFLD more often presented with high vasopressor or inotropic support compared to patients without NAFLD, resulting in significant differences after 6 hours (n = 20 [27.0%] of 74 patients), 12 hours (n = 20 [27.0%] of 74 patients), and on the first postoperative day (n = 12 [16.4%] of 73 patients) of intensive care unit (ICU) treatment. Multivariate analysis revealed time of catecholamine application (P = .001), preoperative left ventricular ejection fraction (P = .001), type of surgery (P = .001), model of endstage liver disease on hospital admission (P = .002), pre-existing pulmonary hypertension (P = .004) and NAFLD-time interaction (P = .05) as independent predictors of high vasopressor and inotropic support. Patients with NAFLD had higher degrees of extrahepatic organ dysfunction, were more dependent on hemodialysis, spent more days in the ICU and within the hospital. Patients with NAFLD and high catecholamine support had the highest mortality rates among the study population. CONCLUSIONS: NAFLD is a common finding in elective cardiac surgery patients. Anesthesiologists and intensivists should be sensitive for the specific risk profile of this population.

ST-Segment Elevation Myocardial Infarction Related to Potential Spontaneous Coronary Thrombosis in Pheochromocytoma Crisis.

Pheochromocytoma crisis is a rare and possibly fatal emergency. Hypersecreted catecholamines may result in myocardial injury via its direct toxic effect on cardiomyocytes or mediating vasoconstriction which will reduce coronary blood flow in this special setting. Interestingly, several case studies have reported the occurrence of ST-segment elevation myocardial infarction in patients with pheochromocytoma crisis. However, no one found the angiographic evidence of occlusive thrombus in the infarct-related coronary artery. Additionally, pheochromocytoma can induce hypercoagulability and promote thrombosis, but spontaneous coronary thrombosis has never been reported in this condition. Here, we report an unusual case of pheochromocytoma crisis presenting with STEMI due to spontaneous coronary thrombosis.

Recurrent Catecholamine-Induced Cardiomyopathy and Hypertensive Emergencies: A presentation of Pheochromocytoma and Related Concerns.

Catecholamine-induced cardiomyopathy (CIC) and pheochromocytoma are both rare entities, and their exact incidence and prevalence are unknown. Pheochromocytoma has been implicated as one of the causes of CIC or Takotsubo syndrome (TTS) by means of case reports and retrospective reviews. However, the evaluation of any patient with TTS and pheochromocytoma is often faced with multiple challenges due to its rarity and atypical presentations, which subsequently leads to delay in diagnosis. Here, we present a case of a 51-year old female who had three distinct episodes of TTS and now presented in a hypertensive emergency with angina, palpitations, headache, nausea, and vomiting. She was treated for non-ST elevation myocardial infarction (NSTEMI) but coronary angiogram revealed patent coronary arteries. Due to the paroxysmal nature of her hypertensive emergencies and variable blood pressure response, pheochromocytoma was suspected. On further evaluation, she was found to have elevated metanephrines and a 6.3 cm left adrenal mass on CT scan. This case emphasizes the importance of considering or identifying pheochromocytoma as an underlying primary etiology for recurrent episodes of TTS and related concerns such as choice of anti-hypertensive agents.

Clinical features, complications, and outcomes of exogenous and endogenous catecholamine-triggered Takotsubo syndrome: A systematic review and meta-analysis of 156 published cases.

Innumerable physical stress factors including externally administered catecholamines, and pheochromocytomas and paragangliomas (PPGLs) have been reported to trigger Takotsubo syndrome (TS). A systematic search of PubMed/MEDLINE identified 156 patients with catecholamine-induced TS up to December 2017. Data were compared within the catecholamine-induced TS cohort, but some comparisons were also done to a previously published large all-TS cohort (n = 1750). The mean age was 46.4 ± 16.4 years (72.3% women). The clinical presentation was dramatic with high complication rates in (68.2%, n = 103; multiple complications 34.6%, n = 54). The most common TS ballooning pattern was apical or mid-apical (45.2%, n = 69), followed by basal pattern (28.8%, n = 45), global pattern (16.0%, n = 25), mid-ventricular (8.3%, n = 13), focal (0.6%, n = 1), and unidentified pattern (1.9%, n = 3). There was an increase in the prevalence of apical sparing ballooning pattern compared to all-TS population (37.7% vs 18.3%, P < .00001). Higher complication rates were observed in TS with global ballooning pattern compared to apical ballooning pattern (23/25, 92% vs 38/65, 58.5%; P = .0022). Higher complication rates were observed in patients with age < 50 years than patients >50 years (73/92, 79.3% vs 29/56, 51.8%, P = 0.0009). Recurrence occurred exclusively in patients with PPGL-induced TS (18/107 patients, 16.8%). PPGL-induced TS was characterized by more global ballooning's pattern (22/104, 21.2% vs 3/49, 6.1%, P = 0.02), and lower left ventricular ejection fraction (25.54 ± 11.3 vs 31.82 ± 9.93, P = 0.0072) compared to exogenous catecholamine-induced TS. In conclusion, catecholamine-induced TS was characterized by a dramatic clinical presentation with extensive left ventricular dysfunction, and high complication rate.

Prognosis of ß-adrenergic blockade therapy on septic shock and sepsis: A systematic review and meta-analysis of randomized controlled studies.

PURPOSE: ß-adrenoceptor antagonist (ß-blocker) may have potential in the treatment of septic shock and sepsis. However, the relevant research findings are still controversial. METHODS: We conducted a systematic review and meta-analysis to explore the efficacy of ß-blocker in patients with septic shock and sepsis. The primary sources of the reviewed studies through August 2018, with restriction on the language of English, were Pubmed and Embase. Randomized controlled trials (RCT) were included to evaluate the efficacy of ß-blocker in the treatment of septic shock and sepsis. Meta analysis was performed using a random effect model. Two researchers independently searched articles, extracted data, and assessed the quality of the included studies. RESULTS: A total of 6 studies related to 5 original RCTs were qualified for inclusion in this systematic review and meta-analysis with a total of 363 patients with sepsis and/or septic shock. ß-blocker was associated with a significantly decreased 28-day mortality compared to usual treatment group as the control (RR = 0.59, 95%CI: 0.48, 0.74; P < 0.00001). Heart rate in ß-blocker was significantly lower than that in the standard care group (SMD = -2.01, 95%CI: -3.03, -0.98; P = 0001). CONCLUSION: ß-blocker of esmolol is safe and effective in improving 28-day mortality and controlling ventricular rate in patients with sepsis after fluid resuscitation, and has no significant adverse effect on tissue perfusion.

A case of catecholamine-induced cardiomyopathy treated with extracorporeal membrane oxygenation.

A 55-year-old female patient was presented with severe dyspnea due to sudden onset of heart failure (ejection fraction (EF) <10%). Echocardiogram showed a takotsubo pattern with an akinetic apical segment. Coronary angiography did not reveal any obstructive disease. She became hypotensive which was refractory to conventional pressor agents. Catecholamine-induced cardiomyopathy was suspected after the CT scan of the abdomen showed a 4 cm necrotic right adrenal mass consistent with pheochromocytoma (PHEO). Venous arterial extracorporeal membrane oxygenation and α blockers were initiated. There was a rapid improvement in cardiac function with EF normalising in 1 week. Subsequently, ß-blockers were added and right adrenalectomy was done 3 weeks after the admission. She did extremely well after surgery with her blood pressure normalising without the need for antihypertensive therapy. Genetic evaluation revealed no pathogenic mutations implicated in the development of PHEO.

Pharmacologic Agents for the Treatment of Vasodilatory Shock.

Vasodilatory shock is a life-threatening syndrome in critically ill patients and is characterized by severe hypotension and resultant tissue hypoperfusion. This shock state requires the use of vasopressor agents to restore adequate vascular tone. Norepinephrine is still recommended as first-line vasopressor in the management of critically ill patients suffering from severe vasodilation. In the recent time, catecholaminergic vasopressor drugs have been associated with possible side effects at higher dosages. This so-called catecholamine toxicity has focused on alternative noncatecholaminergic vasopressors or the use of moderate doses of multiple vasopressors with complementary mechanisms of action. Besides vasopressin and terlipressin, angiotensin II may be a promising drug for the management of vasodilatory shock. In addition, adjunctive drugs, such as hydrocortisone, methylene blue or ascorbic acid can be added to conventional vasopressor therapy. The objective of this review is to give an overview of the current available vasopressor agents used in vasodilatory shock. A thorough search of PubMed was conducted in order to identify the majority of studies related to the subject. Data on the outcome of several drugs and future perspective of possible management strategies for the therapy of vasodilatory shock are discussed.

Minimizing catecholamines and optimizing perfusion.

Catecholamines are used to increase cardiac output and blood pressure, aiming ultimately at restoring/improving tissue perfusion. While intuitive in its concept, this approach nevertheless implies to be effective that regional organ perfusion would increase in parallel to cardiac output or perfusion pressure and that the catecholamine does not have negative effects on the microcirculation. Inotropic agents may be considered in some conditions, but it requires prior optimization of cardiac preload. Alternative approaches would be either to minimize exposure to vasopressors, tolerating hypotension and trying to prioritize perfusion but this may be valid as long as perfusion of the organ is preserved, or to combine moderate doses of vasopressors to vasodilatory agents, especially if these are predominantly acting on the microcirculation. In this review, we will discuss the pros and cons of the use of catecholamines and alternative agents for improving tissue perfusion in septic shock.

Treatments targeting inotropy.

Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation-contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term.

Concentrations of Gaseous Transmitters during Catecholamine Damage to the Myocardium in Rats.

Gaseous transmitters were assayed in rat blood during catecholamine-induced damage to the heart. Hypercatecholaminemia was modeled by single subcutaneous injection of 0.1% epinephrine hydrochloride in a dose of 2 mg/kg. The blood concentrations of NO, H2S, and CO were measured. The catecholamine-induced damage to the myocardium resulted in phasic changes in the blood levels of gaseous transmitters: CO concentration increased in 1 h, H2S increased in 24 h, and NO concentration increased in 72 h after injection.

Association of Vasopressin Plus Catecholamine Vasopressors vs Catecholamines Alone With Atrial Fibrillation in Patients With Distributive Shock: A Systematic Review and Meta-analysis.

Importance: Vasopressin is an alternative to catecholamine vasopressors for patients with distributive shock-a condition due to excessive vasodilation, most frequently from severe infection. Blood pressure support with a noncatecholamine vasopressor may reduce stimulation of adrenergic receptors and decrease myocardial oxygen demand. Atrial fibrillation is common with catecholamines and is associated with adverse events, including mortality and increased length of stay (LOS). Objectives: To determine whether treatment with vasopressin + catecholamine vasopressors compared with catecholamine vasopressors alone was associated with reductions in the risk of adverse events. Data Sources: MEDLINE, EMBASE, and CENTRAL were searched from inception to February 2018. Experts were asked and meta-registries searched to identify ongoing trials. Study Selection: Pairs of reviewers identified randomized clinical trials comparing vasopressin in combination with catecholamine vasopressors to catecholamines alone for patients with distributive shock. Data Extraction and Synthesis: Two reviewers abstracted data independently. A random-effects model was used to combine data. Main Outcomes and Measures: The primary outcome was atrial fibrillation. Other outcomes included mortality, requirement for renal replacement therapy (RRT), myocardial injury, ventricular arrhythmia, stroke, and LOS in the intensive care unit and hospital. Measures of association are reported as risk ratios (RRs) for clinical outcomes and mean differences for LOS. Results: Twenty-three randomized clinical trials were identified (3088 patients; mean age, 61.1 years [14.2]; women, 45.3%). High-quality evidence supported a lower risk of atrial fibrillation associated with vasopressin treatment (RR, 0.77 [95% CI, 0.67 to 0.88]; risk difference [RD], -0.06 [95% CI, -0.13 to 0.01]). For mortality, the overall RR estimate was 0.89 (95% CI, 0.82 to 0.97; RD, -0.04 [95% CI, -0.07 to 0.00]); however, when limited to trials at low risk of bias, the RR estimate was 0.96 (95% CI, 0.84 to 1.11). The overall RR estimate for RRT was 0.74 (95% CI, 0.51 to 1.08; RD, -0.07 [95% CI, -0.12 to -0.01]). However, in an analysis limited to trials at low risk of bias, RR was 0.70 (95% CI, 0.53 to 0.92, P for interaction = .77). There were no significant differences in the pooled risks for other outcomes. Conclusions and Relevance: In this systematic review and meta-analysis, the addition of vasopressin to catecholamine vasopressors compared with catecholamines alone was associated with a lower risk of atrial fibrillation. Findings for secondary outcomes varied.