Intravenous iron in patients with iron deficiency and heart failure: a review of modern evidence.

PURPOSE OF REVIEW: Iron deficiency is common in patients with heart failure, affecting up to half of ambulatory patients and an even greater percentage of patients admitted for acute decompensation. Iron deficiency in this population is also associated with poor outcomes, including worse quality of life in addition to increased hospitalizations for heart failure and mortality. Evidence suggests that patients with iron deficiency in heart failure may benefit from repletion with IV iron. RECENT FINDINGS: In this review, we outline the etiology and pathophysiology of iron deficiency in heart failure as well as various iron formulations available. We discuss evidence for intravenous iron repletion with a particular focus on recent studies that have evaluated its effects on hospitalizations and mortality. Finally, we discuss areas of uncertainty and future study and provide practical guidance for iron repletion. SUMMARY: In summary, there is overwhelming evidence that intravenous iron repletion in patients with iron deficiency in heart failure is both beneficial and safe. However, further evidence is needed to better identify which patients would most benefit from iron repletion as well as the ideal repletion strategy.

Direct Oral Anticoagulants Versus Warfarin in the Treatment of Left Ventricular Thrombus.

BACKGROUND: Use of direct oral anticoagulants (DOACs) for the treatment of left ventricular (LV) thrombus has gained considerable interest. OBJECTIVE: We aimed to evaluate if DOACs are effective in the treatment of LV thrombus compared with warfarin. METHODS: We evaluated the medical records of patients diagnosed with a new LV thrombus at a tertiary medical center. The primary outcome was the composite of thrombus persistence, stroke, or systemic embolism. We adjusted for potential confounders using multiple logistic regression. The safety outcome was the composite of hemorrhagic stroke or bleeding requiring blood transfusion. RESULTS: A total of 129 patients were treated with warfarin and 22, with a DOAC. In unadjusted analysis, 54.3% of patients treated with warfarin met criteria for the efficacy outcome as compared with 40.9% of patients treated with a DOAC (P = 0.25). In adjusted analysis, no difference between groups was observed (odds ratio = 0.39; 95% CI = 0.14-1.06; P = 0.07 for DOAC vs warfarin). In all, 3.9% of patients treated with warfarin met safety criteria as compared with 4.5% of patients treated with a DOAC. A total of 8 patients in the warfarin group had a stroke or systemic embolism as compared with 0 patients in the DOAC group (P = 0.37). CONCLUSION AND RELEVANCE: Our data suggest that DOACs may be reasonable alternatives for treatment of LV thrombus. When added to the totality of available studies, this study demonstrates that the effectiveness of DOACs in LV thrombus remains uncertain. Randomized clinical trials are needed.

Methohexital-Induced Seizure in a Patient Undergoing Conscious Sedation.

BACKGROUND: Methohexital is a short-acting barbiturate used for procedural sedation in the emergency department (ED). As with other sedatives, adverse effects with methohexital include excess sedation and hypotension, but this agent can also lower the seizure threshold. We report a patient who developed a generalized seizure after administration of methohexital. CASE REPORT: A 60-year-old man presented to the ED by ambulance with chest pain and shortness of breath. Paramedics had administered adenosine for supraventricular tachycardia without conversion before arrival to the ED. He had no history of seizures. His initial vital signs in the ED included heart rate of 189 beats/min with a supraventricular rhythm, blood pressure 137/108 mm Hg, respiration 22 breaths/min, and oxygen saturation of 98% on room air. It was decided to attempt synchronized electrical cardioversion, and methohexital 1 mg/kg (120 mg) was administered over 2 min for moderate sedation. Within 15 s of methohexital administration, the patient developed a generalized seizure that lasted for 90 s. After seizure termination, he was successfully cardioverted, returned to his previous baseline level of consciousness within 20 min, and discharged without further problems with a follow-up referral to neurology. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Methohexital is a short-acting barbiturate used for moderate sedation. Its adverse effects are unique in that it can lower the seizure threshold in some patients. Alternative agents for sedation should be considered in individuals with possible seizure disorders.

Inflammation and NLRP3 Inflammasome Activation Initiated in Response to Pressure Overload by Ca2+/Calmodulin-Dependent Protein Kinase II δ Signaling in Cardiomyocytes Are Essential for Adverse Cardiac Remodeling.

BACKGROUND: Inflammation is associated with cardiac remodeling and heart failure, but how it is initiated in response to nonischemic interventions in the absence of cell death is not known. We tested the hypothesis that activation of Ca2+/calmodulin-dependent protein kinase II δ (CaMKIIδ) in cardiomyocytes (CMs) in response to pressure overload elicits inflammatory responses leading to adverse remodeling. METHODS: Mice in which CaMKIIδ was selectively deleted from CMs (cardiac-specific knockout [CKO]) and floxed control mice were subjected to transverse aortic constriction (TAC). The effects of CM-specific CaMKIIδ deletion on inflammatory gene expression, inflammasome activation, macrophage accumulation, and fibrosis were assessed by quantitative polymerase chain reaction, histochemistry, and ventricular remodeling by echocardiography. RESULTS: TAC induced increases in cardiac mRNA levels for proinflammatory chemokines and cytokines in ≤3 days, and these responses were significantly blunted when CM CaMKIIδ was deleted. Apoptotic and necrotic cell death were absent at this time. CMs isolated from TAC hearts mirrored these robust increases in gene expression, which were markedly attenuated in CKO. Priming and activation of the NOD-like receptor pyrin domain-containing protein 3 inflammasome, assessed by measuring interleukin-1ß and NOD-like receptor pyrin domain-containing protein 3 mRNA levels, caspase-1 activity, and interleukin-18 cleavage, were increased at day 3 after TAC in control hearts and in CMs isolated from these hearts. These responses were dependent on CaMKIIδ and associated with activation of Nuclear Factor-kappa B and reactive oxygen species. Accumulation of macrophages observed at days 7 to 14 after TAC was diminished in CKO and, by blocking Monocyte Chemotactic Protein-1 signaling, deletion of CM Monocyte Chemotactic Protein-1 or inhibition of inflammasome activation. Fibrosis was also attenuated by these interventions and in the CKO heart. Ventricular dilation and contractile dysfunction observed at day 42 after TAC were diminished in the CKO. Inhibition of CaMKII, Nuclear Factor-kappa B, inflammasome, or Monocyte Chemotactic Protein-1 signaling in the first 1 or 2 weeks after TAC decreased remodeling, but inhibition of CaMKII after 2 weeks did not. CONCLUSIONS: Activation of CaMKIIδ in response to pressure overload triggers inflammatory gene expression and activation of the NOD-like receptor pyrin domain-containing protein 3 inflammasome in CMs. These responses provide signals for macrophage recruitment, fibrosis, and myocardial dysfunction in the heart. Our work suggests the importance of targeting early inflammatory responses induced by CM CaMKIIδ signaling to prevent progression to heart failure.

Chronic inhalation of e-cigarette vapor containing nicotine disrupts airway barrier function and induces systemic inflammation and multiorgan fibrosis in mice.

Electronic (e)-cigarettes theoretically may be safer than conventional tobacco. However, our prior studies demonstrated direct adverse effects of e-cigarette vapor (EV) on airway cells, including decreased viability and function. We hypothesize that repetitive, chronic inhalation of EV will diminish airway barrier function, leading to inflammatory protein release into circulation, creating a systemic inflammatory state, ultimately leading to distant organ injury and dysfunction. C57BL/6 and CD-1 mice underwent nose only EV exposure daily for 3-6 mo, followed by cardiorenal physiological testing. Primary human bronchial epithelial cells were grown at an air-liquid interface and exposed to EV for 15 min daily for 3-5 days before functional testing. Daily inhalation of EV increased circulating proinflammatory and profibrotic proteins in both C57BL/6 and CD-1 mice: the greatest increases observed were in angiopoietin-1 (31-fold) and EGF (25-fold). Proinflammatory responses were recapitulated by daily EV exposures in vitro of human airway epithelium, with EV epithelium secreting higher IL-8 in response to infection (227 vs. 37 pg/ml, respectively; P < 0.05). Chronic EV inhalation in vivo reduced renal filtration by 20% ( P = 0.017). Fibrosis, assessed by Masson's trichrome and Picrosirius red staining, was increased in EV kidneys (1.86-fold, C57BL/6; 3.2-fold, CD-1; P < 0.05), heart (2.75-fold, C57BL/6 mice; P < 0.05), and liver (1.77-fold in CD-1; P < 0.0001). Gene expression changes demonstrated profibrotic pathway activation. EV inhalation altered cardiovascular function, with decreased heart rate ( P < 0.01), and elevated blood pressure ( P = 0.016). These data demonstrate that chronic inhalation of EV may lead to increased inflammation, organ damage, and cardiorenal and hepatic disease.

CaMKIIδ mediates ß-adrenergic effects on RyR2 phosphorylation and SR Ca(2+) leak and the pathophysiological response to chronic ß-adrenergic stimulation.

Chronic activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the deleterious effects of ß-adrenergic receptor (ß-AR) signaling on the heart, in part, by enhancing RyR2-mediated sarcoplasmic reticulum (SR) Ca(2+) leak. We used CaMKIIδ knockout (CaMKIIδ-KO) mice and knock-in mice with an inactivated CaMKII site S2814 on the ryanodine receptor type 2 (S2814A) to investigate the involvement of these processes in ß-AR signaling and cardiac remodeling. Langendorff-perfused hearts from CaMKIIδ-KO mice showed inotropic and chronotropic responses to isoproterenol (ISO) that were similar to those of wild type (WT) mice; however, in CaMKIIδ-KO mice, CaMKII phosphorylation of phospholamban and RyR2 was decreased and isolated myocytes from CaMKIIδ-KO mice had reduced SR Ca(2+) leak in response to isoproterenol (ISO). Chronic catecholamine stress with ISO induced comparable increases in relative heart weight and other measures of hypertrophy from day 9 through week 4 in WT and CaMKIIδ-KO mice, but the development of cardiac fibrosis was prevented in CaMKIIδ-KO animals. A 4-week challenge with ISO resulted in reduced cardiac function and pulmonary congestion in WT, but not in CaMKIIδ-KO or S2814A mice, implicating CaMKIIδ-dependent phosphorylation of RyR2-S2814 in the cardiomyopathy, independent of hypertrophy, induced by prolonged ß-AR stimulation.

Transitioning disopyramide to mavacamten in obstructive hypertrophic cardiomyopathy: A case series and clinical guide.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic disorder for which first-line treatments for obstructive HCM (oHCM) include beta-blockers, non-dihydropyridine calcium channel blockers, and disopyramide for refractory cases. Mavacamten, a selective cardiac myosin inhibitor, is indicated for symptomatic oHCM to improve functional capacity and symptoms. Use of disopyramide and mavacamten together is not recommended due to concerns of additive negative inotropic effects. Transitioning from disopyramide to mavacamten may be preferred to avoid adverse effects and frequent administration, however, the best approach for making the transition has not been established. CASES: We present a series of seven patients with oHCM who transitioned from disopyramide to mavacamten and underwent echocardiograms mandated by a Risk Evaluation and Mitigations Strategies program. Two methods were employed. The first approach, involving washout of disopyramide before starting mavacamten, resulted in worsening of heart failure symptoms in the first two cases. The second approach, involving tapering disopyramide when starting mavacamten, was successfully implemented in the last five cases, with no adverse effects or worsening of systolic dysfunction. CONCLUSION: Our method of tapering disopyramide when starting mavacamten using a stepwise approach is feasible and safe. Our report fulfills an unmet need by serving as a guide for other clinicians who seek to transition their patients from disopyramide to mavacamten.

Medical Therapies to Improve Left Ventricular Outflow Obstruction and Diastolic Function in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy-both obstructive hypertrophic cardiomyopathy (oHCM) and nonobstructive hypertrophic cardiomyopathy (nHCM) subtypes-is the most common monogenic cardiomyopathy. Its structural hallmarks are abnormal thickening of the myocardium and hyperdynamic contractility, while its hemodynamic consequences are left ventricular outflow tract or intracavitary obstruction (in oHCM) and diastolic dysfunction (in both oHCM and nHCM). Several medical therapies are routinely used to improve these abnormalities with the goal to decrease symptom burden in patients with HCM. Current guidelines recommend nonvasodilating beta blockers as first-line and nondihydropyridine calcium channel blockers followed by disopyramide as second- and third-line medical therapies for symptomatic oHCM and give weaker recommendations for beta blockers and calcium channel blockers in nHCM. These recommendations are based on small studies-mostly nonrandomized-and expert opinion. Our review will summarize the available data on the effectiveness of commonly prescribed medications used in oHCM and nHCM to uncover knowledge gaps, but also new data on cardiac myosin inhibitors.

Emerging Challenges to the Safe and Effective Use of Methadone for Cancer-Related Pain in Paediatric and Adult Patient Populations.

Methadone continues to be an important medication for the treatment of paediatric and adult cancer-related pain. Appropriate patient selection to ensure safe and effective treatment by a team of clinicians who appreciate and are familiar with methadone and its unique pharmacology is crucial. Unlike morphine and other more common opioids, methadone is purported to have involvement with delta-opioid receptor and higher affinity as an N-methyl-D-aspartate-receptor antagonist. Clinically this gives it the advantage of being effective for both nociceptive and neuropathic pain, but also may be useful in the setting of tolerance to other opioids. Methadone also comes in multiple available formulations that can be administrated through a variety of routes beyond the oral route. Challenges with methadone in treating cancer-related pain include drug interactions specifically as it relates to new targeted cancer therapies. Recent guidelines recommend electrocardiogram monitoring with methadone and there is potential for additive cardiac toxicity in the oncology setting. Appropriate dosing of methadone for pain management given age, organ dysfunction, and patients who are on methadone maintenance therapy are also key factors. This article aims to provide clinicians with evidence and clinical practice guidelines for safe and appropriate use of methadone including indication, initiation, and monitoring given its complexity for management of pain in the dynamic oncology setting.

The Enigma of Low-Dose Ketamine for Treatment of Opioid-Induced Hyperalgesia in the Setting of Psychosocial Suffering and Cancer-Associated Pain.

Opioid-induced hyperalgesia is a paradoxical adverse effect of opioid therapy with unclear strategies for its treatment and management. We report the successful use of low-dose ketamine infusion for the treatment of opioid-induced hyperalgesia in a 38-year-old woman presenting with psychosocial suffering and high opioid requirement secondary to pain from a poorly differentiated neuroendocrine tumor. Over the course of a month, her opioid requirement escalated to the gram level of oral morphine equivalents, upon which she was hospitalized at University of California San Diego Health for an acute on chronic pain crisis. Despite use of patient-controlled analgesia, her pain level remained unchanged for nearly 2 days after initiation of a low-dose ketamine infusion. The infusion ultimately allowed reduction of her opioid use to a third of her original daily requirement and improved her function and ability to interact for several days. Although her pain profile became increasingly complicated by psychosocial suffering and disease progression, she did not experience the same pain event for the remainder of her hospital course. Findings from this case report demonstrate the utility of low-dose ketamine infusion in opioid-induced hyperalgesia.

CaMKIIδ-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis.

Inflammation accompanies heart failure and is a mediator of cardiac fibrosis. CaMKIIδ plays an essential role in adverse remodeling and decompensation to heart failure. We postulated that inflammation is the mechanism by which CaMKIIδ contributes to adverse remodeling in response to nonischemic interventions. We demonstrate that deletion of CaMKIIδ in the cardiomyocyte (CKO) significantly attenuates activation of NF-κB, expression of inflammatory chemokines and cytokines, and macrophage accumulation induced by angiotensin II (Ang II) infusion. The inflammasome was activated by Ang II, and this response was also diminished in CKO mice. These events occurred prior to any evidence of Ang II-induced cell death. In addition, CaMKII-dependent inflammatory gene expression and inflammasome priming were observed as early as the third hour of infusion, a time point at which macrophage recruitment was not evident. Inhibition of either the inflammasome or monocyte chemoattractant protein 1 (MCP1) signaling attenuated macrophage accumulation, and these interventions, like cardiomyocyte CaMKIIδ deletion, diminished the fibrotic response to Ang II. Thus, activation of CaMKIIδ in the cardiomyocyte represents what we believe to be a novel mechanism for initiating inflammasome activation and an inflammatory gene program that leads to macrophage recruitment and ultimately to development of fibrosis.