Background: Heart failure is characterized by physical and emotional symptoms and decreased quality of life (QoL). Palliative care can reduce burdens of serious illness but often is limited to inpatient or academic settings. Objectives: To develop and test the Primary Education for Nurses in Palliative care-HF (PENPal-HF) intervention, training outpatient cardiology nurses to address symptom burden, patient priorities for care and QoL, and advance care planning as part of quarterly HF visits. Methods: We conducted a pilot randomized clinical trial for adults with NYHA Stage III or IV HF and >= 2 hospitalizations in the past 12 months, recruited from a community-based cardiology clinic. Participants were randomized 2:1, PENPal-HF plus usual care versus usual care alone. Primary outcomes were feasibility and acceptability. Results: We randomized 30 adults with Stage III HF - 20 to PENPal-HF and 10 to usual care. Most in the intervention group (71%) and in the control group (62%) completed the study through the final outcome assessment in week 56; 5 participants died. Of 20 participants in the intervention, 14 (70%) remained in the study through the end of intervention visits; 11 (55%) completed all visits. Most intervention participants (93.75%) agreed or strongly agreed that they were satisfied with their care, and 87.5% agreed or strongly agreed that all people with HF should receive the intervention. Most intervention group participants (93.75%) reported a perceived improvement in physical symptoms, mood, and/or QoL. Conclusions: This pilot study suggests that nurse-led primary palliative care in outpatient cardiology settings is promising. Research is warranted to determine efficacy and effectiveness. (c) 2022 Elsevier Inc. All rights reserved.

Purpose Heart failure (HF) is a common, debilitating disease that decreases both longevity and leads to decreased quality of life. Palliative care is a clinical subspecialty, and overall approach to care, that emphasizes alleviation of suffering through symptom management, psychosocial support, and assistance with complex treatment decision-making. Despite recommendations from major cardiology societies, specialty palliative care remains underutilized in HF. Accordingly major cardiology societies have called for clinicians without specialty palliative care training to deliver basic palliative competencies (i.e., “primary” palliative care), such as symptom management and goals-of-care elicitation. It is unclear what non-palliative care specialists caring for patients with HF view as barriers and facilitators to delivering primary palliative care. Methods We conducted semi-structured phenomenological interviews with physicians, nurses, and physician assistants caring for patients with HF across the United States, recruited through a snowball convenience sample. Interview topics included: 1) a hypothetical treatment strategy for an advanced HF patient with significant unmet palliative needs; 2) knowledge and attitudes regarding the role of both primary and specialty palliative care in HF; and, 3) barriers and facilitators of primary palliative care integration in standard HF management. Two analysts independently coded data using template analysis, a hybrid inductive/deductive qualitative technique. Results We interviewed 18 clinicians: 4 physicians and 2 advanced practice providers from primary care, cardiology, and palliative care specialties. 61% were female, 89% Caucasian, average age was 43, and the median years in practice, 12. We identified several barriers to primary palliative care integration including 1) structural and organizational barriers like time constraints; 2) attitudinal barriers, such as discomfort addressing goals-of-care; and 3) educational deficits including a perceived lack of training in primary palliative care skills (e.g., symptom management, difficult communication). Clinicians of all non-palliative specialties interviewed desired training in these skills. Conclusion Many clinician-perceived barriers to the provision of primary palliative care in HF may be addressed through education regarding symptom management and advance care planning communication. Others, such as time constraints and organizational barriers, may be reduced through normalizing and integrating palliative care as a natural facet of standard HF management. While clinician respondents endorsed integrating primary palliative care into routine HF care, randomized trials are needed to establish the effectiveness of primary palliative care interventions, including HF primary palliative care curricula.

Stress-induced p38 mitogen-activated protein kinase (MAPK) activity is implicated in pathological remodeling in the heart. For example, constitutive p38 MAPK activation in cardiomyocytes induces pathological features, including myocyte hypertrophy, apoptosis, contractile dysfunction, and fetal gene expression. However, the physiological function of cardiomyocyte p38 MAPK activity in beneficial compensatory vascular remodeling is unclear. This report investigated the functional role and the underlying mechanisms of cardiomyocyte p38 MAPK activity in cardiac remodeling induced by chronic stress. Using both in vitro and in vivo model systems, we found that p38 MAPK activity is required for hypoxia-induced pro-angiogenic activity from cardiomyocytes and that p38 MAPK activation in cardiomyocyte is sufficient to promote paracrine signaling-mediated, pro-angiogenic activity. We further demonstrate that VEGF is a paracrine factor responsible for the p38 MAPK-mediated pro-angiogenic activity from cardiomyocytes and that p38 MAPK pathway activation is sufficient for inducing VEGF secretion from cardiomyocytes in an Sp1-dependent manner. More significantly, cardiomyocyte-specific inactivation of p38α in mouse heart impaired compensatory angiogenesis after pressure overload and promoted early onset of heart failure. In summary, p38αMAPK has a critical role in the cross-talk between cardiomyocytes and vasculature by regulating stress-induced VEGF expression and secretion in cardiomyocytes. We conclude that as part of a stress-induced signaling pathway, p38 MAPK activity significantly contributes to both pathological and compensatory remodeling in the heart.

In cardiac myocytes, excitation-contraction coupling depends upon sarcoplasmic reticular Ca2+ release triggered by Ca2+ influx through L-type Ca2+ channels. Although Na+-Ca2+ exchange (NCX) is essential for Ca2+ extrusion, its participation in the trigger process of excitation-contraction coupling is controversial. To investigate the role of NCX in triggering, we examined Ca2+ sparks in ventricular cardiomyocytes isolated from wild-type (WT) and cardiac-specific NCX knockout (KO) mice. Myocytes from young NCX KO mice are known to exhibit normal resting cytosolic Ca2+ and normal Ca2+ transients despite reduced L-type Ca2+ current. We loaded myocytes with fluo-3 to image Ca2+ sparks using confocal microscopy in line-scan mode. The frequency of spontaneous Ca2+ sparks was reduced in KO myocytes compared with WT. However, spark amplitude and width were increased in KO mice. Permeabilizing the myocytes with saponin eliminated differences between spontaneous sparks in WT and KO mice. These results suggest that sarcolemmal processes are responsible for the reduced spark frequency and increased spark width and amplitude in KO mice. When myocytes were loaded with 1 mM fluo-3 and 3 mM EGTA via the patch pipette to buffer diadic cleft Ca2+, the number of sparks triggered by action potentials was reduced by 60% in KO cells compared to WT cells, despite similar SR Ca2+ content in both cell types. When EGTA was omitted from the pipette solution, the number of sparks triggered in KO and WT myocytes was similar. Although the number of sparks was restored in KO cells, Ca2+ release was asynchronous. These results suggest that high subsarcolemmal Ca2+ is required to ensure synchronous triggering with short spark latency in the absence of NCX. In WT mice, high subsarcolemmal Ca2+ is not required for synchronous triggering, because NCX is capable of priming the diadic cleft with sufficient Ca2+ for normal triggering, even when subsarcolemmal Ca2+ is lowered by EGTA. Thus, reducing subsarcolemmal Ca2+ with EGTA in NCX KO mice reveals the dependence of Ca2+ release on NCX.

Among the myriad of intracellular signaling networks that govern the cardiac development and pathogenesis, mitogen-activated protein kinases (MAPKs) are prominent players that have been the focus of extensive investigations in the past decades. The four best characterized MAPK subfamilies, ERK1/2, JNK, p38, and ERK5, are the targets of pharmacological and genetic manipulations to uncover their roles in cardiac development, function, and diseases. However, information reported in the literature from these efforts has not yet resulted in a clear view about the roles of specific MAPK pathways in heart. Rather, controversies from contradictive results have led to a perception that MAPKs are ambiguous characters in heart with both protective and detrimental effects. The primary object of this review is to provide a comprehensive overview of the current progress, in an effort to highlight the areas where consensus is established verses the ones where controversy remains. MAPKs in cardiac development, cardiac hypertrophy, ischemia/reperfusion injury, and pathological remodeling are the main focuses of this review as these represent the most critical issues for evaluating MAPKs as viable targets of therapeutic development. The studies presented in this review will help to reveal the major challenges in the field and the limitations of current approaches and point to a critical need in future studies to gain better understanding of the fundamental mechanisms of MAPK function and regulation in the heart.

The p38 mitogen-activated protein kinases (p38s) are stress-activated Ser/Thr kinases. Their activation has been associated with various pathological stressors in the heart. Activated p38 is implicated in a wide spectrum of cardiac pathologies, including hypertrophy, myocardial infarction, as well as systolic and diastolic heart failure. In this review, the specific contribution of different isoforms of p38 kinases to cardiac diseases as well as TAB-1-mediated non-canonical activation pathway are discussed as a rationale for inhibiting p38 activity to treat cardiac hypertrophy, ischemic injury, and heart failure. Finally, a summary of current clinical trials targeting p38 kinases in cardiovascular diseases is provided to highlight the potential promise as well as existing challenges of this therapeutic approach. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."

During periods of stress, the heart undergoes a number of physiological and molecular changes. These changes occur through the activation or inhibition of various signaling pathways and take place not only in cardiac myocytes but also the surrounding cells such as endothelial cells, fibroblasts, and inflammatory cells. Communication between these various cells types allows for changes on the cellular level to be translated to changes at the organ level. Previous studies have shown the need for balance between myocyte demand and vascular supply. Inadequate vasculature during periods of increased work load has been shown to lead to functional changes in the myocardium. The exact nature of how this balance is achieved has yet to be elucidated. p38 MAP kinase, a stress activated kinase, is a well studied signaling pathway associated with cardiac function. While its specific role is still somewhat controversial, it has been implicated in myocyte apoptosis, hypertrophy, proliferation and contractility. While previous studies have focused only on myocytes, it remains to be determined what role p38 plays in cell-cell communication. To address this issue, we have investigated the role p38 signaling plays in myocyte-endothelial cell cross talk. Using myocyte specific p38 knockout animals, we have demonstrated that in response to pressure overload, the KO animals showed a significant decrease in vascular marker expression compared to their WT littermates as assessed by quantitative real-time PCR and immunohistochemial analyses. This attenuated vascular induction was also accompanied by a greater loss of function in the KO animals. To better understand this, we have begun to study this myocyte-endothelial communication in vitro. Using conditioned media from neonatal rat ventricular myocytes applied to endothelial cells in a 3D gel culture, we have shown that over activation of p38 in myocytes leads to increased cell growth in cultured endothelial cells. This is accompanied by a significant increase in VEGF mRNA levels in the myocytes with p38 over activation. This indicates that p38 plays a role in myocyte-endothelial cell communication. Therefore, we hypothesize that p38 signaling in myocytes is contributing to cross-talk with the endothelial cells via secreted paracrine factors and that disruption in the myocyte stress response signaling mediated by p38 can lead to detrimental vascular deficiency in stressed myocardium.