Misconceptions and Facts about Heart Failure with Reduced Ejection Fraction.

Heart failure with reduced ejection fraction is a significant driver of morbidity and mortality. There are common misconceptions regarding the disease processes underlying heart failure and best practices for therapy. The terms heart failure with reduced ejection fraction and left ventricular systolic dysfunction are not interchangeable terms. Key therapies for heart failure with reduced ejection fraction target the underlying disease processes, not the left ventricular ejection fraction alone. The absence of congestion does not rule out heart failure. Patients with cardiac amyloidosis can also present with heart failure with reduced ejection fraction. A rise in serum creatinine in acute heart failure exacerbation is not associated with tubular injury. Guideline directed medical therapy should be continued during acute exacerbations of heart failure with reduced ejection fraction and should be started in the same hospitalization in new diagnoses. Marginal blood pressure is not a relative contraindication to optimal guideline directed medical therapy. Guideline directed medical therapy should be continued even if ejection fraction improves. There are other therapies that provide significant benefit besides the four key medications in guideline directed medical therapy.

Association Between Social Vulnerability Index and Cardiovascular Disease: A Behavioral Risk Factor Surveillance System Study.

Background Social and environmental factors play an important role in the rising health care burden of cardiovascular disease. The Centers for Disease Control and Prevention developed the Social Vulnerability Index (SVI) from US census data as a tool for public health officials to identify communities in need of support in the setting of a hazardous event. SVI (ranging from a least vulnerable score of 0 to a most vulnerable score of 1) ranks communities on 15 social factors including unemployment, minoritized groups status, and disability, and groups them under 4 broad themes: socioeconomic status, housing and transportation, minoritized groups, and household composition. We sought to assess the association of SVI with self-reported prevalent cardiovascular comorbidities and atherosclerotic cardiovascular disease (ASCVD). Methods and Results We performed a retrospective cohort analysis of adults (≥18 years) in the Behavioral Risk Factor Surveillance System 2016 to 2019. Data regarding self-reported prevalent cardiovascular comorbidities (including diabetes, hypertension, hyperlipidemia, smoking, substance use), and ASCVD was captured using participants' response to a structured telephonic interview. We divided states on the basis of the tertile of SVI (first-participant lives in the least vulnerable group of states, 0-0.32; to third-participant lives in the most vulnerable group of states, 0.54-1.0). Multivariable logistic regression models adjusting for age, race and ethnicity, sex, employment, income, health care coverage, and association with federal poverty line were constructed to assess the association of SVI with cardiovascular comorbidities. Our study sample consisted of 1 745 999 participants ≥18 years of age. States in the highest (third) tertile of social vulnerability had predominantly Black and Hispanic adults, lower levels of education, lower income, higher rates of unemployment, and higher rates of prevalent comorbidities including hypertension, diabetes, chronic kidney disease, hyperlipidemia, substance use, and ASCVD. In multivariable logistic regression models, individuals living in states in the third tertile of SVI had higher odds of having hypertension (odds ratio (OR), 1.14 [95% CI, 1.11-1.17]), diabetes (OR, 1.12 [95% CI, 1.09-1.15]), hyperlipidemia (OR, 1.09 [95% CI, 1.06-1.12]), chronic kidney disease (OR, 1.17 [95% CI, 1.12-1.23]), smoking (OR, 1.05 [95% CI, 1.03-1.07]), and ASCVD (OR, 1.15 [95% CI, 1.12-1.19]), compared with those living in the first tertile of SVI. Conclusions SVI varies across the US states and is associated with prevalent cardiovascular comorbidities and ASCVD, independent of age, race and ethnicity, sex, employment, income, and health care coverage. SVI may be a useful assessment tool for health policy makers and health systems researchers examining multilevel influences on cardiovascular-related health behaviors and identifying communities for targeted interventions pertaining to social determinants of health.

Premature Atherosclerotic Cardiovascular Disease: What Have We Learned Recently?

PURPOSE OF REVIEW: In contrast to patients with non-premature atherosclerotic cardiovascular disease (ASCVD), patients with premature ASCVD have not observed a similar decline in cardiovascular mortality and recurrent adverse events. We sought to review the underlying risk factors, potential gaps in medical management, associated outcomes, and tools for risk prognostication among patients with premature ASCVD. RECENT FINDINGS: In addition to traditional cardiovascular risk factors (i.e., diabetes, familial hypercholesterolemia), non-traditional risk factors such as chronic inflammatory conditions, recreational drug use, genetics, and pregnancy-related complications play a key role in development and progression of premature ASCVD. Patients with premature ASCVD, and especially women, receive less optimal medical management as compared to their non-premature counterparts. There is an increasing prevalence of cardiovascular risk factors among young adults. Hence, this population remains at an elevated risk for premature ASCVD and subsequent adverse cardiovascular events. Future studies evaluating different risk assessment tools and focusing on young patients across all three major domains of ASCVD are needed.

A case of biventricular failure after pericardial window for large pericardial effusion.

Pericardial tamponade resulting in hemodynamic compromise requiring either pericardiocentesis [Vandyke 1983] or subxiphoid pericardial window has been reported in literature [Armstrong 1984]. There are no large case series, only scattered case reports. Cardiac tamponade is known to affect the diastolic function of the heart but rare reports have documented systolic impairment of the left and right ventricle in the setting of tamponade [Vandyke 1983; Armstrong 1984]. We report a case of a transient biventricular systolic dysfunction in a patient with early cardiac tamponade after surgical drainage of pericardia1 effusion.

Post-operative intrapericardial hematoma presenting as isolated right atrial tamponade.

A 57-year-old male underwent mechanical mitral valve replacement for severe mitral regurgitation of a prolapsed myxomatous mitral valve. The patient's post-operative recovery period was uneventful until the eighth day when he decompensated into pulseless electrical activity arrest. A bedside transthoracic echocardiogram revealed a large, smooth-edged mass nearly obliterating the right atrial cavity. Color Doppler demonstrated flow within the right atrium around the mass. After computed tomography scan showed that an intrapericardial hematoma was extrinsically compressing the right atrium, the patient underwent emergent mediastinal exploration with evacuation of 700 ml of coagulated blood. The patient made a full recovery. .

Nuclear factor-kappaB protects the adult cardiac myocyte against ischemia-induced apoptosis in a murine model of acute myocardial infarction.

BACKGROUND: Previous studies have shown that tumor necrosis factor (TNF) confers cytoprotective responses in cardiac myocytes. However, the mechanisms for the cytoprotective effects of TNF remain unknown. Given that TNF signals through nuclear factor kappaB (NF-kappaB) and given that NF-kappaB mediates cytoprotective responses, we asked whether NF-kappaB activation conferred cytoprotective responses in acute myocardial ischemia/infarction. METHODS AND RESULTS: We examined infarct size and the prevalence of apoptosis in transgenic mice harboring cardiac-restricted expression of a mutated IkappaBalpha protein (IkappaBalphaDeltaN) that prevents nuclear translocation of NF-kappaB in cardiac myocytes. Triphenyltetrazolium chloride staining showed that infarct size was approximately 50% greater (P<0.02) in the IkappaBalphaDeltaN mice compared with littermate controls at 24 hours. The prevalence of cardiac myocyte apoptosis was significantly greater (P<0.008) in the IkappaBalphaDeltaN mice compared with the littermate control mice 3 and 6 hours after left anterior descending occlusion. To explore the mechanism for these findings, we examined protein levels of c-IAP1, c-IAP2, and Bcl-2 as well as manganese superoxide dismutase and c-Jun NH2-terminal kinase activity. These studies showed that protein levels of c-IAP1 and Bcl-2 were significantly lower in the IkappaBalphaDeltaN mice, whereas there was no change in c-IAP2 levels, manganese superoxide dismutase, or c-Jun NH2-terminal kinase activity. CONCLUSIONS: Transgenic mice with a defect in activation of NF-kappaB have increased susceptibility to tissue injury after acute left anterior descending occlusion. These studies suggest that the cytoprotective effects of NF-kappaB are mediated, at least in part, by Bcl-2 or c-IAP1.

Inflammatory mediators and the failing heart: a translational approach.

Recent studies have identified the importance of proinflammatory mediators in regulating cardiac structure in health and disease. Recent studies suggest that cytokines that are expressed within the myocardium in response to a environmental injury, namely tumor necrosis factor-alpha (TNF), interleukin-1 (IL-1) and the interleukin-6 (IL-6) family of cytokines play an important role in initiating and integrating homeostatic responses within the heart. However, these "stress-activated" cytokines all have the potential to produce cardiac decompensation when expressed at sufficiently high concentrations. Indeed, there is now a growing appreciation that these molecules may play an important role in mediating disease progression in the failing heart. The growing appreciation of the pathophysiological consequences of sustained expression of proinflammatory mediators in pre-clinical and clinical heart failure models culminated in a series of multicenter clinical trials that utilized "targeted" approaches to neutralize tumor necrosis factor (TNF) in patients with moderate to advanced heart failure. However, these targeted approaches have resulted in worsening heart failure, thereby raising a number of important questions about what role, if any, proinflammatory cytokines play in the pathogenesis of heart failure. This review will summarize the tremendous growth of knowledge that has taken place in this field, with a focus on what we have learned from the negative clinical trials, as well as the potential direction of future research in this area.

CD14-deficient mice are protected against lipopolysaccharide-induced cardiac inflammation and left ventricular dysfunction.

BACKGROUND: The molecular mechanisms responsible for sepsis-induced myocardial dysfunction remain undefined. CD14 mediates the inflammatory response to lipopolysaccharide (LPS) in various organs including the heart. In this study we investigated the role of CD14 in LPS-induced myocardial dysfunction in vivo. METHODS AND RESULTS: Wild-type and CD14-deficient (CD14-D) mice were challenged with Escherichia coli LPS. Myocardial tumor necrosis factor, interleukin-1beta (IL-1beta), and NOS2 induction was measured before and 6 hours after LPS challenge. Echocardiographic parameters of left ventricular function were measured before and 6 hours after LPS administration. LPS challenge induced a significant increase in myocardial tumor necrosis factor and IL-1beta mRNA and protein expression in wild-type mice. In contrast, mRNA and protein levels for TNF and IL-1beta were significantly blunted in CD14-D mice. An increase in NOS2 protein was noted within 6 hours of LPS provocation only in the hearts of wild-type mice. This was associated with an increase in ventricular cGMP levels. Activation of nuclear factor-kappaB was observed within 30 minutes of LPS in the hearts of wild-type mice but not in CD14-D mice. In wild-type mice, LPS significantly decreased left ventricular fractional shortening, velocity of circumferential shortening, and dP/dt(max). LPS-treated CD14-D mice maintained normal cardiac function. CONCLUSIONS: These results suggest that CD14 is important in mediating the proinflammatory response induced by LPS in the heart and that CD14 is necessary for the development of left ventricular dysfunction during LPS-induced shock in vivo.

Cardiac inflammation and innate immunity in septic shock: is there a role for toll-like receptors?

Our current understanding of the pathogenesis of sepsis suggests that bacteria as well as bacterial-derived products activate an uncontrolled network of host-derived mediators such as proinflammatory cytokines (ie, tumor necrosis factor [TNF] and interleukin [IL]-1beta), which can ultimately lead to cardiovascular collapse and death. Despite the potentially important role that TNF and IL-1beta may play in producing cardiac dysfunction in human septic shock, little is known with regard to the basic biochemical mechanism(s) by which bacterial pathogens induce their expression in the heart. A major advance in understanding the early events that are downstream from bacterial-mediated signaling has been the identification of Toll-like receptors (TLRs). TLR-mediated signaling is known to activate the transcription factor nuclear factor-kappaB and to upregulate TNF expression. It has recently been shown that the heart expresses TLRs, raising the possibility that these receptors may be responsible for mediating the deleterious effects of bacterial pathogens on cardiac function. In this review, we will discuss the emerging role for TLRs in the pathogenesis of the cardiovascular collapse that occurs during sepsis.

Myotrophin/V-1, a protein up-regulated in the failing human heart and in postnatal cerebellum, converts NFkappa B p50-p65 heterodimers to p50-p50 and p65-p65 homodimers.

Myotrophin/V-1 is a cytosolic protein found at elevated levels in failing human hearts and in postnatal cerebellum. We have previously shown that it disrupts nuclear factor of kappaB (NFkappaB)-DNA complexes in vitro. In this study, we demonstrated that in HeLa cells native myotrophin/V-1 is predominantly present in the cytoplasm and translocates to the nucleus during sustained NFkappaB activation. Three-dimensional alignment studies indicate that myotrophin/V-1 resembles a truncated IkappaBalpha without the signal response domain (SRD) and PEST domains. Co-immunoprecipitation studies reveal that myotrophin/V-1 interacts with NFkappaB proteins in vitro; however, it remains physically associated only with p65 and c-Rel proteins in vivo during NFkappaB activation. In vitro studies indicate that myotrophin/V-1 can promote the formation of p50-p50 homodimers from monomeric p50 proteins and can convert the preformed p50-p65 heterodimers into p50-p50 and p65-p65 homodimers. Furthermore, adenovirus-mediated overexpression of myotrophin/V-1 resulted in elevated levels of both p50-p50 and p65-p65 homodimers exceeding the levels of p50-p65 heterodimers compared with Adbetagal-infected cells, where the levels of p50-p65 heterodimers exceeded the levels of p50-p50 and p65-p65 homodimers. Thus, overexpression of myotrophin/V-1 during NFkappaB activation resulted in a qualitative shift by quantitatively reducing the level of transactivating heterodimers while elevating the levels of repressive p50-p50 homodimers. Correspondingly, overexpression of myotrophin/V-1 resulted in significantly reduced kappaB-luciferase reporter activity. Because myotrophin/V-1 is found at elevated levels during NFkappaB activation in postnatal cerebellum and in failing human hearts, this study cumulatively suggests that myotrophin/V-1 is a regulatory protein for modulating the levels of activated NFkappaB dimers during this period.