The pivotal role of heme Oxygenase-1 in reversing the pathophysiology and systemic complications of NAFLD.

The pathogenesis and molecular pathways involved in non-alcoholic fatty liver disease (NAFLD) are reviewed, as well as what is known about mitochondrial dysfunction that leads to heart disease and the progression to steatohepatitis and hepatic fibrosis. We focused our discussion on the role of the antioxidant gene heme oxygenase-1 (HO-1) and its nuclear coactivator, peroxisome proliferator-activated receptor-gamma coactivator (PGC1-α) in the regulation of mitochondrial biogenesis and function and potential therapeutic benefit for cardiac disease, NAFLD as well as the pharmacological effect they have on the chronic inflammatory state of obesity. The result is increased mitochondrial function and the conversion of white adipocyte tissue to beige adipose tissue ("browning of white adipose tissue") that leads to an improvement in signaling pathways and overall liver function. Improved mitochondrial biogenesis and function is essential to preventing the progression of hepatic steatosis to NASH and cirrhosis as well as preventing cardiovascular complications.

EET enhances renal function in obese mice resulting in restoration of HO-1-Mfn1/2 signaling, and decrease in hypertension through inhibition of sodium chloride co-transporter.

BACKGROUND: We have previously reported that epoxyeicosatrienoic acid (EET) has multiple beneficial effects on renal and adipose tissue function, in addition to its vasodilatory action; it increases insulin sensitivity and inhibits inflammation. In an examination of the signaling mechanisms by which EET reduces renal and peri-renal fat function, we hypothesized that EET ameliorates obesity-induced renal dysfunction by improving sodium excretion, reducing the sodium-chloride cotransporter NCC, lowering blood pressure, and enhancing mitochondrial and thermogenic gene levels in PGC-1α dependent mice. METHODS: EET-agonist treatment normalized glucose metabolism, renal ENaC and NCC protein expression, urinary sodium excretion and blood pressure in obese (db/db) mice. A marked improvement in mitochondrial integrity, thermogenic genes, and PGC-1α-HO-1-adiponectin signaling occurred. Knockout of PGC-1α in EET-treated mice resulted in a reversal of these beneficial effects including a decrease in sodium excretion, elevation of blood pressure and an increase in the pro-inflammatory adipokine nephroblastoma overexpressed gene (NOV). In the elucidation of the effects of EET on peri-renal adipose tissue, EET increased adiponectin, mitochondrial integrity, thermogenic genes and decreased NOV, i.e. "Browning' peri-renal adipose phenotype that occurs under high fat diets. Taken together, these data demonstrate a critical role of an EET agonist in the restoration of healthy adipose tissue with reduced release of inflammatory molecules, such as AngII and NOV, thereby preventing their detrimental impact on sodium absorption and NCC levels and the development of obesity-induced renal dysfunction.

EET intervention on Wnt1, NOV, and HO-1 signaling prevents obesity-induced cardiomyopathy in obese mice.

We have previously reported that epoxyeicosatrienoic acid (EET) has multiple beneficial effects on vascular function; in addition to its antiapoptotic action, it increases insulin sensitivity and inhibits inflammation. To uncover the signaling mechanisms by which EET reduces cardiomyopathy, we hypothesized that EET infusion might ameliorate obesity-induced cardiomyopathy by improving heme oxygenase (HO)-1, Wnt1, thermogenic gene levels, and mitochondrial integrity in cardiac tissues and improved pericardial fat phenotype. EET reduced levels of fasting blood glucose and proinflammatory adipokines, including nephroblastoma overexpressed (NOV) signaling, while increasing echocardiographic fractional shortening and O2 consumption. Of interest, we also noted a marked improvement in mitochondrial integrity, thermogenic genes, and Wnt 1 and HO-1 signaling mechanisms. Knockout of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in EET-treated mice resulted in a reversal of these beneficial effects including a decrease in myocardial Wnt1 and HO-1 expression and an increase in NOV. To further elucidate the effects of EET on pericardial adipose tissues, we observed EET treatment increases in adiponectin, PGC-1α, phospho-AMP-activated protein kinase, insulin receptor phosphorylation, and thermogenic genes, resulting in a "browning" pericardial adipose phenotype under high-fat diets. Collectively, these experiments demonstrate that an EET agonist increased Wnt1 and HO-1 signaling while decreasing NOV pathways and the progression of cardiomyopathy. Furthermore, this report presents a portal into potential therapeutic approaches for the treatment of heart failure and metabolic syndrome.NEW & NOTEWORTHY The mechanism by which EET acts on obesity-induced cardiomyopathy is unknown. Here, we describe a previously unrecognized function of EET infusion that inhibits nephroblastoma overexpressed (NOV) levels and activates Wnt1, hence identifying NOV inhibition and enhanced Wnt1 expression as novel pharmacological targets for the prevention and treatment of cardiomyopathy and heart failure.Listen to this article's corresponding podcast at http://ajpheart.physiology.org/content/early/2017/05/31/ajpheart.00093.2017.

Heme-oxygenase and lipid mediators in obesity and associated cardiometabolic diseases: Therapeutic implications.

Obesity-mediated metabolic syndrome remains the leading cause of death worldwide. Among many potential targets for pharmacological intervention, a promising strategy involves the heme oxygenase (HO) system, specifically its inducible form, HO-1. This review collects and updates much of the current knowledge relevant to pharmacology and clinical medicine concerning HO-1 in metabolic diseases and its effect on lipid metabolism. HO-1 has pleotropic effects that collectively reduce inflammation, while increasing vasodilation and insulin and leptin sensitivity. Recent reports indicate that HO-1 with its antioxidants via the effect of bilirubin increases formation of biologically active lipid metabolites such as epoxyeicosatrienoic acid (EET), omega-3 and other polyunsaturated fatty acids (PUFAs). Similarly, HO-1and bilirubin are potential therapeutic targets in the treatment of fat-induced liver diseases. HO-1-mediated upregulation of EET is capable not only of reversing endothelial dysfunction and hypertension, but also of reversing cardiac remodeling, a hallmark of the metabolic syndrome. This process involves browning of white fat tissue (i.e. formation of healthy adipocytes) and reduced lipotoxicity, which otherwise will be toxic to the heart. More importantly, this review examines the activity of EET in biological systems and a series of pathways that explain its mechanism of action and discusses how these might be exploited for potential therapeutic use. We also discuss the link between cardiac ectopic fat deposition and cardiac function in humans, which is similar to that described in obese mice and is regulated by HO-1-EET-PGC1α signaling, a potent negative regulator of the inflammatory adipokine NOV.

Criteria for Referral of Patients With Advanced Heart Failure for Specialized Palliative Care.

BACKGROUND: Patients with advanced heart failure have substantial supportive care needs. Specialist palliative care can be beneficial, but it is unclear who is most appropriate for referral and when patients should be referred. OBJECTIVES: We conducted a Delphi study of international experts to identify consensus referral criteria for specialist palliative care for patients with advanced heart failure. METHODS: Clinicians from 5 continents with expertise in the integration of cardiology and palliative care were asked to rate 34 disease-based, 24 needs-based, and 9 time-based criteria over 3 rounds. Consensus was defined a priori as ≥70% agreement. A criterion was coded as major if the experts endorsed that meeting that criterion alone was adequate to justify a referral. RESULTS: The response rate was 44 of 46 (96%), 41 of 46 (89%), and 43 of 46 (93%) in the first, second, and third rounds, respectively. Panelists reached consensus on 25 major criteria for specialist palliative care referral. The 25 major criteria were categorized under 6 topics, including "advanced/refractory heart failure, comorbidities, and complications" (eg, cardiac cachexia, cardiorenal syndrome) (n = 8), "advanced heart failure therapies" (eg, chronic inotropes, precardiac transplant) (n = 4), "hospital utilization" (eg, emergency room visits, hospitalization) (n = 2), "prognostic estimate" (n = 1), "symptom burden/distress" (eg, severe physical/emotional/spiritual distress) (n = 6), and "decision making/social support" (eg, goals-of-care discussions) (n = 4). The majority (68%) of major criteria had ≥90% agreement. CONCLUSIONS: International experts reached consensus on a large number of criteria for referral to specialist palliative care. With further validation, these criteria may be useful for standardizing palliative care access in the inpatient and/or outpatient settings.

Referral Criteria to Palliative Care for Patients With Heart Failure: A Systematic Review.

BACKGROUND: Patients with heart failure have significant symptom burden, care needs, and often a progressive course to end-stage disease. Palliative care referrals may be helpful but it is currently unclear when patients should be referred and by whom. We conducted a systematic review of the literature to examine referral criteria for palliative care among patients with heart failure. METHODS: We searched Ovid, MEDLINE, Ovid Embase, and PubMed databases for articles in the English language from the inception of databases to January 17, 2019 related to palliative care referral in patients with heart failure. Two investigators independently reviewed each citation for inclusion and then extracted the referral criteria. Referral criteria were then categorized thematically. RESULTS: Of the 1199 citations in our initial search, 102 articles were included in the final sample. We identified 18 categories of referral criteria, including 7 needs-based criteria and 10 disease-based criteria. The most commonly discussed criterion was physical or emotional symptoms (n=51 [50%]), followed by cardiac stage (n=46 [45%]), hospital utilization (n=38 [37%]), prognosis (n=37 [36%]), and advanced cardiac therapies (n=36 [35%]). Under cardiac stage, 31 (30%) articles suggested New York Heart Association functional class ≥III and 12 (12%) recommended New York Heart Association class ≥IV as cutoffs for referral. Prognosis of ≤1 year was mentioned in 21 (21%) articles as a potential trigger; few other criteria had specific cutoffs. CONCLUSIONS: This systematic review highlighted the lack of consensus regarding referral criteria for the involvement of palliative care in patients with heart failure. Further research is needed to identify appropriate and timely triggers for palliative care referral.

Heme Oxygenase-1 Upregulation: A Novel Approach in the Treatment of Cardiovascular Disease.

Significance: Heme oxygenase (HO) plays a pivotal role in both vascular and metabolic functions and is involved in many physiological and pathophysiological processes in vascular endothelial cells (ECs) and adipocytes. Recent Advances: From the regulation of adipogenesis in adipose tissue to the adaptive response of vascular tissue in the ECs, HO plays a critical role in the capability of the vascular system to respond and adjust to insults in homeostasis. Recent studies show that HO-1 through regulation of adipocyte and adipose tissue functions ultimately aid not only in local but also in systemic maintenance of homeostasis. Critical Issues: Recent advances have revealed the existence of a cross talk between vascular ECs and adipocytes in adipose tissue. In the pathological state of obesity, this cross talk contributes to the condition's adverse chronic effects, and we propose that specific targeting of the HO-1 gene can restore signaling pathways and improve both vascular and adipose functions. Future Directions: A complete understanding of the role of HO-1 in regulation of cardiovascular homeostasis is important to comprehend the homeostatic regulation as well as in cardiovascular disease. Efforts are required to highlight the effects and the ability to target the HO-1 gene in models of obesity with an emphasis on the role of pericardial fat on cardiovascular health.

Incidence of new stroke or new myocardial infarction or death at 39-month follow up in patients with diabetes mellitus, hypertension, or both treated with and without angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.

We investigated in 306 patients, mean age 57 ± 10 years, with diabetes mellitus (202 patients) or hypertension (179 patients), whether treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ARBs) reduced the incidence of new stroke or new myocardial infarction (MI) or death. At 39-month follow up, new stroke or new MI or death developed in 49 of 228 patients (21%) treated with ACE inhibitors or ARBs and in 33 of 78 patients (42%) treated without angiotensin-converting enzyme inhibitors or ARBs (P = 0.0001). Stepwise Cox regression analysis showed that significant independent predictors of the time to development of new stroke or new MI or death were 1) use of angiotensin-converting enzyme inhibitors or ARBs (risk ratio, 0.21), 2) diabetes (risk ratio, 4.01), 3) left ventricular hypertrophy (risk ratio, 6.71), 4) prior stroke (risk ratio, 4.00), and 5) prior MI (risk ratio, 3.69).

Cardioprotective Heme Oxygenase-1-PGC1α Signaling in Epicardial Fat Attenuates Cardiovascular Risk in Humans as in Obese Mice.

OBJECTIVE: This study investigated whether levels of signaling pathways and inflammatory adipokines in epicardial fat regulate cardiovascular risks in humans and mice. METHODS: Epicardial fat was obtained from the hearts of patients with heart failure requiring coronary artery bypass surgery, and signaling pathways were compared with visceral fat. The genetic profile of epicardial and visceral fat from humans was also compared with genetic profiles of epicardial and visceral fat in obese mice. Left ventricular (LV) fractional shortening was measured in obese mice before and after treatment with inducers of mitochondrial signaling heme oxygenase 1 (HO-1)-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). An RNA array/heat map on 88 genes that regulate adipose tissue function was used to identify a target gene network. RESULTS: Human epicardial fat gene profiling showed decreased levels of mitochondrial signaling of HO-1-PGC1α and increased levels of the inflammatory adipokine CCN family member 3. Similar observations were seen in epicardial and visceral fat of obese mice. Improvement in LV function was linked to the increase in mitochondrial signaling in epicardial fat of obese mice. CONCLUSIONS: There is a link between cardiac ectopic fat deposition and cardiac function in humans that is similar to that which is described in obese mice. An increase of mitochondrial signaling pathway gene expression in epicardial fat attenuates cardiometabolic dysfunction and LV fractional shortening in obese mice.

Heme oxygenase-mediated increases in adiponectin decrease fat content and inflammatory cytokines tumor necrosis factor-alpha and interleukin-6 in Zucker rats and reduce adipogenesis in human mesenchymal stem cells.

Adiponectin, an abundant adipocyte-derived plasma protein that modulates vascular function in type 2 diabetes, has been shown to provide cytoprotection to both pancreatic and vascular systems in diabetes. Therefore, we examined whether up-regulation of heme oxygenase (HO)-1 ameliorates the levels of inflammatory cytokines and influences serum adiponectin in Zucker fat (ZF) rats. ZF rats displayed a decrease in both HO activity and HO-1 and HO-2 protein levels and an increase in tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 compared with Zucker lean (ZL) rats. Treatment of ZF animals with 2 mg/kg cobalt protoporphyrin IX (CoPP) increased protein levels of HO-1 and HO activity, but HO-2 was unaffected. The increase in HO-1 was associated with a decrease in superoxide levels (p < 0.05) and an increase in plasma adiponectin (p < 0.005), compared with untreated ZF rats. CoPP treatment decreased visceral and s.c. fat content, and it reduced weight gain (p < 0.01). In addition, the inflammatory cytokines TNF-alpha and IL-6 were decreased (p < 0.04 and p < 0.008, respectively). Treatment of human bone marrow-derived adipocytes cultured with CoPP resulted in an increase in HO-1 and a decrease in superoxide levels. Up-regulation of HO-1 caused adipose remodeling, smaller adipocytes, and increased adiponectin secretion in the culture medium of human bone marrow-derived adipocytes. In summary, this study demonstrates that the antiobesity effect of HO-1 induction results in an increase in adiponectin secretion, in vivo and in vitro, a decrease in TNF-alpha and IL-6, and a reduction in weight gain. These findings highlight the pivotal role and symbiotic relationship of HO-1 and adiponectin in the modulation of the metabolic syndrome phenotype.

Comparison of prevalence of >70% diameter narrowing of one or more major coronary arteries in patients with versus without mitral annular calcium and clinically suspected coronary artery disease.

The prevalence of >70% narrowing of 1, 2, or 3 major coronary arteries and of 3 major coronary arteries was investigated in 2,465 patients (1,437 men, 1,028 women; mean age 69 +/- 13 years) with severe, moderate, mild, or no mitral annular calcium (MAC) diagnosed by 2-dimensional echocardiography who underwent coronary angiography for suspected coronary artery disease. Greater than 70% narrowing of 1, 2, or 3 major coronary arteries was present in 259 of 315 patients (82%) with severe MAC (group 1), in 835 of 1,052 patients (79%) with moderate or mild MAC (group 2), and in 756 of 1,098 patients (69%) with no MAC (group 3) (p <0.001 comparing group 1 with group 3 and group 2 with group 3). Greater than 70% narrowing of 3 major coronary arteries was present in 149 of 315 patients (47%) in group 1, in 366 of 1,052 patients (35%) in group 2, and in 325 of 1,098 patients (30%) in group 3 (p <0.001 comparing group 1 with group 3 and group 1 with group 2; p <0.01 comparing group 2 with group 3). In conclusion, MAC is associated with obstructive >or=1-vessel coronary artery disease and with obstructive 3-vessel coronary artery disease.

Incidence of new stroke or new myocardial infarction or death at 39-month follow-up in patients with diabetes mellitus, hypertension or both with and without microalbuminuria.

We investigated in 306 patients, mean age 57 +/- 10 years, with diabetes mellitus (202 patients) or hypertension (179 patients) whether microalbuminuria was a significant independent risk factor for the development of new stroke or new myocardial infarction (MI) or death. At 39-month follow-up, new stroke or new MI or death developed in 44 of 111 patients (40%) with microalbuminuria and in 38 of 195 patients (19%) without microalbuminuria (p = 0.0001). Stepwise Cox regression analysis showed that significant independent predictors of the time to development of new stroke or new MI or death were (1) diabetes (risk ratio = 1.76), (2) left ventricular (LV) mass index (risk ratio = 1.020 for each 1 g/m(2) increase), (3) prior stroke (risk ratio = 5.39), and (4) prior MI (risk ratio = 3.29). Microalbuminuria was not a significant independent predictor of new stroke or new MI or death, but LV mass index, diabetes mellitus, prior stroke, and prior MI were significant independent predictors.

Differences of lateral and septal mitral annulus velocity by tissue Doppler imaging in the evaluation of left ventricular diastolic function.

Left ventricular diastolic dysfunction (LVDD) was investigated in 276 outpatients at a university cardiology practice by tissue Doppler imaging of mitral valve annular velocity. The well-investigated parameters of mitral inflow were used as the standard. Using septal E/Ea ratios, 62 patients (22%) had no LVDD, 44 patients (16%) had mild LVDD, 126 patients (46%) had moderate LVDD, 25 patients (9%) had severe LVDD, and 19 patients (7%) had indeterminate LVDD. Using lateral E/Ea ratios, 131 patients (48%) had no LVDD, 40 patients (14%) had mild LVDD, 62 patients (22%) had moderate LVDD, 9 patients (3%) had severe LVDD, and 12 patients (13%) had indeterminate LVDD. In conclusion, the use of septal tissue Doppler imaging tends to overestimate the severity of LVDD compared with the use of lateral tissue Doppler imaging.

Increased prevalence of coronary artery disease, silent myocardial ischemia, complex ventricular arrhythmias, atrial fibrillation, left ventricular hypertrophy, mitral annular calcium, and aortic valve calcium in patients with chronic renal insufficiency.

Cardiovascular morbidity and mortality is high in patients with chronic renal insufficiency. Patients with chronic renal insufficiency have an increased prevalence of coronary artery disease, silent myocardial ischemia, complex ventricular arrhythmias, atrial fibrillation, left ventricular hypertrophy, mitral annular calcium, and aortic valve calcium than patients with normal renal function. These risk factors for cardiovascular morbidity and mortality contribute to the increased incidence of cardiovascular morbidity and mortality seen in patients with chronic renal insufficiency.

Prevalence and prognosis of intrapulmonary shunts in patients with hepatic cirrhosis.

We investigated the prevalence of intrapulmonary shunts in 82 patients with hepatic cirrhosis referred for echocardiography as part of liver transplantation evaluation. Intrapulmonary shunts were present in 49 of 82 patients (60%). Baseline characteristics were similar in patients with and without intrapulmonary shunts. Mean follow up was 41 +/- 15 months in patients with intrapulmonary shunts and 42 +/- 15 months in patients without intrapulmonary shunts (P not significant). At follow up, 8 of 49 patients (16%) with intrapulmonary shunts and 4 of 33 patients (12%) without intrapulmonary shunts had died (P not significant).

Epoxyeicosatrienoic Acid as Therapy for Diabetic and Ischemic Cardiomyopathy.

Cardiovascular disease remains the leading cause of death worldwide. Among many potential targets for pharmacological intervention, a promising strategy involves epoxyeicosatrienoic acid (EET) and soluble epoxide hydroxylase (sEH) inhibition. sEH is the enzyme that converts EET to its less potent metabolite; therefore, EET is upregulated by its inhibitor. EET has pleotropic effects that collectively reduce inflammation, while increasing vasodilation and insulin sensitivity. Recent reports indicate that EET agonists and sEH inhibitors are capable of not only reversing endothelial dysfunction and hypertension, but also of reversing cardiac remodeling, which is a hallmark of cardiomyopathy and the metabolic syndrome. EET agonists and sEH inhibitors are in development as potential therapies, and at least one drug is already in clinical trials. This review examines the activity of EET in biological systems, proposes a series of pathways to explain its mechanism of action, and discusses how these might be exploited for potential therapeutic use.

Relation of decreased ankle-brachial index to prevalence of atherosclerotic risk factors, coronary artery disease, aortic valve calcium, and mitral annular calcium.

Coronary artery disease was present in 89 of 118 patients (75%) with a decreased ankle-brachial index (ABI) and in 34 of 118 age- and gender-matched patients (29%) with a normal ABI (p <0.001). Aortic valve calcium or mitral annular calcium was present in 81 of 118 patients (69%) with a decreased ABI and in 43 of 118 patients (36%) with a normal ABI (p <0.001).

Prevalence of valve calcium and association of valve calcium with coronary artery disease, atherosclerotic vascular disease, and all-cause mortality in 137 patients undergoing hemodialysis for chronic renal failure.

Of 137 patients (mean age 63 years) who underwent hemodialysis for chronic renal failure, 65 (47%) had mitral valve calcium, mitral annular calcium, or aortic valve calcium. Thirty-eight of 65 patients (59%) who had valve calcium died at 3.5-year follow-up versus 21 of 72 patients (29%) who did not have valve calcium and who died at 4.3-year follow-up (p = 0.0005).