Erik Fung

Adrenomedullin induces direct (endothelium-independent) vasorelaxations and cyclic adenosine monophosphate elevations that are synergistically enhanced by brain natriuretic peptide in isolated rings of rat thoracic aorta.

Our laboratory previously demonstrated that nitric oxide and natriuretic peptides can synergistically enhance cAMP elevations and vasorelaxations in rat aortic rings induced by calcitonin gene-related peptide, likely involving cyclic guanosine monophosphate (cGMP)–mediated inhibition of type-3 phosphodiesterase (PDE3). It was predicted that this cellular mechanism may also serve as a point of synergism between adrenomedullin (ADM) and brain natriuretic peptide (BNP) in aortic smooth muscle cells. The current study shows that ADM (100 n M)-induced vasorelaxations in isolated aortic rings of Sprague-Dawley rats are dependent on endothelium (34.1 ± 4.2% relaxation with endothelium versus 3.0 ± 0.6% relaxation without endothelium;P < 0.001). To determine interactions between ADM and BNP in smooth muscle cells without interference from endothelium-derived factors, further studies used aortic rings denuded of endothelium. Pretreatment with BNP (1 n M), which elevated cGMP levels 1.6 fold, uncovered direct vasorelaxant effects of ADM in endothelium-denuded rings, showing 5.6 ± 1.8%, 20.9 ± 6.1%, and 55 ± 9.4% relaxations with ADM at 1, 10, and 100 n M, respectively (n = 6). ADM (100 n M) significantly (P < 0.05) increased cyclic adenosine monophosphate (cAMP) levels in denuded aortic rings pretreated with BNP (1 n M), but not in denuded rings without BNP. Quazinone (20 &mgr;M), a PDE3 inhibitor, caused similar enhancement of direct cAMP elevations to ADM (100 n M). The data indicate vasodilatory synergism between ADM and BNP in aorta, likely mediated by enhanced accumulation of cAMP in smooth muscle cells resulting from BNP/cGMP–induced inhibition of PDE3. This synergistic mechanism may be especially important in subjects with dysfunctional endothelium, in which BNP may uncover direct vasorelaxant effects of ADM in arteries that normally require healthy (nitric oxide–releasing) endothelium for ADM-induced vasorelaxations to occur.

C-reactive protein and ageing

Increasing evidence shows that C‐reactive protein (CRP) is not only an inflammatory biomarker but also an important risk factor associated with ageing‐related diseases including cardiovascular disease, hypertension, diabetes mellitus, and kidney disease. Recent studies have demonstrated that CRP is pathogenic in a number of diseases including hypertensive cardiovascular and kidney complications, diabetic nephropathy, and acute and chronic kidney diseases. It is well known that CRP binds its receptor, CD32/CD64, to induce the process of inflammation by activating the NF‐κB signalling pathway. In addition, CRP mediates tissue fibrosis in a number of cardiovascular and kidney diseases by activating TGF‐β/Smad signalling via TGF‐β1‐dependent and independent mechanisms. Furthermore, CRP is able to activate mTOR signalling in the diabetic conditions. Our recent studies also revealed that CRP impairs cell regeneration by causing the G1 cell cycle arrest and promotes ageing via a Smad3‐dependent p21/p27 mechanism. In this review, we discuss the roles of CRP in ageing, with a focus on its function and mechanisms in physiological or “healthy” ageing, in ageing‐related diseases, and in cell signalling.

Deletion of Angiotensin-Converting Enzyme-2 Promotes Hypertensive Nephropathy by Targeting Smad7 for Ubiquitin DegradationNovelty and Significance

Angiotensin-converting enzyme-2 (ACE2) is downregulated in hypertensive nephropathy. The present study investigated the mechanisms whereby loss of ACE2 promoted angiotensin II–induced hypertensive nephropathy in ACE2 gene knockout mice. We found that compared with wild-type animals, mice lacking ACE2 developed much more severe hypertensive nephropathy in response to chronic angiotensin II infusion, including higher levels of blood pressure, urinary protein excretion, serum creatinine, and progressive renal fibrosis and inflammation. Mechanistic studies revealed that worsening kidney injury in ACE2 knockout mice was associated with an increase in Smurf2 (Smad-specific E3 ubiquitin protein ligase 2), a decrease in renal Smad7, and marked activation of TGF-&bgr; (transforming growth factor &bgr;)/Smad3 and NF-&kgr;B (nuclear factor &kgr;-light-chain-enhancer of activated B cells) signaling, suggesting that Smurf2-dependent Smad7 ubiquitin degradation may be a key mechanism whereby loss of ACE2 promotes angiotensin II–induced TGF-&bgr;/Smad3 and NF-&kgr;B–mediated hypertensive nephropathy. This was validated by restoring Smad7 locally in the kidneys of ACE2 knockout mice to block angiotensin II–induced TGF-&bgr;/Smad3-mediated renal fibrosis and NF-&kgr;B–driven renal inflammation. Moreover, we found that angiotensin II could induce microRNA-21 in the mouse kidney and in cultured mesangial cells via a Smad3-dependent mechanism, which was enhanced by deleting ACE2 but inhibited by overexpressing renal Smad7. In conclusion, loss of ACE2 promotes angiotensin II–induced renal injury by targeting Smad7 for degradation via a Smurf2-dependent mechanism. Overexpression of renal Smad7 protects against hypertensive nephropathy by inactivating angiotensin II–induced TGF-&bgr;/Smad3 and NF-&kgr;B pathways and by targeting the Smad3-dependent microRNA-21 axis.

The Regulatory T-cell Transcription Factor Foxp3 Protects against Crescentic Glomerulonephritis

Regulatory T cells (Tregs) have been shown to play a protective role in glomerulonephritis (GN) and Foxp3 is a master transcription factor in Treg development. In this study, we examined the functional role and mechanisms of Foxp3 in a mouse model of accelerated anti-glomerular basement membrane (anti-GBM) GN induced in antigen-primed Foxp3 transgenic (Tg) mice. Compared with littermate of wildtype (WT) mice in which induced severe crescentic GN developed with progressive renal dysfunction, Foxp3 Tg mice had reduced crescent formation, urinary protein excretion, plasma creatinine and decline in creatinine clearance. The protective role of Foxp3 in crescentic GN was associated with a markedly suppressed expression of proinflammatory interleukin-1 beta (IL-1β), tumour necrosis factor-alpha (TNF-α) and monocyte chemoattractant protein 1 (MCP-1), and diminished infiltration of the kidneys by CD3+ T cells and F4/80+ macrophages. Moreover, overexpression of Foxp3 resulted in a significant increase in CD4+ Foxp3+ Tregs systemically and in the diseased kidneys, thereby blunting Th1, Th2, and Th17 responses systemically and in the kidneys. In conclusion, Foxp3 protects against kidney injury in crescentic GN through enhancement of Treg numbers and function, and suppression of Th1, Th2 and Th17 immune responses at the systemic and local tissue levels.

Comorbidities, Fragility, and Quality of Life in Heart Failure Patients With Midrange Ejection Fraction

Objective To assess the effects of comorbidities, fragility, and quality of life (QOL) on long-term prognosis in ambulatory patients with heart failure (HF) with midrange left ventricular ejection fraction (HFmrEF), an unexplored area. Patients and Methods Consecutive patients prospectively evaluated at an HF clinic between August 1, 2001, and December 31, 2015, were retrospectively analyzed on the basis of left ventricular ejection fraction category. We compared patients with HFmrEF (n=185) to those with reduced (HFrEF; n=1058) and preserved (HFpEF; n=162) ejection fraction. Fragility was defined as 1 or more abnormal evaluations on 4 standardized geriatric scales (Barthel Index, Older Americans Resources and Services scale, Pfeiffer Test, and abbreviated-Geriatric Depression Scale). The QOL was assessed with the Minnesota Living with Heart Failure Questionnaire. A comorbidity score (0-7) was constructed. All-cause death, HF-related hospitalization, and the composite end point of both were assessed. Results Comorbidities and QOL scores were similar in HFmrEF (2.41±1.5 and 30.1±18.3, respectively) and HFrEF (2.30±1.4 and 30.8±18.5, respectively) and were higher in HFpEF (3.02±1.5, P<.001, and 36.5±20.7, P=.003, respectively). No statistically significant differences in fragility between HFmrEF (48.6%) and HFrEF (41.9%) (P=.09) nor HFpEF (54.3%) (P=.29) were found. In univariate analysis, the association of comorbidities, QOL, and fragility with the 3 end points was higher for HFmrEF than for HFrEF and HFpEF. In multivariate analysis, comorbidities were independently associated with the 3 end points (P≤.001), and fragility was independently associated with all-cause death and the composite end point (P<.001) in HFmrEF. Conclusion Comorbidities and fragility are independent predictors of outcomes in ambulatory patients with HFmrHF and should be considered in the routine clinical assessment of HFmrEF.

23 Anticoagulation for mechanical circulatory support

The success of mechanical circulatory support (MCS) hinges on appropriate anticoagulation. The delicate balance between clotting and bleeding remains challenging to achieve consistently in the post-operative period and requires an individualised approach, especially in patients with acquired warfarin resistance including those with latent malignancies who have failed different anticoagulant regimens. Anecdotal studies and a recent randomised controlled trial have shown that dabigatran is not an alternative to warfarin in this setting.1 2 Predicting clotting or bleeding risk can be informative but published data remain scarce. Whereas the CHA2DS2-VASc risk score has not been demonstrated to predict thromboembolism in patients with left ventricular assist device (LVAD), the HAS-BLED score may have potential for predicting bleeding.3 Although data from a pharmacogenetic study suggested that the AA genotype of VKORC1 (−1639 G>A; allele frequency of 12%) may confer advantage to appropriate warfarin anticoagulation as demonstrated by surrogate markers including decreased time to target international normalised ratio,4 there remains no one-size-fits-all strategy that is reliable and scalable. Perioperatively, the use of intravenous heparin remains the mainstay of anticoagulation at most centres that implant LVADs and/or utilise short-term MCS, and activated clotting time remains the most commonly used measure of anticoagulation. Alternatives to intravenous heparin include bivalirudin and argatroban, but data on their comparative efficacy and safety in MCS are limited. Moreover, these agents may not be available in national health systems of many Asian countries due to costs and, possibly, a difference in the epidemiology of heparin-induced thrombocytopaenia warranting their use. References . Yoshioka D, Toda K, Hidaka T, Yasuda S, Saito S, Domae K, Sawa Y. Anticoagulation therapy for a LVAD patient with acquired warfarin resistance. J Artif Organs2017;20:260–262. . Andreas M, Moayedifar R, Wieselthaler G, Wolzt M, Riebandt J, Haberl T, Angleitner P, Schlöglhofer T, Wiedemann D, Schima H, Laufer G, Zimpfer D. Increased thromboembolic events with dabigatran compared with vitamin K antagonism in left ventricular assist device patients. Circ Heart Fail2017;10:e003709. . Kemal HS, Ertugay S, Nalbantgil S, Ozturk P, Engin C, Yagdi T, Ozbaran M. Utility of CHA2DS2-VASc and HAS-BLED scores as predictor of thromboembolism and bleeding after left ventricular assist device implantation. ASAIO J2017;63:720–724. . Topkara VK, Knotts RJ, Jennings DL, Garan AR, Levin AP, Breskin A, Castagna F, Cagliostro B, Yuzefpolskaya M, Takeda K, Takayama H, Uriel N, Mancini DM, Eisenberger A, Naka Y, Colombo PC, Jorde UP. Effect of CYP2C9 and VKORC1 gene variants on warfarin response in patients with continuous-flow left ventricular assist devices. ASAIO J2016;62:558–564.

22 Supportive cardiology: an innovative practice model to integrate palliative care into the management of advanced heart failure

Despite advances in evidence-based treatment to improve survivorship of patients with heart failure, the progressive deteriorating disease trajectory results in an expanding cohort of patients with advanced disease stage. Patients with advanced heart failure experience persistent physical and psychosocial symptoms despite optimal medical therapy. Frequent disease exacerbations require repeated hospitalisations, which heavily reduce the quality of life of patients and their families, and burden the healthcare system. The World Health Organisation advocates palliative care to improve the quality of life of patients with life-limiting diseases. However, palliative care is under-used in heart failure patients. Heart failure is characterised by its unpredictable progression and blurred boundaries between curative and palliative therapy. Therefore, international guidelines advocate an urgent need for a new care model to introduce supportive and palliative care early and gradually along the disease trajectory, overlapping and complementing active curative therapy. Preliminary research evidence is emerging to support the beneficial effects of palliative care interventions on symptom burden, quality of life and hospital service utilisation among patients with advanced heart failure. However, most of the studies focused on separate consultation by physicians or nurses, rather than an integrated heart failure and palliative care service, or providing transitional care in addition to the hospital-based palliative care service. There is no study examining the effects of integration of palliative care into heart failure management. A nurse-coordinated integrated heart failure-palliative care model is proposed.

Heart Failure and Frailty in the Community-Living Elderly Population: What the UFO Study Will Tell Us

Heart failure and frailty are clinical syndromes that present with overlapping phenotypic characteristics. Importantly, their co-presence is associated with increased mortality and morbidity. While mechanical and electrical device therapies for heart failure are vital for select patients with advanced stage disease, the majority of patients and especially those with undiagnosed heart failure would benefit from early disease detection and prompt initiation of guideline-directed medical therapies. In this article, we review the problematic interactions between heart failure and frailty, introduce a focused cardiac screening program for community-living elderly initiated by a mobile communication device app leading to the Undiagnosed heart Failure in frail Older individuals (UFO) study, and discuss how the knowledge of pre-frailty and frailty status could be exploited for the detection of previously undiagnosed heart failure or advanced cardiac disease. The widespread use of mobile devices coupled with increasing availability of novel, effective medical and minimally invasive therapies have incentivized new approaches to heart failure case finding and disease management.

#Frailty: A snapshot Twitter report on frailty knowledge translation

The objectives of this short report are to: (i) explore #Frailty Twitter activity over a six‐month period; and (ii) provide a snapshot Twitter content analysis of #Frailty usage.