Γυναίκα 75 ετών με σακχαρώδη διαβήτη, αρτηριακή υπέρταση και καρδιακή ανεπάρκεια με κλάσμα εξώθησης 50% Χριστίνα Χρυσοχόου

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1 Γυναίκα 75 ετών με σακχαρώδη διαβήτη, αρτηριακή υπέρταση και καρδιακή ανεπάρκεια με κλάσμα εξώθησης 50% Χριστίνα Χρυσοχόου

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3 Περιστατικό 70 ετών γυναίκα, Υ=155 cm, ΣΒ=70kg ΣΔ υπο μετφορμίνη 850mg x2 ΑΥ ramipril 5mg, metroptolol 50mg, coumadin 2mg, furosemide 20mg Εικόνα ΟΠΟ AF 145b/min, ΑΠ: 150/60mmHg Urea=38 mg/dl, create=1,1mg/dl, Hb=11mg/dl, NtproBNP=3100 pg/ml Gly=180mg/dl, Hba1c=7,5%

4 70-year old woman presented with acute pulmonary edema and AF 145b/min 150/60mmHg

5 Ποια είναι η αρχική σας προσέγγιση Α. Χορήγηση φουροσεμίδης 80mg B. Χορήγηση φουροσεμίδης 40mg και IV νιτρώδη Γ. Χορήγηση φουροσεμίδης 40mg, β- αποκλειστή και IV νιτρώδη Δ. Χορήγηση φουροσεμίδης 40mg, δακτυλίτιδα και IV νιτρώδη Ε. Ηλεκτρική ανάταξη

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7 Πορεία ασθενούς Εγινε χορήγηση φουροσεμίδης 40mg, δακτυλίτιδα και IV νιτρώδη Ετέθη σε φουροσεμίδη 40mg x2, tb digoxin, metoprolol (2 ο 24ωρο) Η ασθενής εμφανίζει αύξηση ουρίας σε 55 mg/dl, create=1,3 mg/dl Μήπως ο ασθενής μας είναι υπερδιουρημένος?

8 Pathophysiological crosstalk between kidney and heart Ronco C, et al. JACC 2012;60: Heart Fail Rev ; 20(1):

9 Ορισμός με βάση το κλάσμα εξώθησης αλλα με βασικό κριτήριο τα συμπτώματα ενώ ο ορισμός επεκτείνεται και σε υψηλά ΚΕ.

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11 A prospective evaluation of the established criteria for heart failure with preserved ejection fraction using the Alberta HEART cohort For the diagnosis of HF-PEF, the positive likelihood ratios were 6.1, 6.9, and 4.8 for the Zile, European Society of Cardiology (ESC) 2007, and ESC 2016 criteria, respectively All three criteria lacked sensitivity to detect HF-PEF (46.5%, 44.1%, and 51.8%, respectively) but were highly specific (92.4%, 93.9%, and 89%, respectively ESC Heart Failure 2018; 5: 19 26

12 Aetiology of HF across ranges of EF

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15 Translational studies have reported low myocardial cgmp content in human HFpEF biopsies; low cgmp production may be the key perturbation in HFpEF, rather than excess cgmp breakdown, explaining the neutral result. PARAGON study?? Since PDE-5 inhibitors improve outcomes in patients with pulmonary arterial hypertension, theoretically targeting patients with HFpEF who have severe pulmonary vascular disease (combined precapillary and postcapillary pulmonary hypertension) may produce a different result.

16 Hypertensive and ischaemic aetiologies for heart failure with reduced (HFrEF), mid-range (HFmrEF), and preserved ejection fraction (HFpEF) in four recent studies. European Journal of Heart Failure (2017) 19,

17 The therapeutic phenotype of chronic heart failure European Heart Journal (2019) 40,

18 Deterioration in right ventricular structure and function over time in patients with heart failure and preserved ejection fraction

19 Ποια από τις παρακάτω θεραπείες έχει δείξει όφελος στην HFpEF? Α. Σπιρονολακτόνη Β. αμεα-αυα Γ. Νιτρώδη Δ. Χαμηλές δόσεις διουρητικών Ε. Καμία θεραπεία

20 Therapy and prognosis of heart failure with a left ventricular ejection fraction >40% (HFmrEF/HFpEF) TOPCAT, higher NTproBNP was associated with a worse prognosis but the treatment benefit was greatest in the lowest-risk tertile(<682ng/l). Irbesartan in HFmrEF/HFpEF (I-PRESERVE) showed a progressive increase in morbidity and mortality with increasing plasma concentrations of NTproBNP. Irbesartan did not improve prognosis overall Trials of nitrates and nitrites in HFpEF have been neutral Only a small number of studies validated the use of echocardiographic parameters in HFpEF. Of all studied parameters, E/e showed the best, albeit modest correlation with invasive measurements of elevated left ventricular filling pressure. Both LAVI, LVMI, E/e and e provide limited additional value for predicting mortality when taken individually. INDIE-HFpEF randomized clinical trial. JAMA 2018;320: European Journal of Heart Failure 2018

21 Τι θα προτείνατε για την κολπική μαρμαρυγή Α. Ηλεκτρική ανάταξη Β. κατάλυση πνευμονικών φλεβών (Ablation) Γ. ελεγχο ρυθμού Δ. καταλυση κολποκοιλιακού κόμβου και εμφύτευση βηματοδότη

22 Atrial fibrillation CABANA study showed neutral effects (EHF congress 2018) N Engl J Med 2018;378:

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25 Zakeri R, Cowie MR. Heart 2018;0:1 8.

26 Σακχαρώδης διαβήτης και καρδιακή ανεπάρκεια

27 Left ventricular ejection fraction and other metrics of risk European Heart Journal (2016) 37, An equivalent risk for death or heart failure in a diabetic patient with an LVEF of 40% and in a non-diabetic patient with an LVEF of 25%

28 Echo and heart failure: when do people need an echo, and when do they need natriuretic peptides? In excluded heart failure by GP In HF patients with atrial fibrillation In right heart failure Caution in obese patients.. In HFmEF (symptoms and heart structure) Why EF seems normal although systolic function is impaired in HFmEF? Progression is characterized by continuous impairment in longitudinal deformation. LVEF decreases at a point when circumferential function also starts to decline. Echo research and practice 2018

29 Επιμήκης Συστολική παραμόρφωση αριστερής κοιλίας

30 EMPA-Heart Cardiolink-6 Η μελέτη EMPA-Heart Cardiolink-6 ανέδειξε ότι η θεραπεία με τον sodium glucose cotransporter-2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) σχετίζεται με ευεργετικές επιδράσεις στην αριστερή κοιλία (δομή και λειτουργία) σε ασθενείς με καρδιαγγειακή νόσο και σακχαρώδη διαβήτη τύπου 2. Η μελέτη συμπεριέλαβε 100 ασθενείς που τυχαιοποιήθηκαν στην empagliflozin 10 mg/day για 6 μήνες και έδειξε σημαντική μείωση της μάζας της αριστερής κοιλίας, της συστολικής αρτηριακής πίεσης, αύξηση του αιματοκρίτη σε αυτούς που έλαβαν το φάρμακο. Διούρηση ή αύξηση κετονών και καλύτερη διαχείριση ενέργειάς ή επίδραση στην καρβονική ανυδράση και πρόκληση μηωσμωτικής διούρησης?

31 Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes Dapagliflozin is a selective inhibitor of sodium glucose cotransporter 2 (SGLT2) that blocks glucose resorption in the proximal tubule of the kidney and promotes glucosuria H μελέτη DECLARE-TIMI 58 μελέτησε ασθενείς με καρδιαγγειακή νόσο και σακχαρώδη διαβήτη τυπου 2 που έλαβαν τον SGLT2 inhibitor dapagliflozin (Farxiga/Forxiga, AstraZeneca) για 4,2 έτη. Η μελέτη συμπεριέλαβε ασθενείς χωρις ιστορικό καρδιαγγειακής νόσου και 7000 ασθενείς με προ-υπάρχουσα νόσο. Στο πρωτογενές καταληκτικό σημείο η dapagliflozin πληρούσε το κριτήριο της μη-κατωτερότητας για τα MACE. Στις δυο αναλύσεις αποτελεσματικότητας δεν έδειξε λιγότερη συχνότητα MACE (8.8% dapagliflozin και 9.4 στο εικονικό φάρμακο; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P = 0.17) αλλά έδειξε λιγότερη συχνότητα καρδιαγγειακού θανάτου και νοσηλειών για καρδιακή ανεπάρκεια, ενώ δεν υπήρχε διαφορά στον ολικό θάνατο. Η διαβητική οξέωση και οι λοιμώξεις στην γεννητική περιοχή ήταν συχνότερες με την dapagliflozin από το εικονικό φάρμακο. November 10, 2018, at NEJM.org.

32 Αναιμία

33 Total and Functional Iron Deficiency 1. Απόλυτη σιδηροπενία (Μείωση των αποθηκών σιδήρου) Αίτια: Χρόνιες απώλειες αίματος, κακή διατροφή, σύνδρομα δυσαπορρόφησης Διάγνωση: χαμηλά επίπεδα φερριτίνης ορού <30 μg/l 2. Λειτουργική σιδηροπενία (Διαταραχές στο μεταβολισμό του σιδήρου στο μυελό των οστών φυσιολογικά ή αυξημένα επίπεδα φερριτίνης) Αίτια: Χρόνια φλεγμονή και νεφρική δυσλειτουργία Διάγνωση: Φερριτίνη ορού μg/l ή φερριτίνη ορού μg/lκαι TSAT< 20% Wish JB. Clin J Am Soc Nephrol 2006;1:S4-8, Munoz M, et al. World J Gastroenterol 2009;15:

34 RES: reticulo-endothelial system, FP: ferroportin, TfR: transferrin receptor, Tf: transferrin, PPI: proton pump inhibitors, IL-6: interleukin 6.

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36 The pathophysiology of iron deficiency in chronic inflammation. Increased cytokine levels in all conditions, and decreased renal clearance in CKD and CHF, result in enhanced hepcidin levels. High hepcidin levels bind, internalize and degrade ferroportin on the lateral membrane of duodenal enterocytes and spleen macrophages. Iron remains trapped in enterocytes, which are then shed in the gut. Iron is also sequestered into macrophages, which are responsible for destroying senescent red blood cells and recycling their iron. Serum ferritin levels are regulated by the iron content of macrophages and increase in inflammation (apoferritin as an acute-phase protein). A decrease in circulating iron leads to lower amounts of iron bound to the iron carrier protein, transferrin, and subsequently to a decline in transferrin saturation and low iron supply to all organs. Furthermore, cytokines may also have negative effects on erythropoietin production in the kidney and erythroid cell maturation, while also increasing macrophage iron retention. Note that the increased iron losses that can occur in specific chronic inflammatory conditions are not illustrated here. Plus and minus signs represent increase/enhancement and decrease, respectively. Am J Hematol. 2017;92:

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38 Q3. How anemia leads to heart failure? A. Promoting Left ventricular hypertrophy B. Causing kidney dysfunction C. Promoting cardiac fibrosis D. Causing cardiac remodeling E. All the above

39 Fractional area (%) Iron deficiency reduced contractile force by 43% (P<0.05) Subsequent addition of transferrin-bound iron could reverse this effect Control 4 days iron deficient 4 days Iron deficient + transferrin-bound iron Time (s) 4 5 6

40 Q3. How anemia leads to heart failure? A. Promoting Left ventricular hypertrophy B. Causing kidney dysfunction C. Promoting cardiac fibrosis D. Causing cardiac remodeling E. All the above

41 Screening, diagnosis of iron deficiency in chronic heart failure: putting the 2016 European Society of Cardiology heart failure guidelines into clinical practice Ferritin is an intracellular iron-storage protein secreted by iron-storing tissues (e.g. liver and reticuloendothelial system). Serum ferritin concentrations are a surrogate marker of stored iron quantity. TSAT(defined as % of transferrin that has iron bound to it) is used as a marker of the availability of circulating iron to supply metabolizing cells. TSAT value is calculated by dividing the serum iron concentration by the total iron-binding capacity (TIBC): TSAT (%) =Serum iron (μg dl)/ TIBC (μg dl) (x100%) European Journal of Heart Failure (2018

42 Practical recommendations on the screening and diagnosis of iron deficiency in patients with heart failure European Journal of Heart Failure (2018) Anemia evaluation : Class I indication

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44 From NP-driven treatment to individualization Cardiovasc Ultrasound. 2014; 12: 27.

45 Intolerance in HFpEF It is debatable whether exercise intolerance in HFpEF is predominantly due to impaired cardiac, chronotropic or peripheral vascular reserve LV filling occurs at lower heart rates, although excess rate lowering may exacerbate chronotropic incompetence in HFpEF. The If blocker, ivabradine, variably demonstrated improved, worsened or no effect on exercise capacity, quality of life and BNP in phase II HFpEF trials. Pulmonary vasodilation may improve pulmonary hypertension in HFpEF Cardiopulmonary exercise test may differentiate HFpEF from pulmonary disease

46 Reframing the association and significance of co-morbidities in heart failure European Journal of Heart Failure (2016) 18,

47 Obesity and Heart Failure: Can Nutritional Status Explain the Paradoxical Relationship? JACC 2002

48 Obesity and failing Heart Obesity exacerbates cardiac dysfunction along with hypertrophy by further triggering mtorser2448/p70s6kthr389 in the failing heart. worsens cardiac insulin resistance and causes a further reduction in basal and insulin-stimulated cardiac glucose oxidation rates that are seen in heart failure. results in an excessive reliance of the failing heart on fatty acid oxidation as a source of ATP production Weight loss (either by switching to a LF diet or by restricting caloric intake) in obese mice with heart failure improves cardiac function and decreases cardiac hypertrophy. enhances the IRS1Tyr628/AktSer473/GSK-3ßSer9 signaling pathway and limits the acetylation of pyruvate dehydrogenase. enhances insulin sensitivity along with basal and insulin-stimulated glucose oxidation in obese mice with heart failure. improves cardiac ATP production in obese failing heart mainly through enhancing the contribution of glucose oxidation to ATP production Front Cardiovasc Med. 2018;5:68 JACC: Basic to Transl Sci. 2017

49 Weight loss in Heart Failure The prevalence of obesity in HFrEF is between 30-40% and HFpEF about 40-55% In patients with HF with moderate degrees of obesity (BMI <35 kg/m2), weight loss cannot be recommended. In more advanced obesity (BMI kg/m2), weight loss may be considered to manage symptoms and exercise capacity. In a model of high fat diet induced obesity and diastolic dysfunction, lowering body weight by switching mice to a low fat diet improves cardiac insulin sensitivity and function Four randomized controlled trials and seven observational studies were included in a meta-analysis which showed increased heterogeneity The observational studies, five of which reported on outcomes following bariatric surgery, despite being small, heterogeneous and high risk of bias, suggested a trend in improvement of left ventricular function, quality of life and exercise capacity following weight loss. Two randomized studies reported improvement in exercise capacity and quality of life. One reported improvement in New York Heart Association functional class in heart failure with preserved ejection fraction Obesity Reviews 19, , September 2018

50 Weight Loss for Heart Failure Management A target weight loss of at least 5%-10% is recommended (AHA) for individuals with BMI 35 kg/m2 Bariatric surgery has emerged as an effective and durable strategy for achieving large degrees of weight loss in eligible candidates. No specific weight loss diet recommended. It is usual to recommend a negative energy balance of kcal/d or absolute intake of kcal/d diet for women and kcal/d for men, aiming for a loss of 1-2 lb/wk. Among weight loss pharmacotherapies Lorcaserin is a centrally acting selective serotonin receptor agonist (5HT2B receptor) that may be overexpressed in HF, so caution is recommended in this population. Recent lorcaserin cardiovascular safety study reported no excess of cardiovascular or HF events compared with placebo in a population with obesity and cardiovascular disease or risk factors, although NYHA functional class III/IV HF and LVEF <20% were excluded. In selected patients with BMI >35 kg/m2and NYHA functional class II/III HF with or without an LVAD, whose eligibility for cardiac transplantation depends on weight loss, bariatric surgery can be considered Studies are needed Nutrition, Obesity, and Cachexia in Patients With Heart Failure: A Consensus Statement from the Heart Failure Society of America Scientific Statements Committee Journal of Cardiac Failure Vol. 00 No

51 Cachexia and Sarcopenia Cachexia is a complex metabolic wasting syndrome characterized by unintentional edema-free weight loss (muscle mass loss, with or without fat mass loss), anorexia, inflammation and abnormal biochemistry (10%): increased inflammatory markers CRP (>5.0 mg/l), IL-6 >4.0 pg/ml, Anemia (<12 g/dl) Low serum albumin (<3.2 g/dl) Sarcopenia is the age-related decline in skeletal muscle mass, function and quality, which can be accelerated by medical comorbidities (20%) Cardiac cachexia, sarcopenia, insulin resistance, low serum cholesterol, and low albumin are all predictors of adverse clinical outcomes in HF Nutrition, Obesity, and Cachexia in Patients With Heart Failure: A Consensus Statement from the Heart Failure Society of America Scientific Statements Committee Journal of Cardiac Failure Vol. 00 No

52 Potential treatments of cachexia appetite stimulants, exercise training anabolic agents, including testosterone, in combination with the application of nutritional supplements and anti-catabolic interventions, although none is of proven benefit and their safety is unknown ghrelin agonists as candidates for the reversal of cachexia and sarcopenia. Mirtazapine, megesterol acetate, dronabinol and n-3 polyunsaturated fatty acids can be considered for anorexic patients within the limitations of their adverse effect profile LVAD patients tend to gain weight after device implantation, especially if underweight or normal-weight before implantation. The mechanisms of this metabolic recovery are uncertain, although normalized perfusion to the gut and skeletal muscle, relief of liver congestion, and improvements in dietary quality and physical activity levels could all be contributors. Nutrition, Obesity, and Cachexia in Patients With Heart Failure: A Consensus Statement from the Heart Failure Society of America Scientific Statements Committee Journal of Cardiac Failure Vol. 00 No ESC 2016

53 Heart failure with preserved ejection fraction: controversies, challenges and future directions Heart failure with preserved ejection fraction (HFpEF) comprises almost half of the population burden of HF. Because HFpEF likely includes a range of cardiac and non-cardiac abnormalities, typically in elderly patients, obtaining an accurate diagnosis may be challenging, not least due to the existence of multiple HFpEF mimics and a newly identified subset of patients with HFpEF and normal plasma natriuretic peptide concentrations Dysregulated nitric oxide cyclic guanosine monophosphate protein kinase G signalling, driven by comorbidities and ageing, may be the fundamental abnormality in HFpEF, resulting in a systemic inflammatory state and microvascular endothelial dysfunction. Zakeri R, Cowie MR. Heart 2018;0:1 8