New-Onset Cancer in the HF Population: Epidemiology, Pathophysiology, and Clinical Management

Purpose of Review Oncological treatments are known to induce cardiac toxicity, but the impact of new-onset cancer in patients with pre-existing HF remains unknown. This review focuses on the epidemiology, pathophysiological mechanisms, and clinical implications of HF patients who develop malignancies. Recent Findings Novel findings suggest that HF and cancer, beside common risk factors, are deeply linked by shared pathophysiological mechanisms. In particular, HF itself may enhance carcinogenesis by producing pro-inflammatory cytokines, and it has been suggested that neurohormonal activation, commonly associated with the failing heart, might play a pivotal role in promoting neoplastic transformation. Summary The risk of malignancies seems to be higher in HF patients compared to the general population, probably due to shared risk factors and common pathophysiological pathways. Additionally, management of these patients represents a challenge for clinicians, considering that the co-existence of these diseases significantly worsens patients’ prognosis and negatively affects therapeutic options for both diseases.

Neurohormonal activation induces intracellular iron deficiency and mitochondrial dysfunction in cardiac cells

Background Iron deficiency (ID) is common in patients with heart failure (HF) and is associated with poor outcomes, yet its role in the pathophysiology of HF is not well-defined. We sought to determine the consequences of HF neurohormonal activation in iron homeostasis and mitochondrial function in cardiac cells. Methods HF was induced in C57BL/6 mice by using isoproterenol osmotic pumps and embryonic rat heart-derived H9c2 cells were subsequently challenged with Angiotensin II and/or Norepinephrine. The expression of several genes and proteins related to intracellular iron metabolism were assessed by Real time-PCR and immunoblotting, respectively. The intracellular iron levels were also determined. Mitochondrial function was analyzed by studying the mitochondrial membrane potential, the accumulation of radical oxygen species (ROS) and the adenosine triphosphate (ATP) production. Results Hearts from isoproterenol-stimulated mice showed a decreased in both mRNA and protein levels of iron regulatory proteins, transferrin receptor 1, ferroportin 1 and hepcidin compared to control mice. Furthermore, mitoferrin 2 and mitochondrial ferritin were also downregulated in the hearts from HF mice. Similar data regarding these key iron regulatory molecules were found in the H9c2 cells challenged with neurohormonal stimuli. Accordingly, a depletion of intracellular iron levels was found in the stimulated cells compared to non-stimulated cells, as well as in the hearts from the isoproterenol-induced HF mice. Finally, neurohormonal activation impaired mitochondrial function as indicated by the accumulation of ROS, the impaired mitochondrial membrane potential and the decrease in the ATP levels in the cardiac cells. Conclusions HF characteristic neurohormonal activation induced changes in the regulation of key molecules involved in iron homeostasis, reduced intracellular iron levels and impaired mitochondrial function. The current results suggest that iron could be involved in the pathophysiology of HF.

Effects of Vitamin D Supplementation on Cardiovascular and Glycemic Biomarkers

Background Experimental and observational studies have suggested a link between vitamin D and cardiovascular and metabolic disease, but this has not been confirmed in randomized controlled trials. We sought to determine whether vitamin D supplementation reduces biomarkers of insulin resistance, inflammation, neurohormonal activation, and lipids. Methods and Results This was a prespecified, secondary analysis of the DAYLIGHT (Vitamin D Therapy in Individuals at High Risk of Hypertension) randomized controlled trial. We measured circulating homeostatic model assessment of insulin resistance, hs‐CRP (high‐sensitivity C‐reactive protein), N‐terminal pro‐B‐type natriuretic peptide, renin, aldosterone, and lipids at baseline and at 6 months in 289 individuals with low vitamin D status (25‐hydroxyvitamin‐D [25‐OH‐D] ≤25 ng/mL) receiving low‐dose (400 IU/d) versus high‐dose (4000 IU/d) vitamin D3 for 6 months. A meta‐analysis of randomized controlled trials reporting biomarker changes after vitamin D supplementation was then performed. Levels of 25‐OH‐D increased in the high‐dose relative to the low‐dose vitamin D group (+15.5 versus +4.6 ng/mL, P <0.001). Changes in biomarkers of glycemia, inflammation, and neurohormonal activation did not differ by dose. Lipids did not differ between groups, other than triglycerides, which increased in the high‐dose compared with the low‐dose group (+11.3 versus −6.2 mg/dL, P <0.001). The meta‐analysis showed potential modest decreases in homeostatic model assessment of insulin resistance and hs‐CRP, but no changes in low‐density lipoprotein, after vitamin D supplementation compared with control groups. Conclusions In the DAYLIGHT randomized controlled trial, high‐dose vitamin D supplementation did not improve biomarkers of glycemia, inflammation, neurohormonal activation, or lipids. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01240512.

Inflammation and neurohormonal activation is increased at hospital admission in patients with ST-elevation myocardial infarction with diabetes compared to non-diabetic patients

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Rigshospitalets Forskningsfond. The Lundbeck Foundation. Background Patients with diabetes have an increased risk of coronary artery disease (CAD). In patients with myocardial infarction (MI), diabetes is associated with a poor outcome. Inflammation and neurohormonal activation have previously been shown to be associated with poor outcomes in patients with ST-elevation MI (STEMI). We therefore sought to assess whether STEMI-patients with diabetes (DM) had increased levels of inflammation and neurohormonal activation upon hospital admission. Methods In 1892 consecutive STEMI-patients from two danish tertiary heart centres, biomarkers reflecting neurohormonal activation (pro-atrial natriuretic peptide (proANP) and mid-regional pro-adrenomedullin (MRproADM)) and inflammation (soluble suppression of tumorigenicity 2 (sST2) and C-reactive peptide (CRP)) were measured upon admission before angiography. Patients were stratified according to DM or not. Results In total, 245 (13%) patients had DM. DM patients were older (mean (SD) 66 (11) vs 63 (13) years old, p = 0.0002), had more comorbidities (hypertension, previous stroke/TIA, ischemic heart disease (IHD), chronic kidney dysfunction (CKD)), and higher body mass index (BMI). In addition, DM patients had a longer time from symptom debut to angiography and more often multivessel disease (MVD). We found no difference in admission troponin plasma concentrations. Upon hospital admission, DM patients had higher concentrations of MRproADM (median (IQR) 0.88 (0.64-1.20) vs. 0.71 (0.58-0.90) nmol/L, p &lt; 0.0001), sST2 (41 (64-31) vs. 39 (55-28) ng/ml, p = 0.01), and CRP (4.5 (1.9-12.1) vs. 3.4 (1.4-8.3) mg/L, p = 0.001) but not proANP (figure). When adjusted for age, BMI, CKD, IHD, time from symptom debut to angiography, and MVD, DM remained associated with increased MRproADM (OR (95% CI) 1.35 (1.05; 1.74), p = 0.02) and sST2 (1.20 (1.02; 1.41), p = 0.03), but no longer with CRP. Patients with DM had a higher one-year all-cause mortality rate (12% vs. 9.4%, p = 0.03). Conclusion STEMI patients with diabetes have increased neurohormonal activation and inflammation at hospital admission compared to patients without diabetes. This may play a role in the increased mortality in STEMI patients with diabetes. Abstract Figure.

Metabolic syndrome and heart failure: mechanism and management

Heart failure (HF) and metabolic syndrome (MetS) are syndromes that affect a large proportion of the world population. MetS is known to be one of the risk factors of HF, and it can also act as comorbidity in HF. This review aims to further discuss the mechanism of MetS in causing HF, the management of MetS in order to prevent HF, and the management of MetS in HF patients. Visceral adiposity is the primary trigger of MetS which is followed by chronic inflammation, insulin resistance, and neurohormonal activation. All the mechanisms causing MetS play also an important role in the progression of HF. The MetS approach can be achieved by managing its components according to the current guidelines and careful management of MetS should be done in patients with HF. MetS is closely related to the progression of HF so that comprehensive management which involves a multidisciplinary team is necessary for managing patients with metabolic syndrome and heart failure.

Underlying Causes of High Output Heart Failure

In the U.S., each year, there are more than 500,000 new cases of all types of heart failure. With high output cardiac failure, there is an elevated cardiac output associated with several conditions and diseases, including obesity, chronic anemia, systemic arterio-venous fistula, hypercapnia, mitochondrial dysfunction, and hyperthyroidism. The underlying pathophysiologic mechanisms relate to a reduction in systemic vascular resistance from arterio-venous shunting or peripheral vasodilation. Often there is a decrease in systemic arterial blood pressure and neurohormonal activation leading to heart failure symptoms of dyspnea and fatigue. In a persistent high output state, patients may experience tachycardia, valvular abnormalities, and ventricular dilatation and/or hypertrophy. In this article, there is a review of high output heart failure, including the prevalence, pathophysiology, and common clinical causes of this disease.

Renal denervation: where do we stand and what is the relevance to the nephrologist?

Catheter-based renal denervation to reduce high blood pressure (BP) has received well-deserved attention after a recent series of sham-controlled trials reported significant antihypertensive efficacy and very favourable tolerability and safety of the intervention. This emerging treatment option is of high relevance to nephrologists. Patients with chronic kidney disease (CKD) are at elevated risk of cardiovascular adverse events and often present with hypertension, which is very difficult to control with medication. Renal denervation promises a new tool to reduce BP and to prevent loss of renal function in this population. The current review considers the role of the kidney and neurohormonal activation in the development of hypertension and the rationale for renal denervation. The current state of the evidence for the effectiveness and tolerability of the procedure is considered from the nephrologists’ perspective, with a focus on the potential future role of renal denervation in the management of CKD patients with hypertension.

B-TYPE NATRIURETIC PEPTIDE(BNP) LEVELS AND ITS PROGNOSTIC VALUE IN ACUTE CORONARY SYNDROMES(ACS)

Objectives: This study was designed to evaluate the prognostic value of B-type natriuretic peptide (BNP) in patients across the entire spectrum of acute coronary syndromes (ACS). Method: We measured BNP levels at baseline in 100 consecutive patients between 24-96 hours after the onset of ischemic symptoms in patients of acute coronary syndromes. We did comparison between BNP levels and established prognostic markers Trop-T to determine short term morbidity and mortality. Results: Patients with baseline BNP levels (> 80pg/ml, n=28) were at higher risk of new or progressive congestive heart failure (CHF) [17.8% vs. 1.39%, P = 0.002), new or recurrent myocardial infarction [17.8% vs. 2.8, P = 0.008) and death [17.8% vs. 1.39%, P= 0.002) within a period of 30 days. The mortality within 30 days in patients with BNP > 80pg/ml was 17.9% (P=0.002)compared to 5.7%(P=0.718) in patients with positive Trop-T (> 0.1ng/ml). Conclusion: A single measurement of BNP obtained between 24-96 hours after the onset of ischemic symptoms provides predictive information for use in risk stratifications across the spectrum of acute coronary syndromes. Cardiac neurohormonal activation may be a unifying feature among patients at high risk for death after acute coronary syndromes. BNP levels should be measured in all patients of Acute coronary syndromes.

Empagliflozin in Heart Failure

Background: Sodium-glucose cotransporter-2 inhibitors improve heart failure–related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional diuretics such as furosemide induce substantial neurohormonal activation, contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the sodium-glucose cotransporter-2 inhibitors may help circumvent these limitations. Methods: Twenty patients with type 2 diabetes mellitus and chronic, stable heart failure completed a randomized, placebo-controlled crossover study of empagliflozin 10 mg daily versus placebo. Patients underwent an intensive 6-hour biospecimen collection and cardiorenal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with the above protocol repeated. Results: Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours ( P <0.0001). Fractional excretion of sodium increased significantly with empagliflozin monotherapy versus placebo (fractional excretion of sodium, 1.2±0.7% versus 0.7±0.4%; P =0.001), and there was a synergistic effect in combination with bumetanide (fractional excretion of sodium, 5.8±2.5% versus 3.9±1.9%; P =0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (−208 mL [interquartile range, −536 to 153 mL] versus −14 mL [interquartile range, −282 to 335 mL]; P =0.035) and plasma volume (−138 mL, interquartile range, −379 to 154±453 mL; P =0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation because the change in norepinephrine was superior ( P =0.02) and all other neurohormones were similar ( P <0.34) during the empagliflozin versus placebo period. Furthermore, there was no evidence of potassium wasting ( P =0.20) or renal dysfunction ( P >0.11 for all biomarkers), whereas both serum magnesium ( P <0.001) and uric acid levels ( P =0.008) improved. Conclusions: Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in patients with heart failure and may represent a mechanism contributing to the superior long-term heart failure outcomes observed with these agents. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03027960.