Cardiorenal Function Research Articles

Effects of elevation of ANP and its deficiency on cardiorenal function.

Atrial natriuretic peptide (ANP), encoded by Nppa, is a vasodilatory hormone that promotes salt excretion. Genome-wide association studies identified Nppa as a causative factor of blood pressure development, and in humans, ANP levels were suggested as an indicator of salt sensitivity. This study aimed to provide insights into the effects of ANP on cardiorenal function in salt-sensitive hypertension. To address this question, hypertension was induced in SSNPPA–/– (KO of Nppa in the Dahl salt-sensitive [SS] rat background) or SSWT (WT Dahl SS) rats by a high-salt (HS) diet challenge (4% NaCl for 21 days). Chronic infusion of ANP in SSWT rats attenuated the increase in blood pressure and cardiorenal damage. Overall, the SSNPPA–/– strain demonstrated higher blood pressure and intensified cardiac fibrosis (with no changes in ejection fraction) compared with SSWT rats. Furthermore, SSNPPA–/– rats exhibited kidney hypertrophy and higher glomerular injury scores, reduced diuresis, and lower sodium and chloride excretion than SSWT when fed a HS diet. Additionally, the activity of epithelial Na+ channel (ENaC) was found to be increased in the collecting ducts of the SSNPPA–/– rats. Taken together, these data show promise for the therapeutic benefits of ANP and ANP-increasing drugs for treating salt-sensitive hypertension.

Chronic kidney disease and transcatheter aortic valve implantation

Transcatheter aortic valve implantation (TAVI) is an established treatment option for patients with severe aortic stenosis. Patients with aortic stenosis have a higher prevalence of chronic kidney disease (CKD). CKD is generally associated with an increased risk of mortality, cardiovascular events, and readmission for heart failure; this supports the concept of a cardio-renal syndrome (CRS). CRS encompasses a spectrum of disorders of the heart and kidneys, wherein dysfunction in one organ may cause dysfunction in the other. TAVI treatment is expected to break this malignant cycle of CRS and improve cardio-renal function after the procedure. However, several reports demonstrate that patients with CKD have been associated with poor outcomes after the procedure. In addition, TAVI treatments for patients with advanced CKD and those with end-stage renal disease on hemodialysis are considered more challenging. Adequate management to preserve cardio-renal function in patients undergoing TAVI may reduce the risk of cardio-renal adverse events and improve the long-term prognosis. The current comprehensive review article aims to assess the prognostic impact of CKD after TAVI and seek optimal care in patients with CKD even after successful TAVI.

MO115: Cardiorenal Units as Management Strategy to Improve Outcomes in Cardiorenal Syndrome

Abstract BACKGROUND AND AIMS Cardiorenal syndrome (CRS), defined as the spectrum of disorders that acutely or chronically affect both heart and kidney function, is often a challenging condition with paucity of evidence-based therapy. The increasing burden of this entity has prompted the creation of cardiorenal units (CRU) as integrating programs intended to provide a combined multidisciplinary approach to maximize all chances for organ and patient recovery. Here we describe the early results of the creation of one CRU in a high complexity university hospital. METHOD This observational study included all patients diagnosed with CRS, who have been seen in the cardiorenal day care unit, formed by specific trained nephrologist, cardiologist and nurses. Assessment of cardiorenal function and volume status was performed by conventional cardiac ultrasound plus V-Scan, GFR estimation by CKD EPI, NT-proBNP determination and bioelectrical impedance when indicated. RESULTS Cardiorenal Unit of Puerta de Hierro University Hospital was created in January 2021. A total of 68 patients have been evaluated with a mean follow-up of 4 months (SD 3.2). Most frequent cardiologic diagnoses were 63.9% heart fellow with reduced function (HFrF) and 37.1% heart failure with preserved ejection fraction (HFpEF) and the presence on pulmonary hypertension or tricuspid regurgitation were 29.4% and 50.9%. 51.6% patients showed diuretic resistance. Most frequent renal diagnosis were pure CRS 36.9%, and 27.7% and 24.6% CRS associated to diabetic kidney disease or nephroangioesclerosis, respectively. Mean FGe rate when patients were initially evaluated was 31.5 mL/min/1.73 m2 (SD 11.0) with demonstration of albuminuria in 48.5% of patients. The integrated cardiorenal management of these patients included initiation or adjustment of specific cardio-nephroprotective drugs [SGLT2 inhibitors (46.8%), ARNi (25.8%), aldosterone receptor antagonists (4.8%)] or diuretic regime adjustment including iv administration (54.8%). Peritoneal dialysis was indicated in three patients and haemodialysis in one patient. Approximately 13.2% patients suffer new episodes of heart failure that needed hospitalization or unexpected medical attention at the day-care clinic. One patient died during follow-up (1.5%). CONCLUSION We conclude that this coordinated cardionephro approach of CRS was useful to optimize drug therapy aimed to mid-long term goals of cardionephro protection and to implement advanced therapies for fluid management in patients with diuretic resistance.

Are There Any Differences in the Prognostic Value of Left Ventricular Ejection Fraction in Coronary Artery Disease Patients With or Without Moderate and Severe Mitral Regurgitation?

BackgroundLeft ventricular ejection fraction (LVEF) is a vital variable to describe left ventricle systolic function and contractility of left ventricle. However, the association between LVEF and the prognostic effect in patients with moderate or severe mitral regurgitation (MR) is still controversial.MethodsThis study comprised 30,775 coronary artery disease (CAD) patients who underwent coronary arteriography (CAG) in the Cardiorenal ImprovemeNt (CIN) registry from January 2007 to December 2018. Patients were divided into none or mild MR group and moderate or severe MR group, and 3 levels of LVEF ≥50, 40–50%, and <40% were further distinguished according to hospital baseline. Univariate and multivariate Cox proportional analyses were used to investigate the association between LVEF levels and long-term all-cause mortality in patients with different MR severities.ResultsOf 30,775 CAD patients (62.9 ± 10.6 years, females 23.8%), 26,474 (86.0%) patients had none or mild MR. Compared with none or mild MR patients, patients with moderate or severe MR were older and had worse cardio-renal function. In multivariable Cox proportional analysis, LVEF <40% was independently associated with higher mortality compared with LVEF ≥ 50% in all kinds of MR severity {none or mild MR [adjusted hazard ratio (HR): 1.79; 95% CI: 1.56–2.05, p < 0.001], moderate or severe MR [adjusted HR: 1.57; 95% CI: 1.29–1.91, p < 0.001]}.ConclusionsLVEF is a reliable prognostic index in CAD patients, even in those with moderate or severe MR. LVEF monitoring would still be clinically useful in CAD patients with moderate or severe MR. Clinical trials are needed to prospectively evaluate the optimal threshold for LVEF in patients with moderate or severe MR.

Prevalence and Mortality of Moderate or Severe Mitral Regurgitation Among Patients Undergoing Percutaneous Coronary Intervention With or Without Heart Failure: Results From CIN Study With 28,358 Patients.

AimThis study investigated the prevalence and mortality associated with moderate or severe mitral regurgitation (MR) among patients undergoing percutaneous coronary intervention (PCI), with or without heart failure (HF).MethodsWe analyzed patients undergoing PCI without mitral valve surgery from the Cardiorenal ImprovemeNt (CIN) study (ClinicalTrials.gov NCT04407936). Patients without echocardiography to determine MR occurrence or lacking follow-up death data were excluded. Primary endpoints were 1-year and long-term all-cause mortality, with a median follow-up time of 5 years (interquartile range: 3.1–7.6).ResultsOf 28,358 patients undergoing PCI treatment [mean age: 62.7 ± 10.7; women: 6,749 (25.6%)], 3,506 (12.4%) had moderate or severe MR, and there was a higher rate of moderate or severe MR in HF group than non-HF group (28.8 vs. 5.6%, respectively). Regardless of HF conditions, patients with moderate or severe MR were older and had worse cardio-renal function and significantly increased 1-year mortality [adjusted hazard ratio (aHR): 1.82, 95% confidence interval (CI): 1.51–2.2], and long-term mortality [aHR: 1.43, 95% CI: 1.3–1.58]. There was no significant difference between patients with HF and those with non-HF (P for interaction > 0.05).ConclusionOne-eighth of the patients undergoing PCI had moderate or severe MR. Furthermore, one-third and one-seventeenth experienced moderate or severe MR with worse cardiorenal function in the HF and non-HF groups, and increased consistent mortality risk. Further studies should explore the efficacy of mitral interventional procedures for moderate or severe MR after PCI treatment, regardless of HF.

Cardiorenal function and survival in in-hospital cardiac arrest: A nationwide study of 22,819 cases

BackgroundWe studied the association between cardiorenal function and survival, neurological outcome and trends in survival after in-hospital cardiac arrest (IHCA). MethodsWe included cases aged ≥ 18 years in the Swedish Cardiopulmonary Resuscitation Registry during 2008 to 2020. The CKD-EPI equation was used to calculate estimated glomerular filtration rate (eGFR). A history of heart failure was defined according to contemporary guideline criteria. Logistic regression was used to study survival. Neurological outcome was assessed using cerebral performance category (CPC). ResultsWe studied 22,819 patients with IHCA. The 30-day survival was 19.3%, 16.6%, 22.5%, 28.8%, 39.3%, 44.8% and 38.4% in cases with eGFR < 15, 15–29, 30–44, 45–59, 60–89, 90–130 and 130–150 ml/min/1.73 m2, respectively. All eGFR levels below and above 90 ml/min/1.73 m2 were associated with increased mortality. Probability of survival at 30 days was 62% lower in cases with eGFR < 15 ml/min/1.73 m2, compared with normal kidney function. At every level of eGFR, presence of heart failure increased mortality markedly; patients without heart failure displayed higher mortality only at eGFR below 30 ml/min/1.73 m2. Among survivors with eGFR < 15 ml/min/1.73 m2, good neurological outcome was noted in 87.2%. Survival increased in most groups over time, but most for those with eGFR < 15 ml/min/1.73 m2, and least for those with normal eGFR. ConclusionsAll eGFR levels below and above normal range are associated with increased mortality and this association is modified by the presence of heart failure. Neurological outcome is good in the majority of cases, across kidney function levels and survival is increasing.

P38-MAPK and JAK/STAT Pathway Inhibition Reduces Indoxyl Sulfate-Induced Impairment of Human Endothelial Cells

Indoxyl sulfate (IS) accumulates in chronic kidney disease (CKD) patients and cannot be cleared by dialysis. It is detrimental to cardiorenal function via pro-oxidant and pro-inflammatory actions, but the effect of IS on the vasculature is largely unknown. This study determined the effect of IS in human aortic endothelial cells (HAECs). p38-MAPK and JAK-STAT pathways appear to play an important pathological role in IS-induced vasculopathy, thus the pathways were inhibited with novel drug VCP-979 and JAK Inhibitor I (JI), respectively, to reverse IS-induced impairment of HAECs.

Proenkephalin and the risk of new-onset heart failure: data from prevention of renal and vascular end-stage disease.

BackgroundEnkephalins of the opioid system exert several cardiorenal effects. Proenkephalin (PENK), a stable surrogate, is associated with heart failure (HF) development after myocardial infarction and worse cardiorenal function and prognosis in patients with HF. The association between plasma PENK concentrations and new‐onset HF in the general population remains to be established.HypothesisWe hypothesized that plasma PENK concentrations are associated with new‐onset HF in the general population.MethodsWe included 6677 participants from the prevention of renal and vascular end‐stage disease study and investigated determinants of PENK concentrations and their association with new‐onset HF (both reduced [HFrEF] and preserved ejection fraction [HFpEF]).ResultsMedian PENK concentrations were 52.7 (45.1–61.9) pmol/L. Higher PENK concentrations were associated with poorer renal function and higher NT‐proBNP concentrations. The main determinants of higher PENK concentrations were lower estimated glomerular filtration rate (eGFR), lower urinary creatinine excretion, and lower body mass index (all p < .001). After a median 8.3 (7.8–8.8) years follow‐up, 221 participants developed HF; 127 HFrEF and 94 HFpEF. PENK concentrations were higher in subjects who developed HF compared with those who did not, 56.2 (45.2–67.6) versus 52.7 (45.1–61.6) pmol/L, respectively (p = .003). In competing‐risk analyses, higher PENK concentrations were associated with higher risk of new‐onset HF (hazard ratio [HR] = 2.09[1.47–2.97], p < .001), including both HFrEF (HR = 2.31[1.48–3.61], p < .001) and HFpEF (HR = 1.74[1.02–2.96], p = .042). These associations were, however, lost after adjustment for eGFR.ConclusionsIn the general population, higher PENK concentrations were associated with lower eGFR and higher NT‐proBNP concentrations. Higher PENK concentrations were not independently associated with new‐onset HFrEF and HFpEF and mainly confounded by eGFR.

Apela inhibits systemic and renal inflammatory reactions in mice with type I cardiorenal syndrome.

This study investigated the effect of apela on renal function and anti-inflammatory effect on whole body and kidney tissue in mice with type I cardiorenal syndrome (CRS). The murine type I CRS model was established and apela was subcutaneously infused for two weeks. Cardiac and renal functions were evaluated by echocardiography and blood biochemistry, respectively. The systemic and renal inflammatory responses were examined with molecular biological and histological methods. Human renal glomerular endothelial cells (RGECs) were used to evaluate the adhesion effect of monocytes in vitro. Compared to mice from the control group (CRS + vehicle), the plasma levels of N-terminal pro-brain natriuretic peptide, blood urea nitrogen and creatinine were significantly decreased, while the mean left ventricular ejection fraction was increased in apela-treated CRS mice at the 4th week. The expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) in the circulation and kidney was decreased in apela-treated mice compared with control mice, and apela improved cardio-renal pathology in mice with type I CRS. Additionally, Apela significantly suppressed the expression of MCP-1, TNF-α, intercellular adhesion molecule-1 and vascular intercellular adhesion molecule-1 in RGECs induced by angiotensin II (Ang II), and inhibited the promoting effect of Ang II on the adhesion of THP-1 cells to RGECs. Western blot results showed that the expression of phosphorylated nuclear factor kappa B (phospho-NFκB) in CRS mice was increased, but the expression of phospho-NFκB was down-regulated after apela treatment. Furthermore, apela significantly inhibited the Ang II-mediated increase in phospho-NFκB expression in RGECs in vitro, but the administration of an apelin peptide jejunum receptor (APJ) inhibitor blocked the inhibitory effect of apela. This study revealed that apela improves cardiorenal function and reduces systemic and renal inflammatory response in type I CRS mice and the apela/APJ system may alleviate renal inflammatory responses by inhibiting the NFκB signalling pathway.

Abstract 14: An Anti-inflammatory Proton Sensing-receptor Contributes To Cardiovascular Protection Of Gut Microbiota-derived Metabolites

High fibre (HF) diet protects against hypertension via the production of acidic metabolites, e.g. short-chain fatty acids, by the gut microbiota. While these metabolites have a direct role in blood pressure (BP) regulation, their acidic nature may activate proton-sensing receptors, which have anti-inflammatory functions. G-protein coupled receptor 65 (GPR65) is a proton-sensing receptor activated around pH 6.5 and is critical for gut homeostasis. We hypothesized that GPR65 is involved in the cardiovascular protection by dietary fibre. We first measured cecal pH of C57BL/6 (WT) mice after a 7-day dietary intervention with either HF or low fibre (LF) diets (n=6/group). HF diet lowered cecal pH to a level where GPR65 is highly activated, compared to the LF diet (6.5±0.1 vs 7.6±0.1, P&lt;0.001). The impact of pH and GPR65 on T cell production of IFNγ, a pro-inflammatory cytokine, in vitro was measured by flow cytometry. Acidic pH inhibited the production of IFNγ by CD8+ T cells (pH 6.5 vs pH 7.5, P&lt;0.001). Cells lacking GPR65 had higher IFNγ at both pH (P&lt;0.001). To determine if GPR65 is involved in BP regulation by dietary fibre, WT and GPR65 knockout ( Gpr65 -/- ) mice were implanted with minipumps containing angiotensin II (Ang II, 0.5mg/kg/day, 28 days, n=8-9/group) and fed with HF diet. BP, cardiorenal function and immune cell infiltration were measured. Gpr65 -/- mice had higher BP compared to WT mice after 2 weeks (mean arterial pressure ± SEM; WT 79.8±2.4 vs Gpr65 -/- 95.8±1.6mmHg, P&lt;0.001) and 4 weeks of Ang II infusion (WT 92.3±2.4 vs Gpr65 -/- 99.5±1.3, P=0.062). Gpr65 -/- mice developed cardiac (P=0.035) and renal (P=0.025) hypertrophy, and impaired renal natriuretic (P=0.054) and diuretic (P=0.056) function compared to WT mice. This was accompanied by higher macrophage (P=0.009) and γδ T cell (P=0.014) infiltration in the kidneys. In conclusion, our data suggest that pH-sensing by GPR65 contributes to the protection against hypertension by dietary fibre via inflammatory mechanisms. This is a novel mechanism that contributes to BP regulation via the gut microbiota.

Malnutrition and the risk for contrast-induced acute kidney injury in patients with coronary artery disease.

Malnutrition is a common comorbidity of coronary artery disease (CAD) and is often associated with adverse events. The malnutrition often means lower cholesterol, albumin and high lymphocyte, as risk factors of Contrast-Induced Acute Kidney Injury (CI-AKI). We aim to evaluate the association between malnutrition and CI-AKI following coronary angiography (CAG) in CAD patients. We analyzed 3170 CAD patients with variables of nutritional status (Controlling Nutritional Status score (CONUT)) from the prospective multicenter study, REICIN (NCT01402232) including 4,271 consecutive patients undergoing CAG from January 2013 to February 2016. Patients were divided into the normal group (CONUT score 0-1) and malnutrition group (CONUT score > 1). The association of malnutrition and the risk of CI-AKI was examined in all CAD patients using multivariable logistics regression analysis. Among the 3170 patients (mean age: 63.1 ± 10.7years), 1865 (58.8%) suffered from malnutrition, 111 (3.5%) developed CI-AKI, including 23 (1.76%) in normal group and 88 (4.72%) in malnutrition group (p < 0.01). The malnourished patients were older, and likely had anemia and worse cardiorenal function. After adjustment for confounders, the risk of CI-AKI was 1.04 times higher in the malnutrition group than in the normal group (adjusted OR: 2.04, 95% CI 1.28-3.38, p < 0.01). Among CAD patients undergoing CAG, malnutrition is extremely common and associated with a double risk of CI-AKI. Further studies are needed to investigate the potential renal protection of intervening malnutrition in CAD patients.

Dietary inflammatory index and cardiorenal function in women with diabetes and prediabetes

Background and aimsPrevious studies had shed a new light on the importance of multiple inflammatory mechanisms in the pathogenesis of arterial stiffness. The dietary inflammatory index (DII®) is a new tool for estimating the overall inflammatory potential of the diet. The aim of this study is to assess the association of the inflammatory potential of diet with peripheral arterial stiffness and renal function in women with diabetes and prediabetes. Methods and resultsThis is an observational cross-sectional study. A total of 2644 females aged 45–75 years were included for the study. Dietary intake in the past 12 months was assessed by a validated China National Nutrition and Health Survey 2002 (CNHS2002) food-frequency questionnaire. Energy-adjusted DII (E-DII) scores were calculated from daily dietary information. In a multivariable linear regression analysis adjusted for potential confounders, E-DII was positively associated with brachial ankle pulse wave velocity (baPWV) in participants with diabetes (β = 12.820; 95% CI = 2.565, 23.076; P = 0.014) and prediabetes (β = 29.025; 95% CI = 1.110, 56.940; P = 0.042), but not in females with normal glucose homeostasis. In addition, per unit increase of E-DII was significantly associated with lower eGFR (β = -1.363; 95% CI = -2.335, −0.392; P = 0.006) in patients with diabetes. ConclusionWe identified a direct association between E-DII and arterial stiffness, decreasedeGFR in middle-aged and elderly women with diabetes or prediabetes. Future studies are needed to verify and clarify the role of E-DII as an intervention target for cardiorenal complications of chronic hyperglycemia.

Pathophysiological Mechanisms for Heart Failure with Preserved Ejection Fraction (HF‐pEF): A Mathematical Modeling Analysis

While there are many treatment options for heart failure with reduced ejection fraction (HF-rEF), therapeutic improvements in long-term outcomes for patients with heart failure with preserved ejection fraction (HF-pEF) have proven elusive. Part of the challenge is the heterogeneous phenotype and poorly understood mechanisms responsible for HF-pEF. A wide range of pathophysiological mechanisms have been proposed to cause or contribute to HF-pEF such as cardiac interstitial fibrosis, cardiac hypertrophy, impaired cardiac metabolism and bioenergetics, impaired LV relaxation, endothelial dysfunction, impaired nitric oxide (NO) bioavailability, vascular stiffening, and systemic inflammation, among others. In this study, we used a mathematical modeling approach to evaluate the contribution of a subset of these hypothesized mechanisms in producing a hemodynamic phenotype of HF-pEF. Utilizing an existing model of cardiorenal function, we created a virtual reference patient with baseline hypertension and associated LV hypertrophy as a comorbidity, since a history of hypertension is highly prevalent in HF-pEF. We varied parameters associated with hypothesized HF-pEF mechanisms over a wide range, alone and in combination. Cardiac changes included increased myocardial stiffness (representing fibrosis), decreased myocardial contractility (representing impaired cardiac bioenergetics), and impaired LV relaxation. Vascular changes included increased arterial stiffness and increased arterial resistance. HF-pEF was defined as a state with elevated LV end diastolic pressure (LVEDP), increased interstitial fluid volume (IFV), and normal ejection fraction (EF). As expected, hypertension and LV hypertrophy alone were not sufficient to increase LV EDP or IFV. Our simulations predicted that increasing LV stiffness or decreasing LV contractility tended to increase LVEDP and IFV, while changing both stiffness and contractility together magnified their effects. However, substantial changes in these parameters also suppressed EF into the HF-rEF range. A range of parameter values was identified that elevated LVEDP and IFV while keeping EF above 50%. In addition, inducing delayed ventricular relaxation had minimal effect on LVEDP or EF, but did elevate mean pulmonary venous pressure. On the vascular side, decreases in systemic or pulmonary vascular compliance had minimal effects on LVEDP or EF, but increased IFV. In summary, increased LV stiffness and mild decreases in LV contractility, on top of existing hypertension and hypertrophy, are predicted to contribute to the shift toward elevated preload and volume retention characteristic of heart failure, without suppressing ejection fraction. Decreased vascular compliance may exacerbate fluid overload.

Can the in-hospital mortality gap between STEMI patients with and without diabetes mellitus be reduced? The cardio-renal hypothesis

Background and aimsDiabetes mellitus (DM) is a frequent comorbidity in ST-elevation-myocardial infarction (STEMI) patients and carries a higher risk of in-hospital mortality. We recently demonstrated that the higher in-hospital mortality of STEMI patients with DM, when compared to that of patients without DM, is mainly associated with their more frequent cardiac and renal dysfunction. These exploratory results prompted us to hypothesize that this higher risk in DM patients is mediated by their lower cardio-renal functional reserve. Methods and resultsWe included 5152 STEMI patients treated with primary angioplasty. By using an advanced statistical methodology (path analysis), able to clarify the putative causal paths between variables of interest, we reported that the higher in-hospital mortality of STEMI patients with DM is possibly caused by its adverse impact on cardio-renal function. ConclusionThis statistical approach allows to reinforce the well-known notion that DM is associated with an increased in-hospital mortality risk in STEMI and sheds lights on the causal relationship among DM, cardio-renal dysfunction, and higher in-hospital mortality. Whether the mortality gap between DM and non-DM patients with STEMI can be reduced by pharmacological strategies combining cardio-renal protective effects is an intriguing question that deserves an answer in the future.

Effects of intensive blood pressure control on mortality and cardiorenal function in chronic kidney disease patients

Background Blood pressure (BP) variability is highly correlated with cardiovascular and kidney outcomes in patients with chronic kidney disease (CKD). However, appropriate BP targets in patients with CKD remain uncertain. Methods We searched PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) of CKD patients who underwent intensive BP management. Kappa score was used to assess inter-rater agreement. A good agreement between the authors was observed to inter-rater reliability of RCTs selection (kappa = 0.77; P = 0.005). Results Ten relevant studies involving 20 059 patients were included in the meta-analysis. Overall, intensive BP management may reduce the incidence of cardiovascular disease mortality (RR: 0.69, 95% CI: 0.53 to 0.90, P: 0.01), all-cause mortality (RR: 0.77, 95% CI: 0.67 to 0.88, P < 0.01) and composite cardiovascular events (RR: 0.84 95% CI: 0.75 to 0.95, P < 0.01) in patients with CKD. However, reducing BP has no significant effect on the incidence of doubling of serum creatinine level or 50% reduction in GFR (RR: 1.26, 95% CI: 0.66 to 2.40, P = 0.48), composite renal events (RR 1.07, 95% CI: 0.81 to 1.41, P = 0.64) or SAEs (RR: 0.97, 95% CI: 0.90 to 1.05, P = 0.48). Conclusion In patients with CKD, enhanced BP management is associated with reduced all-cause mortality, cardiovascular mortality, and incidence of composite cardiovascular events.

Ambient Temperature and Cardiorenal Connection in Elderly Patients with Stable Heart Failure.

Heart failure increases among the elderly; however, the influence of ambient temperature on cardiorenal function has not been well investigated. Patients (n = 110, mean age 82.9 years, 43 males) with stable heart failure and creatinine < 3.0 mg/dl were studied. Medical records, such as ejection fraction, B-type natriuretic peptide (BNP), and estimated glomerular filtration rate (eGFR) at each visit every 1-3 months were collected by the end-point for death, additional prescription to treat heart failure, or heart failure hospitalization. The ambient temperatures at each visit were obtained from the Japan Meteorological Agency. During the follow-up period (median 399 days and 7 visits), follow-up BNP showed a trend toward a positive correlation with the diurnal temperature range. After dividing into two groups by median baseline eGFR, follow-up BNP was positively correlated with minimum temperature (p = 0.039) and the diurnal temperature range (p = 0.007) in the Low-eGFR group but not in the High-eGFR group. Follow-up eGFR was negatively correlated with the ambient day temperature in both groups (p ≤ 0.002). Follow-up BNP was positively correlated with follow-up eGFR (p < 0.0001) only in the Low-eGFR group and not in the High-eGFR group, suggesting that BNP and eGFR increase in winter and BNP and eGFR decrease in summer in the Low-eGFR group. In conclusions, heart failure may be worsened by larger diurnal temperature range or in winter in patients with renal impairment. This population should be carefully managed in the clinic according to the ambient temperature.

Association between lipoprotein (a) level and chronic cardio-renal syndrome in elderly patients

Objective: To explore the relationship between lipoprotein(a) [Lp(a)] and chronic cardio-renal syndrome (CRS) in elderly patients. Methods: Chronic heart failure (CHF) patients age ≥ 65 years old, who hospitalized in the department of Cardiology of Hebei General Hospital from December 2017 to October 2019, were included in this study. According to the estimate glomerular filtration rate (eGFR) level, patients were divided into CRS group (eGFR<60 ml·min-1·1.73 m-2) and CHF group (eGFR ≥60 ml·min-1·1.73 m-2). The blood index and basic disease information were collected and compared. Left ventricular ejection fraction (LVEF) were measured by echocardiography. The correlation between clinical indicators and cardio-renal function (LVEF and eGFR) was assessed. The multivariate logistic regression analysis was used to evaluate the related risk factors of CRS in elderly patients; subgroup logistic regression analysis was performed according to the basic disease of patients to assess the relationship between Lp(a) and CRS. Results: A total of 172 elderly patients (85 males (49.4%), aged 79 (71, 84) years) were finally enrolled. Among them, 88 cases (51.2%) were in CRS group and 84 cases (48.8%) were in CHF group. Age (80 (74, 84) years old vs. 74 (70, 82) years old) and LP (a) levels (222.0 (112.0, 445.3) mg/L vs. 155.0 (97.0, 348.7) mg/L) were significantly higher in the CRS group than in the CHF group (P<0.05). Lp(a) levels were negatively correlated with LVEF (r=-0.155, P=0.043) and eGFR (r=-0.220, P=0.004) in total cohort. In the subgroup analysis of patients with 2 high-incidence basic diseases (coronary heart disease and hypertension), Lp(a) was negatively correlated with LVEF (r=-0.250, P=0.007) in the coronary heart disease group, and negatively correlated with eGFR (r=-0.233, P=0.013) in the hypertension group. Multivariate logistic regression analysis showed that age (OR = 1.069, 95%CI: 1.017-1.124, P= 0.009) and Lp(a) (OR = 3.719, 95%CI: 1.339-10.326, P = 0.012) were independent correlates of CRS. The results of logistic regression analysis showed that Lp(a) was an independent correlative factor of CRS in the subgroups of coronary heart disease (OR=3.207, 95%CI: 1.129-9.108, P=0.029) and hypertension (OR=3.054, 95%CI: 1.086-8.587, P=0.034). Conclusion: Serum Lp(a) level is independently related with CRS in elderly patients.

Neural tone and cardio-renal outcomes in patients with type 2 diabetes mellitus: a review of the literature with a focus on SGLT2 inhibitors.

Recent clinical trials involving the systemic effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) have revealed beneficial outcomes pertaining to the microvascular sequelae of type 2 diabetes mellitus (T2DM) such as nephropathy, as well as macrovascular effects such as major adverse cardiovascular effects (MACE). Such findings have spurred the elevation of these agents to level A-tiers of recommendation within clinical guidelines addressing the management of complicated T2DM. While the mechanisms of SGLTi (-flozin drugs) are still being elucidated, a paucity of data exists within the literature appraising the role of neuromodulation and associated mechanisms in the aforementioned outcome studies. Given the role of the nervous system in orchestrating the pathologic processes that hamper cardio-renal status, insight into this topic offers an expanded perspective on T2DM. In this review we investigate the mechanisms by which SGLTi improve cardio-renal function in T2DM patients with emphases on neural tone and nervous system physiology.

The involvement of renal afferents in the maintenance of cardiorenal diseases.

Elevated sympathetic vasomotor activity is a common feature of cardiorenal diseases. Therefore, the sympathetic nervous system is an important therapeutic target, particularly the fibers innervating the kidneys. In fact, renal denervation has been applied clinically and shown promising results in patients with hypertension and chronic kidney disease. However, the underlying mechanisms involved in the cardiorenal protection induced by renal denervation have not yet been fully clarified. This mini-review highlights historical and recent aspects related to the role of renal sensory fibers in the control of cardiorenal function under normal conditions and in experimental models of cardiovascular disease. Results have demonstrated that alterations in renal sensory function participate in the maintenance of elevated sympathetic vasomotor activity and cardiorenal changes; as such, renal sensory fibers may be a potential therapeutic target for the treatment of cardiorenal diseases. Although it has not yet been applied in clinical practice, selective afferent renal denervation may be promising, since such an approach maintains efferent activity and can provide more refined control of renal function compared with total renal denervation. However, more studies are needed to understand the mechanisms by which renal afferents partially contribute to such changes, in addition to the need to evaluate the safety and advantages of the approach for application in the clinical practice.

Higenamine Improves Cardiac and Renal Fibrosis in Rats With Cardiorenal Syndrome via ASK1 Signaling Pathway

The pathogenesis of cardiorenal syndrome (CRS) is very complex, and currently there is no effective treatment for CRS. Higenamine (HI) has been shown to improve cardiac function in rats with heart failure. However, the role of higenamine in CRS remains unknown. Here, in vitro, higenamine treatment markedly reduced neonatal rat cardiac fibroblast collagen synthesis and inhibited neonatal rat cardiac myocyte hypertrophy. In our study, a rat model of type 2 CRS was induced by left anterior descending coronary artery ligation combined with 5/6 subtotal nephrectomy (STNx). Higenamine treatment decreased serum creatinine (Scr), blood urea nitrogen, and brain natriuretic peptide levels and was capable of improving left ventricular remodeling and systolic function in CRS rats, accompanied with decreased expression of transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (α-SMA) and collagen I (Col1A1). Moreover, higenamine significantly inhibited the protein expression of phosphorylated apoptosis signal-regulated kinase 1 (p-ASK1) and downstream mitogen-activated protein kinases (MAPK) (ERK, P38)/NF-κB in cardiorenal tissues of CRS rats and neonatal rat cardiac fibroblast/neonatal rat cardiac myocyte cells. Our study demonstrated that higenamine improved cardiorenal function in CRS rats and attenuated heart and kidney fibrosis possibly via targeting ASK1/MAPK (ERK, P38)/NF-κB signaling pathway. This finding extends our knowledge on the role of higenamine in cardiorenal fibrosis, providing a potential target to prevent the progression of CRS.