Effects of Sacubitril/Valsartan on the Renal Resistance Index.

BACKGROUND: Sacubitril/valsartan plays a key role in improving left ventricular remodeling and prognosis in patients with heart failure with a reduced ejection fraction (HFrEF). Moreover, some data support its role in preserving renal function. In order to better clarify the effects of sacubitril/valsartan in cardiorenal syndrome, this study evaluated its effects on the renal resistance index (RRI). METHODS: A group of patients with HFrEF was enrolled. The RRI was assessed with renal echo-color Doppler at enrollment and again after at least six months of sacubitril/valsartan treatment. In a subgroup of patients, the RRI was also evaluated at least six months before enrollment. The variations in echocardiographic parameters reflecting the left and right ventricular function, as well as creatinine and the estimated glomerular filtration rate, were also evaluated. RESULTS: After treatment with sacubitril/valsartan, significant improvements in the left ventricular ejection fraction, and a decrease in the left atrial and ventricular volumes were observed. The RRI also showed a significant decrease. No relationship was found between the improvements in the parameters reflecting cardiac function and changes in the RRI. CONCLUSIONS: Treatment with sacubitril/valsartan is associated with improvements in both left ventricular function and renal perfusion, through decreasing the renal resistance. These data help to clarify the effects of the drug on cardiorenal syndrome progression.

Reverse cardiac remodeling after fluid balance optimization in patients with end-stage renal disease.

BACKGROUND: In patients with end-stage renal disease (ESRD) undergoing hemodialysis, cardiovascular diseases, and in particular chronic heart failure are the leading causes of morbidity and mortality. Nevertheless, few data are available about the impact of fluid optimization on echocardiographic parameters of cardiac function in patients with ESRD. METHODS AND RESULTS: In five patients with ESRD undergoing hemodialysis who had developed nonischemic dilated cardiomyopathy, an optimal fluid volume management based on a strict bioelectrical impedance analysis-assisted dry weight target and dietary sodium and water restriction led to left ventricular reverse remodeling and improvement in hemodynamic parameters. The reverse remodeling further improved after kidney transplantation. CONCLUSIONS: This case series supports the possible beneficial effect of volume status optimization on cardiac function and the potential reversibility of cardiac dysfunction after kidney transplantation.

TSH Variations in Chronic Heart Failure Outpatients: Clinical Correlates and Outcomes.

BACKGROUND: Hypothyroidism is a frequently observed comorbidity in patients with chronic heart failure (CHF), possibly giving rise to unfavorable outcomes. AIM: The aim of the study was to evaluate the impact of TSH changes over time on cardiac function and prognosis of outpatients with CHF. METHODS: Patients underwent clinical, electrocardiographic, and echocardiographic evaluations at baseline and after 12 months. Moreover, blood chemistry tests were performed to evaluate renal function, cardiac biomarkers, fT3, fT4, and TSH levels. Based on TSH serum levels, patients were retrospectively classified into four categories: Group 1, patients with improved thyroid function at one-year follow up vs. baseline; Group 2, patients with stable and mildly high TSH values (3.74 - 10 mUI/L); Group 3, patients with worsening thyroid function; Euthyroid patients Group, TSH levels within the normal range of reference at baseline as well as at 12 months follow-up. We considered as end-points: one-year changes of laboratory and echocardiographic parameters; hospitalizations due to worsening of HF (acute decompensated heart failure - ADHF); death for all causes. RESULTS: Among 257 patients, 174 (67.7%) were euthyroid at baseline and after 12 months. Group 1 patients (n. 22, 8.6%) showed a significant improvement in systolic and diastolic function, filling pressures, NT-proBNP and Galectin-3. Group 2 patients (n. 34, 13.2%) did not exhibit significant modifications in studied parameters. Group 3 patients (n. 27, 10.5%) showed worsening of diastolic function and NT-proBNP and a greater risk of ADHF (HR: 2.12; 95%CI: 1.20-3.74; p: 0.009) and death (HR: 4.05; 95%CI: 2.01-8.15; p<0.001). CONCLUSION: In patients with CHF, changes in thyroid function over time influenced echocardiographic parameters and biomarkers reflecting modifications of cardiac function and prognosis, thus suggesting the clinical relevance of thyroid deficiency screening and correction.

Right Ventricular Function in Chronic Heart Failure: From the Diagnosis to the Therapeutic Approach.

There is growing attention for the study of the right ventricle in cardiovascular disease and in particular in heart failure. In this clinical setting, right ventricle dysfunction is a significant marker of poor prognosis, regardless of the degree of left ventricular dysfunction. Novel echocardiographic methods allow for obtaining a more complete evaluation of the right ventricle anatomy and function as well as of the related abnormalities in filling pressures. Specific and effective therapies for the right ventricle dysfunction are still not well defined and this represents the most difficult and important challenge. This article focuses on available diagnostic techniques for studying right ventricle dysfunction as well as on the therapies for right ventricle dysfunction.

Mineralcorticoid Receptor Antagonist Withdrawal for Hyperkalemia and Mortality in Patients with Heart Failure.

BACKGROUND: Hyperkalemia is one of the most frequent side effects related to renin-angiotensin-aldosterone system (RAAS) inhibition, and can influence optimization of heart failure (HF) therapy. AIM: To evaluate the occurrence of hyperkalemia in a series of outpatients with chronic HF and its relationship with RAAS inhibitor therapy. METHOD: We evaluated consecutive outpatients with HF and a reduced left ventricular ejection fraction. The incidence of hyperkalemia and consequent changes in RAAS inhibitor therapy were evaluated for each patient. RESULTS: A history of hyperkalemia or at least 1 episode of hyperkalemia during follow-up was observed in 104 of 351 patients. Hyperkalemia mainly influenced mineralocorticoid receptor antagonist (MRA) therapy and, among patients with hyperkalemia, not taking MRA was associated with a greater risk of death on univariate analysis (HR = 6.39; 95% CI 2.76-14.79, p < 0.001) and multivariate analysis (HR = 5.24; 95% CI 1.87-14.72, p = 0.002) after correction for age, ischemic cardiomyopathy, diabetes, systolic arterial pressure, New York Heart Association class 3, left ventricular ejection fraction, presence of hyponatremia, glomerular filtration rate calculated by the EPI formula, and presence of N-terminal pro-B-type natriuretic peptide >1,000 pg/mL. CONCLUSION: The occurrence of hyperkalemia is common among outpatients with HF and it is the main cause of MRA withdrawal, which is associated with a worse prognosis. In this setting, the possibility of managing hyperkalemia using new classes of drugs could allow continuation of MRA therapy.

Thyroid Disorders and Prognosis in Chronic Heart Failure: A Long-Term Follow-Up Study.

BACKGROUND: Thyroid disorders may have a negative impact on the prognosis of patients affected by chronic heart failure (CHF). OBJECTIVE: The aim of the current study was to evaluate the prognostic role of all thyroid disorders over a long term follow-up in a single centre large sample of CHF outpatients. METHODS: In all patients, the function of the thyroid was evaluated at the enrolment and during the follow- up. On the basis of free triiodothyronine (T3), free thyroxine (fT4) and thyroid-stimulating hormone (TSH) serum levels, patients were classified into one of the following four categories: euthyroid subjects, patients affected by hypothyroidism, low T3 (LT3) syndrome and hyperthyroidism. During the follow-up, death for all causes was assessed as primary end-point, whereas time to the first hospitalization for heart failure worsening was the secondary end-point analyzed. RESULTS: Among 762 patients, 190 patients were affected by hypothyroidism (Hypo). LT3 syndrome was diagnosed in 15 patients and 59 patients were affected by hyperthyroidism (Hyper). During a long term follow-up (5.1±3.7 years), 303 patients died. Patients with Hypo showed an increased risk of death as well as of hospitalization due to heart failure worsening at univariate regression analysis. At multivariate regression analysis, Hypo remained associated with hospitalization after correction for age >75 years, ischemic aetiology, diabetes, therapy with ACE-inhibitors or ARBs, therapy with betablockers and with aldosterone antagonists, NYHA class 3, systolic arterial pressure <95 mmHg, left ventricular ejection fraction <30%, estimated glomerular filtration rate <60 ml/min, hyponatremia and NTproBNP> 1000 pg/ml. At multivariate analysis, the independent association with death was significant only for the subgroup of patients with TSH >10 mIU/L. LT3 was independently associated with both heart failure hospitalization and death, whereas Hyper was not associated with any of the two considered end-points. CONCLUSION: Hypo is associated with a worse prognosis over a long-term follow-up. The association with heart failure hospitalization is not dependent on the baseline TSH levels, whereas the association with death is significant only when TSH >10 mIU/L. Finally, Hyper does not have any association with a worse prognosis.

Association between high Gal-3 serum levels and worsening of renal function in chronic heart failure outpatients.

Aim: The aim of the study was to evaluate the association between Gal-3 serum levels and the progression of renal dysfunction in chronic heart failure outpatients. Methods & results: This prospective study of 260 chronic heart failure patients showed that Gal-3 was associated with 1-year worsening of renal function both in univariate (odds ratio: 1.12; 95% CI: 1.06-1.18; p < 0.001) and in forward stepwise multivariate (odds ratio: 1.09; 95% CI: 1.03-1.15; p = 0.004) logistic regression analyses. Moreover, high Gal-3 levels at baseline were associated with a progressive decline in the estimated glomerular filtration rate. Conclusion: Gal-3 is a biomarker associated with the progression of renal function decline thus further supporting its possible usefulness in predicting cardiorenal syndrome progression.

New Frontiers in the Therapeutic Approach of Patients with Cardiovascular and Endocrine Diseases.

BACKGROUND AND OBJECTIVE: Cardiovascular disease is the most important cause of morbidity and mortality worldwide, with a significant economic burden, which is expected to increase in the next years. Alongside the management of cardiac manifestations and major risk factors for atherosclerosis, great attention has been paid to the role of comorbidities in initiating and worsening cardiac conditions. DISCUSSION: The cardiovascular impact of a broad spectrum of endocrine disorders has been evaluated, with particular regard to their effects on cardiac function and cardiovascular prognosis in affected patients. Among the different endocrine conditions considered, the association between subclinical hypothyroidism and cardiovascular events is still uncertain. A number of observational studies have linked subclinical hypothyroidism (in particular severe elevation of TSH levels) with incident cardiovascular disease and poor prognosis, however thyroid replacement therapy is still controversial, especially in the elderly, due to the lack of evidence coming from randomized controlled trials. With regards to testosterone deficiency, even though it has been associated with metabolic abnormalities and poor prognosis in patients affected by cardiovascular diseases, the cardiac safety of replacement therapy has still to be completely clarified. Similarly, growth hormone deficiency showed detrimental effects on cardiovascular events and risk factors which seem to be reverted by replacement therapy, even if unequivocal evidence from randomized clinical trials is still lacking Another relevant chapter in cardiovascular disease management is about the cardiovascular outcomes of diabetes medical treatments. In recent years, a growing interest has been developed around the cardiovascular safety of antidiabetic medications which has led to a great number of publications addressing this issue for the different classes of antidiabetic drugs. Interestingly, the recently approved classes, i.e. incretins and SGLT-2 inhibitors, have additionally demonstrated a protective effect against major cardiovascular events, shedding new light on the management of diabetes in patients affected by cardiovascular disease. CONCLUSION: Important controversies still exist regarding the cardiac implications of the therapies adopted in endocrine diseases. Owing the large prevalence of these conditions, particularly in the cardiovascular population, further research is awaited in order to clarify the potential advantage and the possible cardiac risk related to treatment of the endocrine comorbidities.

Renal Venous Pattern: A New Parameter for Predicting Prognosis in Heart Failure Outpatients.

AIM OF THE STUDY: In chronic heart failure (CHF) patients, renal congestion plays a key role in determining the progression of renal dysfunction and a worse prognosis. The aim of this study was to define the role of Doppler venous patterns reflecting renal congestion that predict heart failure progression. METHODS: We enrolled outpatients affected by CHF, in stable clinical conditions and in conventional therapy. All patients underwent a clinical evaluation, routine chemistry, an echocardiogram and a renal echo-Doppler. Pulsed Doppler flow recording was performed at the level of interlobular renal right veins in the tele-expiratory phase. The venous flow patterns were divided into five groups according to the fluctuations of the flow. Type A and B were characterized by a continuous flow, whereas type C was characterized by a short interruption or reversal flow during the end-diastolic or protosystolic phase. Type D and E were characterized by a wide interruption and/or reversal flow. The occurrence of death and/or of heart transplantation and/or of hospitalization due to heart failure worsening was considered an event during follow-up. RESULTS: During a median follow-up of 38 months, 126 patients experienced the considered end-point. Venous pattern C (HR 4.04; 95% CI: 2.14⁻7.65; p < 0.001), pattern D (HR 7.16; 95% CI: 3.69⁻13.9; p < 0.001) and pattern E (HR 8.94; 95% CI: 4.65⁻17.2; p < 0.001) were all associated with events using an univariate Cox regression analysis. Moreover, both the presence of pattern C (HR: 1.79; 95% CI: 1.09⁻2.97; p: 0) and of pattern D or E (HR: 1.90; 95% CI: 1.16⁻3.12; p: 0.011) remained significantly associated to events using a multivariate Cox regression analysis after correction for a reference model with an improvement of the overall net reclassification index (0.46; 95% CI 0.24⁻0.68; p < 0.001). CONCLUSIONS: Our findings demonstrate the independent and incremental role of Doppler venous patterns reflecting renal congestion in predicting HF progression among CHF patients, thus suggesting its possible utility in daily clinical practice to better characterize patients with cardio-renal syndrome.

The effects of heart rate control in chronic heart failure with reduced ejection fraction.

Elevated heart rate has been associated with worse prognosis both in the general population and in patients with heart failure. Heart rate is finely modulated by neurohormonal signals and it reflects the balance between the sympathetic and the parasympathetic limbs of the autonomic nervous system. For this reason, elevated heart rate in heart failure has been considered an epiphenomenon of the sympathetic hyperactivation during heart failure. However, experimental and clinical evidence suggests that high heart rate could have a direct pathogenetic role. Consequently, heart rate might act as a pathophysiological mediator of heart failure as well as a marker of adverse outcome. This hypothesis has been supported by the observation that the positive effect of beta-blockade could be linked to the degree of heart rate reduction. In addition, the selective heart rate control with ivabradine has recently been demonstrated to be beneficial in patients with heart failure and left ventricular systolic dysfunction. The objective of this review is to examine the pathophysiological implications of elevated heart rate in chronic heart failure and explore the mechanisms underlying the effects of pharmacological heart rate control.

Heart Failure and Kidney Disease.

Kidney disease is commonly found in heart failure (HF) patients. They share many risk factors and common pathophysiological pathways which often lead to mutual dysfunction. Both haemodynamic and non-haemodynamic mechanisms are involved in the development of renal impairment in heart failure patients. Moreover, the presence of a chronic kidney disease is a significant independent predictor of worse outcome in chronic as well as in acute decompensated HF. As a consequence, an accurate evaluation of renal function plays a key role in the management of HF patients. Serum creatinine levels and glomerular filtration rate (GFR) estimates are the corner stones of renal function evaluation in clinical practice. However, to overcome their limits, several emerging glomerular and tubular biomarkers have been proposed over the last years. Alongside the renal biomarkers, imaging techniques could complement the laboratory data exploring different pathophysiological pathways. In particular, Doppler evaluation of renal circulation is a highly feasible technique that can effectively identify HF patients prone to develop renal dysfunction and with a worse outcome. Finally, some classes of drugs currently used in heart failure treatment can affect renal function and their use can be influenced by the presence of chronic kidney disease.

Right ventriculo-arterial coupling assessed by two-dimensional strain: A new parameter of right ventricular function independently associated with prognosis in chronic heart failure patients.

AIM OF THE STUDY: To evaluate whether right ventriculo-arterial coupling obtained by the estimation of the two-dimensional right ventricular (RV) longitudinal strain and of the pulmonary arterial systolic pressure (PASP) could improve prognostic stratification of chronic heart failure (CHF) outpatients. METHODS: CHF outpatients in a stable clinical condition and in conventional therapy were enrolled. The global RV longitudinal strain (RV-GLS) and the strain of the RV free wall (RV-fwLS) were evaluated. PASP was estimated on the basis of tricuspid regurgitation velocity and the estimated central venous pressure. Both RV-GLS and RV-fwLS were then indexed for PASP. RESULTS: Of the 315 patients evaluated, 69 died during follow-up. Both RV-GLS/PASP and RV-fwLS/PASP were significantly associated with an increased risk of death at univariate (HR: 0.43; 95%CI: 0.34-0.56; p<0.001 and HR: 0.44; 95% CI: 0.34-0.57; p<0.001, respectively) and multivariate analysis (HR: 0.66; 95% CI: 0.49-0.89; p: 0.008 and HR: 0.65; 95% CI: 0.49-0.85; p: 0.002, respectively) after correction for age, NYHA class, mean arterial pressure, left ventricular ejection fraction, natremia, glomerular filtration rate and NT-proBNP. CONCLUSIONS: Indexing RV function, assessed by speckle-tracking analysis, with an estimation of pulmonary systolic arterial pressure provides a parameter of ventricular arterial coupling that is independently associated with an increased risk of mortality.

Role of imaging in the evaluation of renal dysfunction in heart failure patients.

Heart failure and kidney disease share common pathophysiological pathways which can lead to mutual dysfunction, known as cardiorenal syndrome. In heart failure patients, renal impairment is related to hemodynamic and non-hemodynamic factors. Both decreased renal blood flow and renal venous congestion due to heart failure could lead to impaired renal function. Kidney disease and worsening renal function are independently associated with poor prognosis in heart failure patients, both in acute and chronic clinical settings. The aim of this review is to assess the role of renal imaging modalities in the evaluation and management of heart failure patients. Renal imaging techniques could complete laboratory data, as estimated glomerular filtration rate, exploring different pathophysiological factors involved in kidney disease and adding valuable information about renal structure and function. In particular, Doppler examination of arterial and venous hemodynamics is a feasible and non invasive technique, which has proven to be a reliable method for prognostic stratification in patients with cardiorenal syndrome. The renal resistance index, a measure related to renal hemodynamics, can be calculated from the Doppler evaluation of arterial flow. Moreover, the analysis of Doppler venous flow patterns can integrate information from the arterial study and evaluate renal congestion. Other imaging modalities are promising, but still confined to research purposes.

[The APULIA HF multicenter study: efficacy of a management protocol shared between hospital and territorial health services for acute decompensated heart failure patients]. / Studio multicentrico APULIA HF: efficacia di un protocollo di gestione condiviso fra ospedale e territorio dei pazienti ospedalizzati per scompenso cardiaco acuto.

BACKGROUND: The aim of this study was to demonstrate the efficacy of a management model to reduce hospitalizations in patients recently admitted for acute decompensated heart failure. METHODS: The management model was based on a close integration between hospital and territory health services. Clinical evaluation, ECG, echocardiographic findings, total body bioimpedance and brain natriuretic peptide serum levels were used to assess clinical stability of patients at discharge and during follow-up. A dedicated nurse (care manager) was involved in patient empowerment, telephone follow-up, check of adherence to therapy and clinical conditions, and management of scheduled evaluations. All hospitalizations occurring prior to or after enrolment in the municipalities involved in the study were considered, as well as the hospitalizations occurring among enrolled patients. RESULTS: A total of 301 patients were enrolled, 226 of them from the Centers of the Puglia Region, Italy. An overall reduction of 6% in total hospitalizations with DRG 127 was observed; the reduction was most evident in the two centers with the smaller reference population (-16% and -26%, respectively). In the group of patients enrolled, an overall reduction in hospital admissions was observed after comparing the period before and after enrolment. A significant increase in the prescription rate of angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, beta-blockers and aldosterone antagonists was also observed. Finally, an overall reduction in the costs for patient management was demonstrated. Similar results were obtained in the two additional Centers of the Basilicata and Lazio Regions. CONCLUSIONS: An integrated management between hospital and territory allows optimization of the management of heart failure patients, with improvement of therapy and reduction in hospitalizations and management costs.

A Multiparametric Approach Based on NT-proBNP, ST2, and Galectin3 for Stratifying One Year Prognosis of Chronic Heart Failure Outpatients.

Galectin-3 and ST2 are emerging biomarkers involved in myocardial fibrosis. We evaluate the relevance of a multiparametric biomarker approach based on increased serum levels of NT-proBNP, galectin-3, and ST2 in stratifying the prognosis of chronic heart failure (CHF) outpatients. In 315 CHF outpatients in stable clinical condition clinical and echocardiographic evaluations were performed. Routine chemistry and serum levels of NT-proBNP, galectin-3, and ST2 were also assessed. During a 12 month follow-up, cardiovascular death, and/or heart failure (HF) occurred in 64 patients. The presence of NT-proBNP, galectin-3, and ST2 were higher than the recommended cutoffs and were all associated with events at univariate Cox regression analysis, as well as in a multivariate analysis including the three biomarkers. When a score based on the number of biomarkers above the recommended cut-offs was used (in a range of 0-3), it was associated with events both with respect to the univariate (HR 2.96, 95% CI 2.21-3.95, p < 0.001, C-index 0.78) and the multivariate (HR 1.52, 95% CI 1.06-2.17, p: 0.023, C-index 0.87) analyses, after correction for the variables of a reference model. Our results suggest that an easy prognostic approach based on the combination of three biomarkers, although with partially-overlapping pathophysiological mechanisms, is able to identify patients with the highest risk of heart failure progression.