Advanced Congestive Heart Failure Research Articles

Challenging Transcatheter Treatment of a “Complex” Refractory Congestive Heart Failure

A 61-year-old man with a history of postischemic dilated cardiomyopathy was referred in advanced congestive heart failure to our department (Department of Cardiology). He had a history of acute inferolateral myocardial infarction complicated by left ventricular (LV) aneurysm treated elsewhere by coronary artery bypass grafts, aneurysm resection, and automatic implantable cardioverter defibrillator implantation a few years before. At the time of admission, he was in functional New York Heart Association class III-IV with signs and symptoms of congestive heart failure and low cardiac output.

The critical role of respiratory sinus arrhythmia on temporal cardiac dynamics.

Temporal cardiac properties provide alternative information in analyzing heart rate variability (HRV), which may be disregarded by the standard HRV analyses. Patients with congestive heart failure (CHF) are known to have distinct temporal features from the healthy individuals. However, the underlying mechanism leading to the variation remains unclear. Whether or not these parameters can finely classify the severity for CHF patients is uncertain as well. In this work, an electrocardiogram was monitored in advanced CHF patients using 24-h Holter in four conditions, including baseline, one and three months after atenolol therapy, and healthy individuals. Slope and area under the curve (AUC) of multiscale entropy (MSE) curve over short (scales 1-5) and long (scales 6-20) scales, and detrended fluctuation analysis (DFA) scaling exponents at short (4-11 beats) and intermediate (>11 beats) window sizes were calculated. The results show that short-time scale MSE-derived parameters (slope: -0.08 ± 0.10, -0.03 ± 0.10, 0.02 ± 0.06, 0.08 ± 0.06; AUC: 4.03 ± 2.11, 4.69 ± 1.28, 4.73 ± 0.94, and 6.17 ± 1.23) and short-time scale DFA exponent (0.79 ± 0.16, 0.95 ± 0.22, 1.11 ± 0.19, and 1.35 ± 0.20) can hierarchically classify all four conditions. More importantly, simulated R-R intervals with different fractions and amplitude of respiratory sinus arrhythmia (RSA) components were examined to validate our hypothesis regarding the essentiality of RSA in the improvement of cardiovascular function, and its tight association with unpredictability and fractal property of HRV, which is in line with our hypothesis that RSA contributes significantly to the generation of the unpredictability and fractal behavior of HR dynamics.NEW & NOTEWORTHY Temporal cardiac properties provide useful diagnostic parameters for patients with congestive heart failure (CHF). Our study hierarchically classified CHF patients with β-blocker treatment by using multiscale entropy and detrended fluctuation analysis. Also, we provided the evidence to validate the critical role of respiratory sinus arrhythmia in the fractal properties of heart rate variability.

Ischemic Mitral Regurgitation: Current Understanding and Surgical Options.

Secondary, or functional, mitral regurgitation (MR) occurs with impaired coaptation of structurally normal valve leaflets due to abnormal structure and/or function of the left ventricle (LV). A leading cause of functional mitral regurgitation is ischemic cardiomyopathy, resulting in left ventricular dysfunction and subsequent congestive heart failure (CHF) and ischemic mitral regurgitation (IMR). The value of surgical or transcatheter correction of IMR remains controversial, since the underlying pathology of IMR is attributed to a dysfunctional left ventricle. However, even mild IMR has been shown to be harmful to CHF patients, as IMR is both a surrogate of advanced CHF and an independent contributor to CHF morbidity and mortality. While observational and randomized studies have examined surgical treatment of IMR with conflicting outcomes, additional well-designed randomized controlled trials should be performed to further clarify the optimal treatment for IMR. Additionally, close attention should be paid to the quality of interventions performed, as durable reduction in IMR provides the best hope of a positive clinical outcome. This review focuses on the pathophysiology of IMR, current evidence regarding surgical and transcatheter interventions, and future directions in management of IMR.

Hemodynamic Parameters That Predict Success with an Ambulatory Counterpulsation Heart Assist System in Advanced Congestive Heart Failure

Purpose The intravascular ventricular assist system (iVAS) is a long-term, ambulatory counterpulsation heart assist system designed for long term use in patients with advanced congestive heart failure (aCHF). A feasibility trial has been conducted and early analysis showed several pre-implant parameters, particularly cardiac power efficiency (CPE), could predict hemodynamic success. The data has been reanalyzed with completion of the trial. Methods A multicenter, US FDA approved feasibility trial enrolled 44 patients with aCHF to receive the iVAS device as a bridge to transplant or decision. Hemodynamic parameters, including CPE, were collected pre-implantation. CPE is defined as the cardiac power index (CPI) divided by the pulmonary capillary wedge pressure (PCWP). Patients were optimized with inotropes or intra-aortic balloon pumps (IABP). Patients had hemodynamic success (HS) if they were weaned off inotropes and had clinically acceptable hemodynamics. The success (HS) and non-success (NHS) groups were compared. Results Demographics were as follows: the average age was 58.9 ± 7.7, 82% were male, 48% had ischemic cardiomyopathy, the mean pre-operative left ventricular ejection fraction was 23.6 ± 10.7, and 86% were on inotropes and/or an IABP. HS was achieved in 30 patients, 69.8%, with 13 NHS patients, 30.2%. Table 1 displays pre-implant hemodynamics in both groups. While many parameters differed between groups, the most predictive parameter was CPE with an area under the receiver operator curve of 0.986. A CPE cutoff of ≥ 0.0175 has a sensitivity of 92.6% and specificity of 100%. Conclusion Cardiac reserve is required for a counterpulsation device to be effective. This study further supports the use of CPE as a very accurate predictor of hemodynamic success with the iVAS device. This parameter combines power and preload to better assess a patient's cardiac reserve and improve patient selection.

A Long-Term Counterpulsation Heart Assist System Used as a Bridge to Decision in Advanced Congestive Heart Failure

Purpose The intravascular ventricular assist system (iVAS) is a minimally invasive, ambulatory, counterpulsation heart assist system that is inserted through the subclavian artery and sits in the descending aorta. It has been evaluated in a feasibility trial with expanded indications to include patients who were a bridge to decision (BTD). The objective was to evaluate the role of iVAS as a BTD device. Methods As part of a multicenter US FDA approved feasibility trial, 13 of 44 patients were implanted with iVAS as a BTD. Patients were in advanced congestive heart failure (CHF), did not have an irreversible contraindication to transplant, and were not listed at the time of implantation. Results Four patients were bridge to candidacy (BTC) due to substance abuse - three received a transplant and one is still in a probationary period. Two patients were Jehovah's Witnesses who needed their anemia and end organ function to improve prior to escalation of therapy. Both had comorbidities that precluded transplant and they received a left ventricular assist device (LVAD). One patient was implanted for recovery but the anatomy of his aorta proved incompatible with an iVAS and he received a LVAD. Two patients were initially too frail to receive a LVAD or transplant - one improved and received a transplant and the other is ongoing as a BTC. Two patients received an iVAS for intractable angina. One patient had transplant arteriopathy but also had severe peripheral vascular disease that precluded transplant. The iVAS was explanted after a year and symptom improvement. The other patient had nonrevascularizable coronary disease and had relief of his angina but died suddenly at home from an unknown cause. Two patients had cardiogenic shock after myocardial infarction and were supported for over 6 months. The average duration of iVAS support was 129 ± 101 days. At the time of iVAS implant, 8/13 patients had contraindications to LVAD. At 6 months, 11/13 had been successfully supported with iVAS and reached the intended goal. Conclusion The utility and versatility of the iVAS as a BTD was demonstrated in this trial. Outcomes were excellent in very challenging patients, many with contraindications for LVADs. The iVAS allowed a variety of patients time to improve their physical condition and transplant candidacy and is an important adjunct in treating complex advanced CHF patients.

Intra-Aortic Balloon Pumps as Bridge to Heart Transplantation - A Single Center Experience

Purpose An intra-aortic balloon pump (IABP) can help optimize and bridge to transplant (BTT) patients with advanced congestive heart failure. We retrospectively reviewed the application and safety of this technique at our center. Methods Between January 2016 and April 2018, 32 patients underwent IABP as BTT including femoral (n=11), subclavian (n=17), and axillary (n=4) approaches with a median duration of support of 5 (IQR 3;14), 18 (IQR 15;36) and 30 (IQR 18;39) days, respectively. Results The mean age was 57.5 +/- 9.4 years, 15 (48%) had NICM, and 30 (94%) patients were in INTERMACS 1&2 profiles. Prolonged IABP support was associated with significant improvements in mean pulmonary artery pressure (from 35.8 +/- 11.1 to 28.2 +/- 7.9, p=0.02); cardiac index (from 2.0 +/- 0.5 to 2.5 +/- 0.6, p Conclusion IABP provides reasonable hemodynamic support for BTT in many patients with end stage heart failure; however, over one third developed complications of prolonged support. Further investigation is needed to identify which patients are most appropriate for BTT IABP.

Palliative care need in patients with advanced heart failure hospitalized in a tertiary hospital.

To evaluate the need for palliative care in patients with advanced Congestive Heart Failure (CHF) hospitalized in a cardiology ward. Application of the World Health Organization Palliative Needs tool (NECPAL) with the assistant physician, patient and/or caregiver for evaluation of indication of Palliative Care (PC). 82 patients with a diagnosis of class III/IV Heart Failure or ejection fraction less than or equal to 40% in echocardiography of the last 12 months were included: Mean age 68 ± 20 years, 51 male patients and 31 female patients. Forty-three patients (52.4%) were married or in consensual union and ten (12%) lived alone. The death of 46 patients (56.1%) in the subsequent 12 months would not surprise their physician, and forty-five patients (55%) had palliative care indication according to the NECPAL. About half of patients hospitalized for class III/IV Heart Failure would have an indication of Palliative Care for the relief of suffering caused by the disease.

Effects of milrinone on inflammatory response-related gene expressions in cultured rat cardiomyocytes.

Congestive heart failure (CHF) is defined as a cardiac dysfunction leading to low cardiac output and inadequate tissue perfusion. Intravenous positive inotropes are used to increase myocardial contractility in hospitalized patients with advanced heart failure. Milrinone is a phosphodiesterase Ⅲ inhibitor and used most commonly for inotropic effect. The well-known PROMISE study investigated the effects of milrinone on mortality in patients with severe CHF, and concluded that long-term therapy with milrinone increased morbidity and mortality among patients with advanced CHF. Previous studies have suggested that phosphodiesterase inhibitors can have potential effects on inflammatory pathways. Hence, we hypothesized that milrinone may alter inflammatory gene expressions in cardiomyocytes, thus leading to adverse clinical outcomes. We used rat cardiomyocyte cell line H9C2 and studied the impact of exposing cardiomyocytes to milrinone (10 μmol/L) for 24 hours on inflammatory gene expressions. RNA extracted from cultured cardiomyocytes was used for whole rat genome gene expression assay (41,000 genes). The following changes in inflammatory response-related gene expressions were discovered. Genes with increased expressions included: THBS2 (+9.98), MMP2 (+3.47), DDIT3 (+2.39), and ADORA3 (+3.5). Genes with decreased expressions were: SPP1 (-5.28) and CD14 (-2.05). We found that the above mentioned gene expression changes seem to indicate that milrinone may hinder the inflammatory process which may potentially lead to adverse clinical outcomes. However, further in vivo and clinical investigations will be needed to illustrate the clinical relevance of these gene expression changes induced by milrinone.

Clinical Impact of Diabetes Mellitus on Short-Term Outcomes andIn-Hospital Mortality of Cardiac Mechanical Support with Left Ventricular Assist Device (LVAD): A Retrospective Study from a National Database.

Cardiac support with left ventricular assist devices (LVAD) is a growing field. LVAD are increasingly used for patients with advanced congestive heart failure. Multiple studies have evaluated the outcomes of cardiac support with LVAD in patients with and without diabetes mellitus (DM), yet we still have conflicting results. This study aimed to assess the clinical impact of diabetes mellitus on patients undergoing cardiac support with LVAD. Diabetic patients who underwent mechanical support with LVAD between 2011 and 2014 were identified in the National Inpatient Sample (NIS) database using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The primary outcome was the effect of diabetes mellitus on inpatient mortality. Secondary outcomes were the impact of diabetes on other immediate post-LVAD complications and the cost of hospitalization. Multivariable logistic regression models analysis was performed to address potential confounding. After adjusting for patient-level and hospital-level characteristics, diabetic patients who underwent cardiac support with LVAD have no significant increase in in-hospital mortality (OR: 0.79, 95% CI (0.57-1.10), p = 0.166), post-LVAD short-term complications and cost of hospitalization (OR: 0.97, 95% CI (0.93-1.01), p = 0.102). Cardiac mechanical support with LVAD implantation is feasible and relatively safe in patients with diabetes and stage-D heart failure as a bridge for transplantation or as destination therapy for patients who are not candidates for transplantation. However, further trials and studies using bigger study sample and more comprehensive databases, need to be conducted for a stronger and more valid evidence.

The Use of Intranasal Fentanyl for the Palliation of Incident Dyspnea in Advanced Congestive Heart Failure: A Pilot Study

Background:Dyspnea is distressing in palliative patients with end-stage heart failure and many are hospitalized to optimize this symptom. We hoped to conduct a pilot study to determine whether the ...

Respiratory syncytial virus-associated illness in adults with advanced chronic obstructive pulmonary disease and/or congestive heart failure.

BackgroundRespiratory syncytial virus (RSV) is recognized as a serious pathogen in people with chronic cardiopulmonary conditions. Immunoprophylaxis might be considered for adults at high‐risk for frequent and severe RSV infection. Thus, we studied the incidence of RSV‐related medically attended acute respiratory illness (MARI) in adults with severe chronic obstructive pulmonary disease (COPD) and/or congestive heart failure (CHF).MethodsSubjects ≥50 years of age with Gold Class III/IV COPD and/or American Heart Association class III/IV CHF and exposure to children ≥once per month were recruited. Subjects were evaluated over 1.5 to 2.5 years for RSV‐associated MARI, defined as polymerase chain reaction (PCR) and/or seroresponse.ResultsFour hundred forty‐five subjects were enrolled between October 2011 and May 2012. Overall, 99 RSV infections were documented by PCR or serology for a cumulative incidence of 22.2%. Of these, 42 (9.4%) subjects had protocol‐specified RSV‐MARI for an incidence of 4.68/100 patient‐seasons. All‐cause MARI was common (63.85/100 patient‐seasons) with rhinovirus most commonly identified.ConclusionRSV infection was common in adults with severe COPD and/or advanced CHF. Given the severity of underlying cardiopulmonary diseases in the study population, most illnesses were surprisingly mild. Thus, active immunization rather than passive immunoprophylaxis with monoclonal antibodies may be a more cost‐effective strategy.

Study protocol for a cohort study of patients with advanced heart failure in Singapore

IntroductioUnderstanding the symptom and health expenditure burden among patients with advanced congestive heart failure (CHF) and their family caregivers is essential to reform policy and practice needed to provide quality...

Associations between understanding of current treatment intent, communication with healthcare providers, preferences for invasive life-sustaining interventions and decisional conflict: results from a survey of patients with advanced heart failure in Singapore

ObjectivesTo make informed choices about use of future invasive life-sustaining interventions (ILSI), patients with congestive heart failure (CHF) need to correctly understand the intent of their current treatments. However, healthcare...

The Use of Intranasal Fentanyl for the Palliation of Incident Dyspnea in Advanced Congestive Heart Failure: A Pilot Study.

Dyspnea is distressing in palliative patients with end-stage heart failure and many are hospitalized to optimize this symptom. We hoped to conduct a pilot study to determine whether the administration of intranasal fentanyl would decrease activity-induced dyspnea in this patient population. Patients performed two 6-minute walk tests with and without the administration of 50 μg of intranasal fentanyl. Vital signs were recorded before and after each walk, as were participant reported dyspnea and adverse events scores. Twenty-four patients were screened, 13 were deemed eligible, and 6 completed the study. Dyspnea scores changed from a mean of 6.00 immediately after the walk without fentanyl to a mean of 3.83 after the walk with fentanyl ( P = .048). Mean respiratory rate decreased from 21.0 to 18.7 ( P = .034) breaths per minute and was considered a favorable outcome by the participants. Distance walked did not significantly increase with the fentanyl pretreatment (136.0-144.2 m; P = .283), although the participants reported feeling better while walking a similar distance. In this pilot study, the preadministration of intranasal fentanyl prior to activity in palliative, end-stage hospitalized heart failure patients, safely reduced tachypnea, and the feeling of shortness of breath. This approach may help palliate advanced heart failure patients by alleviating symptoms brought on by exertional activities.

Optimal hydration volume among high-risk patients with advanced congestive heart failure undergoing coronary angiography.

We investigated the relationship between weight-adjusted hydration volumes and the risk of developing contrast-induced acute kidney injury (CI-AKI) and worsening heart failure (WHF) and explored the relative safety of optimal hydration volumes in patients with advanced congestive heart failure (CHF) undergoing coronary angiography (CAG) or percutaneous coronary intervention. We included 551 patients with advanced CHF (New York Heart Association class > 2 or history of pulmonary edema) undergoing CAG (follow-up period 2.62 ± 0.9 years). There was a significant association between hydration volume-to-weight ratio (HV/W) (quintile Q1, Q2, Q3, Q4, and Q5) and the incidence of CI-AKI (3.7%, 14.6%, 14.3%, 21.1%, and 31.5%, respectively) and WHF (3.6%, 5.4%, 8.3%, 13.6%, and 19.1%, respectively) (all P-trend < 0.001). Receiver operating curve analysis indicated that HV/W = 15 mL/kg and the mean HV/W (60.87% sensitivity and 64.96% specificity) were fair discriminators for CI-AKI (C-statistic 0.696). HV/W >15 mL/kg independently predicted CI-AKI (adjusted odds ratio [OR] 2.33; P = 0.016) and WHF (adjusted OR 2.13; P = 0.018). Moreover, both CI-AKI and WHF were independently associated with increased long-term mortality. Thus, for high-risk patients with advanced CHF undergoing CAG, HV/W > 15 mL/kg might be associated with an increased risk of developing CI-AKI and WHF. The potential benefits of a personalized limitation of hydration volume need further evaluation.

It's Time to Talk: Challenges in Providing Integrated Palliative Care in Advanced Congestive Heart Failure. A Narrative Review.

Background:Congestive heart failure is an increasingly prevalent terminal illness in a globally aging population. Prognosis for this disease remains poor despite optimal therapy. Evidence suggests that a palliative care approach may be beneficial – and is currently recommended – in advanced congestive heart failure but these services remain underutilized.Objectives:To identify the main challenges to the access and delivery of palliative care in patients with advanced congestive heart failure, and to summarize recommendations for clinical practice based on the available literature.Methods:MEDLINE and EMBASE were searched for articles published from 1995-2017 pertaining to end of life care in individuals suffering from CHF. Only four randomized controlled trials were found.Results:We identified ten key challenges to access and delivery of palliative care services in this patient population: (1) Prognostic uncertainty, (2) Provider education/training, (3) Ambiguity surrounding coordination of care, (4) Timing of palliative care referral, (5) Inadequate community supports, (6) Difficulty communicating uncertainty, (7) Fear of taking away hope, (8) Insufficient advance care planning, (9) Inadequate understanding of illness, and (10) Discrepant patient/family care goals. Provider and patient education, early discussion about prognosis, and a multidisciplinary team-based approach are recommended as we move towards a model where symptom palliation exists concurrently with active disease-modifying therapies.Conclusion:Despite evidence that palliative care may improve symptom control and quality of life in patients with advanced congestive heart failure, a multitude of current challenges hinder access to these services. Education, early discussion of prognosis and advance care planning, and multidisciplinary team-based care may be a helpful initial approach as further targeted work addresses these challenges.

Ambulatory Intra Aortic Balloon Pump in Advanced Heart Failure.

Cardiac transplantation is the gold standard treatment for patients with advanced congestive heart failure that is refractory to maximal medical therapy. However, donor heart availability remains the major limiting factor, resulting in a large number of patients waiting long periods of time before transplantation. As a result, mechanical circulatory support devices have been increasingly used as a 'bridge' in order to sustain organ function and stabilise haemodynamics while patients remain on the transplant waiting list or undergo left ventricular assist device surgery. Intra aortic balloon pumps (IABP) are commonly used for temporary circulatory support in patients with advanced heart failure. IABP is traditionally placed percutaneously through the transfemoral artery approach. The major limitation with this approach is ambulatory restriction that can promote deconditioning, particularly in situations of prolonged circulatory support. A subclavian/axillary artery approach IABP insertion allows patients to be ambulatory during the pre-transplant period. In this review, we aim to summarise the physiology of IABP, the evidence for its use in advanced CHF and the efficacy and safety of subclavian artery IABP insertion.

The first-in-human experience with a minimally invasive, ambulatory, counterpulsation heart assist system for advanced congestive heart failure

The intravascular ventricular assist system (iVAS) is a new, minimally invasive, ambulatory counterpulsation heart assist system delivered via the subclavian artery and powered by a portable driver. It is designed for recovery, bridge to transplantation (BTT) or for prolonging medical therapy. We report the first-in-human (FIH) experience with iVAS. This is a prospective, non-randomized single arm, U.S. Food and Drug Administration (FDA)-approved early feasibility trial in patients listed for cardiac transplantation. The primary end-point was survival to transplant or stroke-free survival at 30 days. Fourteen patients were enrolled and 13 (92.8%) were treated with iVAS. At time of implant, the average age was 58 ± 6.7 years; 85% were male; 28% had ischemic cardiomyopathy; and 3 were Interagency Registry for Mechanically Assisted Devices (INTERMACS) Level 2, 9 were Level 3, and 1 was Level 4. The mean left ventricular ejection fraction was 22%, left ventricular internal diameter diastole was 7.13 mm, and 69% had moderate or severe mitral regurgitation. There were no intra-operative complications. Intensive care unit stay after implant was 6 ± 6 days. All patients were transplanted after 32 ± 21 days. There were no deaths or thromboembolic events: 1 patient required escalation of mechanical support, and post-implant complications included pleuritis/pericarditis (n = 1) and neuropathy (n = 2). No intra-operative blood transfusions were required. This study demonstrates a high rate of successful outcomes with an excellent risk-to-benefit profile. This FIH experience reveals that the iVAS can be successfully inserted in a standardized approach, provide hemodynamic support, can be interrupted for short periods, and allows for ambulation. A multicenter trial to investigate effectiveness and safety is warranted.

Efficacy and safety of dronedarone in the treatment of patients with atrial fibrillation

ABSTRACTIntroduction: Dronedarone, a derivative of amiodarone with structural modifications, was designed to have similar electrophysiological properties with a less toxic profile.Areas covered: Brief overview of the pharmacology of dronedarone followed by a summary of randomized clinical trials testing the efficacy of dronedarone in maintaining normal sinus rhythm and clinical outcomes associated with these trials. In depth discussion and commentary on trial findings which may seem contradictory at first approach and brief discussion of post-marketing surveillance studies.Expert opinion: Dronedarone is a moderately efficacious anti-arrhythmic agent which is safe for use in a carefully selected patient population, maintained in normal sinus rhythm, without advanced congestive heart failure, structural heart disease, permanent atrial fibrillation, digoxin use. It is especially useful in younger patients who lack other risk factors for cardiovascular events and, who stand to gain the most by avoiding long-term pulmonary and thyroid toxicities associated with more effective, but also significantly more toxic agents such as amiodarone.

The Diabetic Foot as a Proxy for Cardiovascular Events and Mortality Review.

This article reviewed very recent papers (2016) discussing or bringing clinical evidences of the possible common pathways leading to diabetic foot syndrome (DFS) and increased mortality rates. Diabetic patients with diabetic foot syndrome have a mortality rate greater than twofold when compared with non-ulcerated diabetics. In addition, the 5-year mortality rate following amputation is estimated at 39-68%, a life expectancy comparable to aggressive types of cancer or advanced congestive heart failure. The majority of patients with diabetic foot ulcer also present insulin resistance, central obesity, dyslipidemia, and hypertension that characterize the metabolic syndrome that, in turn, is associated with an elevated risk of major cardiovascular events. Sensory neuropathy is the primary cause of more the 60% of diabetic foot ulcer. Diabetic peripheral neuropathy is a microvascular complication of diabetes mellitus and in type 2 diabetes, not only hyperglycemia but also other metabolic alterations and persistent inflammatory status due to adiposity play a major role in axon injury. Elevated triglycerides have been showed to be an independent risk factor for lower extremity amputation in diabetic patients. Also, toxic adiposity, oxidative stress, mitochondrial dysfunction, activation of the polyol pathway, accumulation of advanced glycation end products (AGEs), and elevation of inflammatory markers are also implicated in diabetic vascular disease and neuropathy. The hypotheses that the association between DFS and increased rates of mortality reflects the progression of micro- and macrovascular complications are reinforced by the additional association of DFU to renal failure and retinopathy.