The Effect of Sodium-Glucose Cotransporter Inhibitors on Renal Function as Adjunctive to Insulin in Adults with Type 1 Diabetes: An Updated Multilevel Meta-analysis of Randomized Controlled Trials.

INTRODUCTION: This systematic review aimed to summarize the existing evidence from published randomized controlled trials (RCTs) on the impact of sodium-glucose cotransporter (SGLT) inhibitors on albuminuria levels and renal function in patients with type 1 diabetes mellitus (T1D). METHODS: The literature search was performed through Medline (via PubMed), Cochrane Library, and Scopus until November 11, 2023. Double-independent study selection, data extraction, and quality assessment were performed. Evidence was pooled with three-level mixed-effects meta-analysis. RESULTS: In total, 5221 participants with T1D among 11 RCTs were analyzed. All RCTs had low risk of bias according to the Cochrane Collaboration tool (RoB 2). SGLT inhibitors were associated with a significantly greater reduction in urine albumin-to-creatinine ratio (UACR) compared to controls (MD = - 23.13%; 95% CI = [- 33.69, - 12.57]; P < 0.001; level of evidence high). On the basis of subgroup analysis, this effect was consistent across all available SGLT inhibitors, irrespective of the dosage. Finally, a neutral class effect was observed on the estimated glomerular filtration rate (eGFR, MD = - 1.03 mL/min/1.73 m2; 95% CI = [- 2.26, 0.19]; P = 0.1; level of evidence moderate). Only empagliflozin was associated with a significant reduction in eGFR compared to placebo (MD = - 2.23 mL/min/1.73 m2; 95% CI = [- 3.62, - 0.84]; P = 0.002). CONCLUSION: Our findings suggest that adjunctive therapy with SGLT inhibitors results in a significant reduction in albuminuria, while their use is associated with a neutral effect on creatinine clearance, as a measure of renal function. Future renal outcome trials are needed to assess SGLT inhibitors' role in the pharmacological armamentarium against diabetic nephropathy in T1D.

Effect of tirzepatide on albuminuria levels and renal function in patients with type 2 diabetes mellitus: A systematic review and multilevel meta-analysis.

AIM: The present systematic review aimed to summarize the available evidence from published randomized controlled trials (RCTs) regarding the effect of tirzepatide on albuminuria levels and renal function in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: Medline (via PubMed), Cochrane Library and Scopus were searched until 20 October 2023. Double-independent study selection, data extraction and quality assessment were performed. Evidence was pooled with a three-level mixed-effects meta-analysis. RESULTS: In total, 9533 participants from eight RCTs were analysed. All RCTs had a low risk of bias, according to the Cochrane Collaboration tool (RoB2). Tirzepatide was associated with a significantly greater reduction in urine albumin-to-creatinine ratio compared with controls [mean difference (MD) -26.9%; 95% confidence interval (CI) (-34.76, -19.04); p < .001; level of evidence (LoE) moderate]. This effect remained significant in participants with baseline urine albumin-to-creatinine ratio ≥30 mg/g [MD -41.42%; 95% CI (-54.38, -28.45); p < .001; LoE moderate]. Based on subgroup analysis, the comparative effect of tirzepatide was significant against placebo and the insulin regimen, whereas no difference was observed compared with semaglutide. The beneficial effect of tirzepatide on albuminuria levels remained significant across all investigated doses (5, 10 and 15 mg), showing a dose-response relationship. A neutral effect was observed on the estimated glomerular filtration rate [MD 0.39 ml/min/1.73m2 ; 95% CI (-0.64, 1.42); p = .46; LoE moderate]. CONCLUSION: Our findings suggest that tirzepatide probably leads to a significant reduction in albuminuria across all administered doses, while its use is associated with a neutral effect on creatinine clearance as a measure of renal function.

Prognostic value of ΔSYNTAX% score in octogenarians undergoing percutaneous coronary intervention.

OBJECTIVES: To verify whether incomplete revascularisation (IR), quantified using the rSYNTAX (Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) score and ΔSYNTAX% score, could predict short- (in-hospital mortality) and long-term outcomes (12-month mortality) in octogenarians undergoing percutaneous coronary intervention (PCI). METHODS & RESULTS: A retrospective analysis of 665 consecutive octogenarian patients presenting for PCI to a UK centre was performed. The baseline SYNTAX and rSYNTAX scores were assessed from angiographic images. ΔSYNTAX% score was calculated (ΔSYNTAX% = ((SYNTAX - rSYNTAX)/SYNTAX) × 100%)) to measure the relative completeness of revascularisation. Kaplan-Meier analysis assessed survival at 12 months by tertiles of rSYNTAX and ΔSYNTAX% scores. Increasing ΔSYNTAX% score was associated with reduced in-hospital mortality (P = 0.017), and improved survival benefit (log rank 14.8, P = 0.001) at 12 months. CONCLUSIONS: Enhancing the completeness of revascularisation in octogenarians selected to undergo PCI is associated with a lower in-hospital mortality and a survival benefit at 12 months.

Tirzepatide for the treatment of heart failure in Type 2 diabetes mellitus: (SUR)PASS, or not?

Type 2 diabetes mellitus (T2DM) is a rising pandemic, while cardiovascular disease, including heart failure, represents a frequent concomitance, increasing overall morbidity and mortality and, of course, healthcare cost. Tirzepatide is a dual agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, constituting a novel treatment option in T2DM. This agent exerts additional effects in addition to improvement in glycemic control, which can be of benefit for individuals with T2DM, especially those at risk for or with established cardiovascular disease or heart failure. Current evidence is limited, although suggestive of the cardiovascular safety of tirzepatide. This article provides an overview of available evidence regarding the use of tirzepatide in T2DM, with emphasis on clinical efficacy.

Iron therapy and severe arrhythmias in HFrEF: rationale, study design, and baseline results of the RESAFE-HF trial.

AIMS: The Iron Intravenous Therapy in Reducing the burden of Severe Arrhythmias in HFrEF (RESAFE-HF) registry study aims to provide real-word evidence on the impact of intravenous ferric carboxymaltose (FCM) on the arrhythmic burden of patients with heart failure with reduced ejection fraction (HFrEF), iron deficiency (ID), and implanted cardiac implantable electronic devices (CIEDs). METHODS AND RESULTS: The RESAFE-HF (NCT04974021) study was designed as a prospective, single-centre, and open-label registry study with baseline, 3, 6, and 12 month visits. Adult patients with HFrEF and CIEDs scheduled to receive IV FCM as treatment for ID as part of clinical practice were eligible to participate. The primary endpoint is the composite iron-related endpoint of haemoglobin ≥ 12 g/dL, ferritin ≥ 50 ng/L, and transferrin saturation > 20%. Secondary endpoints include unplanned HF-related hospitalizations, ventricular tachyarrhythmias detected by CIEDs and Holter monitors, echocardiographic markers, functional status (VO2 max and 6 min walk test), blood biomarkers, and quality of life. In total, 106 patients with a median age of 72 years (14.4) were included. The majority were male (84.9%), whereas 92.5% of patients were categorized to New York Heart Association II/III. Patients' arrhythmic burden prior to FCM administration was significant-19 patients (17.9%) received appropriate CIED therapy for termination of ventricular tachyarrhythmia in the preceding 12 months, and 75.5% of patients have frequent, repetitive multiform premature ventricular contractions. CONCLUSIONS: The RESAFE-HF trial is expected to provide evidence on the effect of treating ID with FCM in HFrEF based on real-world data. Special focus will be given on the arrhythmic burden post-FCM administration.

Syncope without prodromes is associated with excessive plasma release of adenosine at the time of syncope during head-up tilt table test.

BACKGROUND: In syncopal patients without underlying structural disease, we sought to investigate the association of Adenosine Plasma Levels (ADP) with the clinical presentation of neurally mediated syncope (NMS) and the outcomes of Head-Up Tilt Table Test (HUTT) and Adenosine test (ADT). METHODS: We studied 124 patients with different clinical types of NMS, i.e., Vasovagal (VVS, n=58), non-prodromes (NPS, n=18), or situational syncope (SS, n=48), using a standard protocol including HUTT and ADT. During HUTT, ADP was measured in the supine position, at table tilting and in syncope. RESULTS: Baseline ADP did not differ among groups. ADP at syncope were higher in NPS (n=5) compared to VVS (n=20): 0.23 vs. 0.12 µΜ, p=0.03, and SS (n=22): 0.04 µΜ, p=0.02. In NPS, ADP increased from supine to syncope (n=5): 0.15 vs. 0.23 µΜ, p=0.04. In VVS, ADP increased only from supine to tilt position: 0.11 vs. 0.14 µΜ, p=0.02. In SS, ADP did not change during HUTT. In positive vasodepressor HUTT, ADP increased from supine to tilt position (p=0.002) and at syncope (p=0.01). In SS, 20.0% exhibited cardioinhibitory HUTT vs. 6.8% in other forms of syncope (p=0.04). In SS, 22.9% manifested positive ADT vs 6.6% in other types of syncope (p=0.012). CONCLUSION: The subset of NPS patients with positive HUTT, show excessive ADP release at the time of syncope. This may explain the lack of prodromes in this form of syncope. Such observations contribute to the understanding of distinct profiles of clinical forms of syncope and may differentiate the management approach accordingly.

The impact of atrial mechanical function on age-dependent presentation of neurocardiogenic syncope.

BACKGROUND: The contribution of atrial and ventricular function in neurocardiogenic syncope (NCS) pathophysiology is elusive. HYPOTHESIS: We assessed the influence of echocardiographic properties to the age of presentation and NCS recurrences. METHODS: We assigned 124 patients with symptoms suggesting NCS, to those with syncope initiation at age <35 (group A, n = 56) and >35 years (group B, n = 68). Echocardiographic indices were measured before head-up tilt test (HUTT). RESULTS: A total of 55 had positive HUTT (44%) with a trend favoring group A (p = .08). Group A exhibited lower left atrial (LA) volume index (17 ± 6 vs. 22 ± 11 ml/m2 , p = .015), higher LA ejection fraction (69 ± 10 vs. 63 ± 11%, p = .008), LA peak strain (reservoir phase 41 ± 13 vs. 31 ± 14%, p = .001, contraction phase 27 ± 11 vs. 15 ± 10%, p < .001) and LA peak strain rate (reservoir phase 1.83 ± 1.04 vs. 1.36 ± 0.96 1/s, p = .012, conduit phase 2.36 ± 1.25 vs. 1.36 ± 0.78 1/s, p = .001). Group A showed smaller minimum right atrial (RA) volume, better RA systolic function, superior left ventricular diastolic indices, and lower filling pressures. Group A patients were more likely to have >3 recurrences (82.0% vs. 50.1%, p < .05). CONCLUSIONS: Patients with younger age of NCS onset and more syncopal recurrences manifest smaller LA and RA dimensions with distinct patterns of systolic and diastolic function and better LA reservoir and contraction properties. These findings may indicate an increased susceptibility to preload reduction, thereby triggering the NCS mechanism.

Efficient syncope prediction from resting state clinical data using wavelet bispectrum and multilayer perceptron neural network.

Neurally mediated syncope (NMS) is the most common type of syncope, and head up tilt test (HUTT) is, so far, the most appropriate tool to identify NMS. In this work, an effort to predict the NMS before performing the HUTT is attempted. To achieve this, the heart rate variability (HRV) at rest and during the first minutes of tilting position during HUTT was analyzed using both time and frequency domains. Various features from HRV regularity and complexity, along with wavelet higher-order spectrum (WHOS) analysis in low-frequency (LF) and high-frequency (HF) bands were examined. The experimental results from 26 patients with history of NMS have shown that at rest, a time domain entropy measure and WHOS-based features in LF band exhibit significant differences between positive and negative HUTT as well as among 10 healthy subjects and NMS patients. The best performance of multilayer perceptron neural network (MPNN) was achieved by using an input vector consisted of WHOS-based HRV features in the LF zone and systolic blood pressure from the resting period, yielding an accuracy of 89.7%, assessed by 5-fold cross-validation. The promising results presented here pave the way for an early prediction of the HUTT outcome from resting state, contributing to the identification of patients at higher risk NMS. The HRV analysis along with systolic blood pressure at rest predict NMS using a multilayer perceptron neural network.

Is the Adenosine Test Obsolete in the Clinical Assessment of Syncope of Unknown Origin?

Syncope is a common clinical condition affecting 50% of the general population; however, its exact pathophysiology and underlying mechanisms remain elusive. The adenosine test (ADT) has been proposed as a complementary diagnostic test in the work-up of syncope of unknown origin aiming to further elucidate the underlying pathogenetic mechanism of spontaneous syncope. Although ADT has not been endorsed by the recent European Society of Cardiology guidelines on syncope management, the use of a quick, safe and non-invasive test which can contribute to an accurate diagnosis and rationalised therapy, may deserve further consideration. This review summarises the evidence on the role of ADT in the investigation and management of syncope of unknown origin and highlights future perspectives in this area. The authors also analyse the current challenges and research targets on adenosine plasma levels and its receptors due to the involvement of the adenosine pathway in the ADT response.

Iron deficiency as therapeutic target in heart failure: a translational approach.

Heart failure (HF) is a potentially debilitating condition, with a prognosis comparable to many forms of cancer. It is often complicated by anemia and iron deficiency (ID), which have been shown to even further harm patients' functional status and hospitalization risk. Iron is a cellular micronutrient that is essential for oxygen uptake and transportation, as well as mitochondrial energy production. Iron is crucially involved in electrochemical stability, maintenance of structure, and contractility of cardiomyocytes. There is mounting evidence that ID indeed hampers the homeostasis of these properties. Animal model and stem cell research has verified these findings on the cellular level, while clinical trials that treat ID in HF patients have shown promising results in improving real patient outcomes, as electromechanically compromised cardiomyocytes translate to HF exacerbations and arrhythmias in patients. In this article, we review our current knowledge on the role of iron in cardiac muscle cells, the contribution of ID to anemia and HF pathophysiology and the capacity of IV iron therapy to ameliorate the patients' arrhythmogenic profile, quality of life, and prognosis.

Arrhythmic risk stratification in post-myocardial infarction patients with preserved ejection fraction: the PRESERVE EF study.

AIMS: Sudden cardiac death (SCD) annual incidence is 0.6-1% in post-myocardial infarction (MI) patients with left ventricular ejection fraction (LVEF)≥40%. No recommendations for implantable cardioverter-defibrillator (ICD) use exist in this population. METHODS AND RESULTS: We introduced a combined non-invasive/invasive risk stratification approach in post-MI ischaemia-free patients, with LVEF ≥ 40%, in a multicentre, prospective, observational cohort study. Patients with at least one positive electrocardiographic non-invasive risk factor (NIRF): premature ventricular complexes, non-sustained ventricular tachycardia, late potentials, prolonged QTc, increased T-wave alternans, reduced heart rate variability, abnormal deceleration capacity with abnormal turbulence, were referred for programmed ventricular stimulation (PVS), with ICDs offered to those inducible. The primary endpoint was the occurrence of a major arrhythmic event (MAE), namely sustained ventricular tachycardia/fibrillation, appropriate ICD activation or SCD. We screened and included 575 consecutive patients (mean age 57 years, LVEF 50.8%). Of them, 204 (35.5%) had at least one positive NIRF. Forty-one of 152 patients undergoing PVS (27-7.1% of total sample) were inducible. Thirty-seven (90.2%) of them received an ICD. Mean follow-up was 32 months and no SCDs were observed, while 9 ICDs (1.57% of total screened population) were appropriately activated. None patient without NIRFs or with NIRFs but negative PVS met the primary endpoint. The algorithm yielded the following: sensitivity 100%, specificity 93.8%, positive predictive value 22%, and negative predictive value 100%. CONCLUSION: The two-step approach of the PRESERVE EF study detects a subpopulation of post-MI patients with preserved LVEF at risk for MAEs that can be effectively addressed with an ICD. CLINICALTRIALS.GOV IDENTIFIER: NCT02124018.

Electrocardiographic conduction and repolarization markers associated with sudden cardiac death: moving along the electrocardiography waveform.

The QT interval along with its heart rate corrected form (QTc) are well-established ECG markers that have been found to be associated with malignant ventricular arrhythmogenesis. However, extensive preclinical and clinical investigations over the years have allowed for novel clinical ECG markers to be generated as predictors of arrhythmogenesis and sudden cardiac death. Repolarization markers include the older QTc, QT dispersion and newer Tpeak - Tend intervals, (Tpeak - Tend) / QT ratios, T-wave alternans (TWA), microvolt TWA and T-wave area dispersion. Meanwhile, conduction markers dissecting the QRS complex, such as QRS dispersion (QRSD) and fragmented QRS, were also found to correlate conduction velocity and unidirectional block with re-entrant substrates in various cardiac conditions. Both repolarization and conduction parameters can be combined into the excitation wavelength (λ). A surrogate marker for λ is the index of Cardiac Electrophysiological Balance (iCEB: QT / QRSd). Other markers based on conduction-repolarization are [QRSD x (Tpeak-Tend) / QRSd] and [QRSD x (Tpeak-Tend) / (QRSd x QT)]. Advancement in technology permitted sophisticated electrophysiological analyses such as principal component analysis and periodic repolarization dynamics to further improve risk stratification. This was closely followed by other novel indices including ventricular ectopic QRS interval, the f99 index and EntropyXQT, which integrates mathematical and physical calculations for determining the risk markers. Though proven to be effective in limited patient cohorts, more clinical studies across different cardiac pathologies are required to confirm their validity. As such, this review seeks to encapsulate the development of old and new ECG markers along with their associated utility and shortcomings in clinical practice.

Left atrial deformation as a potent predictor for paroxysmal atrial fibrillation in patients with end-stage renal disease.

It is widely known that various factors contribute to left atrial (LA) mechanical dysfunction in patients with end stage renal disease (ESRD). However, the connection between atrial dysfunction and arrhythmic events such as paroxysmal atrial fibrillation (PAF), in this group of patients, remains unclear. The purpose of our study was to evaluate prospectively the association between LA deformation indices and PAF in ESRD patients. 79 patients (41 men, mean age 57 ± 17) with ESRD and preserved left ventricular systolic function comprised the study population. All patients underwent a baseline comprehensive echocardiography study and were followed for a mean period of 16 ± 5 months. PAF episodes, first and the following events, were reported. LA longitudinal strain reflecting LA reservoir function and LA longitudinal strain rate reflecting LA pump function were specifically evaluated as LA deformation indices of interest, using 2D speckle tracking echocardiography. At the end of follow up period nine patients died. 15 of the rest 70 reported one or more episodes of PAF. LA indexed volumes were significantly higher in patients with PAF (32 ± 26 vs. 21.5 ± 9 ml/m2, p = 0.002), mean LA strain was significantly reduced (17 ± 7 vs. 27 ± 9%, p < 0.001) as well as mean LA stain rate (- 1.19 ± 0.5 vs. - 1.95 ± 0.5 1/s, p < 0.001). Multivariate analysis showed that LA strain rate when adjusted with age together with PAF history remained the single most significant echocardiographic parameter for PAF prediction. Impaired LA strain and LA strain rate are associated with PAF in ESRD patients. LA strain rate might be a better independent predictor of PAF, compared to standard echocardiographic indices. Further prospective studies are needed to validate its relevance in routine clinical practice.

Role of ranolazine in the prevention and treatment of atrial fibrillation: A meta-analysis of randomized clinical trials.

BACKGROUND: Randomized controlled trials (RCTs) on the use of ranolazine (RN) for prevention and cardioversion of atrial fibrillation (AF) have yielded conflicting results. OBJECTIVE: The purpose of this study was to conduct a meta-analysis of RCTs to examine the potential role of RN in the prevention and cardioversion of AF. METHODS: PubMed and EMBASE were searched until June 2016. Of 484 initially identified studies, 8 RCTs were finally analyzed. RESULTS: The analysis of RCTs showed that RN significantly reduced the incidence of AF compared to the control group in various clinical settings, such as after cardiac surgery, in acute coronary syndromes, and post-electrical cardioversion of AF (relative risk [RR] 0.67, 95% confidence interval [CI] 0.52-0.87, Z = 3.06, P = .002). Furthermore, a higher conversion rate of AF from the combined use of RN and amiodarone compared to amiodarone alone (RR 1.23, 95% CI 1.08-1.40, Z = 3.07, P = .002) was clear, with conversion time significantly shorter in RN plus amiodarone compared to the amiodarone group (weighted mean difference [WMD] = -10.38 hours, 95% CI -18.18 to -2.57, Z = 2.61, P = .009). CONCLUSION: Our meta-analysis suggests that RN may be effective in AF prevention, whereas it potentiates and accelerates the conversion effect of amiodarone of recent-onset AF. Larger RCTs with long-term follow-up in diverse clinical settings are needed to further clarify the impact of RN on AF therapy.

The use of adenosine and adenosine triphosphate testing in the diagnosis, risk stratification and management of patients with syncope: current evidence and future perspectives.

Syncope is a significant source of cardiovascular-related morbidity yet the etiology is frequently obscure and the identification of patients at highest risk is challenging. Adenosine (AD) and adenosine triphosphate (ATP) administrations have been suggested as potentially useful non-invasive tools in the diagnostic workup of patients with neurally-mediated or bradycardia-related syncope. It has been postulated that both compounds by modulating the autonomic innervation in the heart and exerting negative chronotropic and dromotropic effects in the conduction system, may unmask the mechanism of syncope. However, the clinical implications derived from the efficacy of both tests in the investigation of syncope remain unclear mainly due to inconclusive and occasionally contradictory results of published studies. This review article summarizes recent and past information in the use of ATP and AD in the investigation of syncope with emphasis on clinical trials. We present the current level of evidence for the use of these agents in clinical practice, identify areas where further research is warranted and highlight the future perspectives of these agents as complements to an accurate risk-stratification of patients with syncope.