Impact of sacubitril/valsartan and gliflozins on cardiac resynchronization therapy response in ischemic and non-ischemic heart failure patients.

AIMS: Angiotensin receptor-neprilysin inhibitor (ARNi) and sodium-glucose co-transporter 2 inhibitor (SGLT2i) improve outcomes in heart failure with reduced ejection fraction (HFrEF) patients, however their effects in cardiac resynchronization therapy (CRT) recipients have been scarcely explored. This study investigated whether ARNi and SGLT2i 1) improve the rate of clinical and echocardiographic CRT response and 2) have different impact based on the ischemic or non-ischemic etiology. METHODS: HFrEF patients referred for CRT implant were grouped in no treatment (group 1), only ARNi (group 2) and both ARNi and SGLT2i (group 3). Clinical and echocardiographic response were evaluated at 12 months. RESULTS: A total of 178 patients were enrolled. At one-year follow-up, 74.4% patients in group 2 (p = 0.031) and 88.9% in group 3 (p = 0.014) were classified as clinical responders vs 54.5% in the no treatments group. In multivariable analysis, ARNi/SGLT2i use was an independent predictor of CRT response (OR 3.72; CI 95%, 1.40-10.98; p = 0.011), confirmed in both groups 2 and 3. At 12 months, the median Δ LVEF increase was 6% and 8.5% in groups 2 and 3 respectively, vs 4.5% in group 1 (p = 0.042 and p = 0.029) with significantly more echocardiographic responders in groups 2 and 3 (76% and 78% vs 50%, p = 0.003 and p = 0.036). Significantly more ischemic HFrEF patients than non-ischemic were considered clinical and echocardiographic responders in the treatment groups. CONCLUSIONS: ARNi alone or in combination with SGLT2i in CRT patients improves the clinical and echocardiographic response at 12 months. Ischemic patients seem to benefit more from these treatments.

Unexpected impairment of INa underpins reentrant arrhythmias in a knock-in swine model of Timothy syndrome.

Timothy syndrome 1 (TS1) is a multi-organ form of long QT syndrome associated with life-threatening cardiac arrhythmias, the organ-level dynamics of which remain unclear. In this study, we developed and characterized a novel porcine model of TS1 carrying the causative p.Gly406Arg mutation in CACNA1C, known to impair CaV1.2 channel inactivation. Our model fully recapitulated the human disease with prolonged QT interval and arrhythmic mortality. Electroanatomical mapping revealed the presence of a functional substrate vulnerable to reentry, stemming from an unforeseen constitutional slowing of cardiac activation. This signature substrate of TS1 was reliably identified using the reentry vulnerability index, which, we further demonstrate, can be used as a benchmark for assessing treatment efficacy, as shown by testing of multiple clinical and preclinical anti-arrhythmic compounds. Notably, in vitro experiments showed that TS1 cardiomyocytes display Ca2+ overload and decreased peak INa current, providing a rationale for the arrhythmogenic slowing of impulse propagation in vivo.

Early evaluation of atrial high rate episodes using remote monitoring in pacemaker patients: Results from the RAPID study.

Aim: Remote monitoring (RM) of implantable cardiac devices has enabled continuous surveillance of atrial high rate episodes (AHREs) with well-recognized clinical benefits. We aimed to add evidence on the role of the RM as compared to conventional follow-up by investigating the interval from AHRE onset to physician's evaluation and reaction time in actionable episodes. Methods and Results: A total of 97 dual-chamber pacemaker recipients were followed with RM (RM-ON group; N = 64) or conventional in-office visits (RM-OFF group; N = 33) for 18 months. In-office visits were scheduled at 1, 6, 12, and 18 months in the RM-OFF group and at 1 and 18 months in the RM-ON group. The overall AHRE rate was 1.98 per patient-year (95% confidence interval [CI], 1.76-2.20) with no difference between the two groups (RM-ON vs. RM-OFF weighted-HR, 0.88; CI, 0.36-2.13; p = .78). In the RM-ON group, 100% AHREs evaluated within 11 days from onset, and within 202 days in the RM-OFF group, with a median evaluation delay 79 days shorter in the RM-ON group versus the RM-OFF group (p < .0001). Therapy adjustment in actionable AHREs occurred 77 days earlier in the RM-ON group versus the control group (p < .001). In the RM-ON group, there were 50% less in-office visits as compared to the RM-OFF group (p < .001). Conclusions: In our pacemaker population with no history of atrial fibrillation, RM allowed significant reduction of AHRE evaluation delay and prompted treatment of actionable episodes as compared to biannual in-office visit schedule.

Appropriate ICD Interventions for Ventricular Arrhythmias Are Predicted by Higher Syntax Scores I and II in Patients with Ischemic Heart Disease.

AIMS: The occurrence of ventricular arrhythmias (VAs) in ischemic heart disease (IHD) patients is related to the presence and extent of fibrotic/scar tissue. As coronary atherosclerosis is the underlying cause of myocardial ischemia and fibrosis, in IHD patients implanted with an implantable cardioverter defibrillator (ICD) we investigated the relation between the VA burden and the complexity of coronary atherosclerotic lesions. METHODS AND RESULTS: In IHD patients who underwent coronary angiography and ICD implant, the Syntax scores I and II (SSI-II), as index of the severity of the coronary atherosclerotic disease, and the occurrence of VA were assessed. Overall 144 patients were included (123 males). Of these 22 patients (15%) experienced at least one episode of VA (cycle length 298 ± 19 msec) that required ICD intervention. The number of episodes per patient and per year was 4 ± 6 and 2.8 ± 4, respectively. Patients that experienced a VA compared to those free from arrhythmic events did not have distinct baseline clinical characteristics except for a higher SS I and SS II (21 (IQR 13-38) vs. 16 (IQR 10-23); p = 0.037; and 50 (IQR 39-62) vs. 42 (IQR 34-50); p = 0.012). In the binary logistic regression analyses the SS I and II were the only independent predictors of VA occurrence. A higher SS II was also associated with an earlier time to first event (p = 0.005). CONCLUSION: Higher SS I-II scores reflect a more severe coronary atherosclerosis and are associated with a greater VA burden. Further studies are needed to better clarify the ability of SSI-II to stratify the risk of IHD patients to develop life-threatening VA.

Does the Age Affect the Outcomes of Cardiac Resynchronization Therapy in Elderly Patients?

BACKGROUND: More and more heart failure (HF) patients aged ≥ 75 years undergo cardiac resynchronization therapy (CRT) device implantation, however the data regarding the outcomes and their predictors are scant. We investigated the mid- to long-term outcomes and their predictors in CRT patients aged ≥ 75 years. METHODS: Patients in the Cardiac Resynchronization Therapy Modular (CRT MORE) Registry were divided into three age-groups: <65 (group A), 65-74 (group B) and ≥75 years (group C). Mortality, hospitalization, and composite event rate were evaluated at 1 year and during long-term follow-up. RESULTS: Patients (n = 934) were distributed as follows: group A 242; group B 347; group C 345. On 12-month follow-up examination, 63% of patients ≥ 75 years displayed a positive clinical response. Mortality was significantly higher in patients ≥ 75 years than in the other two groups, although the rate of hospitalizations for HF worsening was similar to that of patients aged 65-74 (7 vs. 9.5%, respectively; p = 0.15). Independent predictors of death and of negative clinical response were age >80 years, chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD). Over long-term follow-up (1020 days (IQR 680-1362)) mortality was higher in patients ≥ 75 years than in the other two groups. Hospitalization and composite event rates were similar in patients ≥ 75 years and those aged 65-74 (9 vs. 11.8%; p = 0.26, and 26.7 vs. 20.5%; p = 0.06). CONCLUSION: Positive clinical response and hospitalization rates do not differ between CRT recipients ≥ 75 years and those aged 65-74. However, age > 80 years, COPD and CKD are predictors of worse outcomes.

Insulin Resistance Predicts Severity of Coronary Atherosclerotic Disease in Non-Diabetic Patients.

BACKGROUND: Insulin resistance (IR) in patients with type 2 diabetes mellitus (T2DM) represents a predictor of coronary artery disease (CAD). However, how IR is able to impact the severity of coronary atherosclerosis in non-diabetic patients is unknown. OBJECTIVES: We investigated the relation between the IR and the extent and severity of coronary atherosclerosis in non-diabetic patients referred to coronary angiography (CA) Methods: Consecutive patients undergoing to CA for acute coronary syndromes or stable angina were analyzed. The IR was assessed by mean of the homeostasis model assessment of insulin resistance (HOMA-IR) whereas the SYNTAX score (SS) was used as index of the severity of coronary atherosclerosis Results: Overall, 126 patients were included, with a median SS of 12 (IQR 5.25-20.5). Patients were divided in four groups according to the distribution in quartiles of SS (SS1-2-3-4). A significant correlation between HOMA-IR and SS was observed, especially in women. A progressive increase of HOMA-IR was observed in parallel with the increasing severity (from SS1 to SS4) and extension (1-2-3-vessel disease) of coronary atherosclerosis. Multivariable analysis showed that the HOMA-IR was the strongest independent predictor of severe (SS4) and extensive (three-vessel disease) coronary atherosclerosis. CONCLUSION: Insulin resistance goes hand in hand with the extension and severity of coronary atherosclerosis in non-diabetic patients. The HOMA index is an independent predictor of three-vessel disease at CA. The HOMA index could be useful for risk stratification of CAD even in absence of T2DM.

Contrast-induced nephropathy after cardiac resynchronization therapy implant impairs the recovery of ejection fraction in responders.

AIMS: Data regarding contrast-induced nephropathy (CIN) after cardiac resynchronization therapy (CRT) implant are limited. We aimed to investigate the incidence and determinants of CIN and its impact on CRT response and outcomes. METHODS AND RESULTS: Patients who underwent CRT implant were retrospectively analysed, and CIN was defined as an increase of serum creatinine ≥0.3 mg/dL or ≥1.5 times the baseline value. Response to CRT was defined as a reduction of left ventricle end-systolic volume (LVESV) of 15% or the increase of five percentage points in ejection fraction (EF) as assessed by echocardiography at 6 months. Follow-up visits were scheduled at 3, 6, and 12 months. Contrast-induced nephropathy occurred in 13/107 patients (12%). Among baseline clinical, echocardiographic, and laboratory characteristics, only a high baseline serum creatinine was associated with the occurrence of CIN. Symptoms, EF, and LVESV at 6 months improved in both CIN and non-CIN patients, and the rate of responders to CRT was similar. Among responders, at 6 months, those with CIN had significantly lower EF (28.5% vs. 35.7% P = 0.003). At a median follow-up of 112 weeks, 43% of patients experienced a clinical event with similar incidence in CIN and non-CIN patients, and likewise survival was similar. Non-responders to CRT had worse survival while among responders those with CIN had worse survival than non-CIN patients (71% vs. 90%, P = 0.0035). CONCLUSIONS: The incidence of CIN is rather high. Although CIN does not influence response to CRT overall, however among responders impairs the recovery of EF and survival.

Transcoronary concentration gradients of circulating microRNAs in heart failure.

AIMS: Circulating levels of microRNAs (miRNAs) are emergent promising biomarkers for cardiovascular disease. Altered expression of miRNAs has been related to heart failure (HF) and cardiac remodelling. We measured the concentration gradients across the coronary circulation to assess their usefulness to diagnose HF of different aetiologies. METHODS AND RESULTS: Circulating miRNAs were measured in plasma samples simultaneously obtained from the aorta and the coronary venous sinus in patients with non-ischaemic HF (NICM-HF, n = 23) ischaemic HF (ICM-HF, n = 41), and in control patients (n = 11). A differential modulation of circulating levels of miR-423, -34a, -21-3p, -126, -199 and -30a was found across the aetiology groups. Interestingly, a positive transcoronary gradient was found for miR-423 (P < 0.001) and miR-34a (P < 0.001) only in the ICM-HF group. On the contrary, a positive gradient was found for miR-21-3p (P < 0.001) and miR-30a (P = 0.030) only in the NICM-HF group. Finally, no significant variations were observed in the transcoronary gradient of miR-126 or miR-199. CONCLUSIONS: The present findings suggest that circulating levels of miRNAs are differentially expressed in patients with HF of different aetiologies. The presence of a transcoronary concentration gradient suggests a selective release of miRNAs by the failing heart into the coronary circulation. The presence of aetiology-specific transcoronary concentration gradients in HF patients might provide important information to better understand their role in HF, and suggests they could be useful biomarkers to distinguish HF of different aetiologies.