Risk stratification for worsening renal function and renal decline in heart failure patients with reduced ejection fraction after sacubitril/valsartan treatment.

BACKGROUND: In the real-world setting, data regarding renal decline following sacubitril/valsartan treatment are lacking. This study aimed to develop a scoring system to predict renal outcome in sacubitril/valsartan-treated patients. METHODS: Between 2017 and 2018, a total of 1505 heart failure patients with reduced ejection fraction (HFrEF) undergoing sacubitril/valsartan treatment were consecutively enrolled from 10 hospitals to serve as the derivation cohort. Another 1620 HFrEF patients receiving sacubitril/valsartan were included as the validation cohort. Worsening renal function (WRF) was defined as a serum creatinine increase of >0.3 mg/dL and/or >25 % at 8 months of sacubitril/valsartan treatment. The derivation cohort was used to identify independent predictive factors for WRF through multivariate analysis, which were then used to develop the risk score system. RESULTS: Among the 3125 HFrEF patients, 689 (22.0 %) patients had WRF at 8 months following sacubitril/valsartan treatment. In the derivation cohort, six prognostic factors (age, functional class, history of peripheral arterial disease, diabetes mellitus, gout or hyperuricemia, and serum albumin level) were independently associated with WRF, and were combined into a risk predicting score. This score showed accurate discrimination in the derivation and validation cohorts (Harrell's concordance indexes 0.74 and 0.71, 95 % confidence intervals 0.71-0.78 and 0.69-0.74, respectively). Patients with a higher risk score experienced a more rapid decline in renal function, poorer clinical outcomes, and a higher rate of discontinuation of sacubitril/valsartan treatment. CONCLUSIONS: This study developed a score for WRF after sacubitril/valsartan treatment, which may assist clinicians with risk stratification and therapeutic decision-making.

Effects of Ivabradine on Patients with Depressed Left Ventricular Function after Cardiac Resynchronization Therapy.

Background: The potential synergistic effect of ivabradine and cardiac resynchronization therapy (CRT) in heart failure (HF) patients has rarely been studied. We aimed to evaluate the clinical benefits of ivabradine in patients with left ventricular dysfunction following CRT implantation. Methods: Two hundred and thirty-one patients receiving CRT were consecutively enrolled between January 2014 and December 2018 from two HF centers. A total of 123 patients had left ventricular ejection fraction (LVEF) < 40% and resting sinus heart rate (HR) ≥ 75 bpm after six months of CRT implantation. Among these patients, 45 were treated with ivabradine (Group 1), and 78 did not receive ivabradine treatment (Group 2). Results: Baseline characteristics and prescription rates of HF medications other than ivabradine were similar between the two groups. In Group 1, the mean HR decreased from 82.2 ± 11.4 bpm to 76.3 ± 10.5 bpm (p = 0.012), and the mean LVEF increased from 29.9 ± 6.5% to 38.8 ± 12.4% (p < 0.001). Atrial pacing percentage, biventricular pacing percentage, and burden of atrial fibrillation (AF) were not significantly different between the two groups during the study period. The patients' daily physical activity increased significantly in Group 1 compared to Group 2 (Δ daily activity 0.4 ± 0.7 hours/day vs. -0.1 ± 7.2 hours/day, p < 0.001). Conclusions: Ivabradine could effectively reduce HR and improve physical activity. It was safe to use and did not increase AF burden or affect biventricular pacing percentage in CRT recipients.

The Characteristics and Outcomes of Patients with Heart Failure and Reduced Ejection Fraction: The Eligibility of Novel Heart Failure Medications.

BACKGROUND: Renin-angiotensin system inhibitors and beta-blockers are the initial treatment of choice for heart failure with reduced ejection fraction (HFrEF), whereas sacubitril/valsartan (SAC/VAL) and ivabradine are considered to second-line therapies. The eligibility of SAC/VAL and ivabradine according to the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) labels, Taiwan National Health Insurance (TNHI) reimbursement regulations, and European Society of Cardiology (ESC) heart failure (HF) guidelines are diverse, and they may not fulfill the needs of real-world HFrEF patients. METHODS: Patients hospitalized for HF with left ventricular ejection fraction (LVEF) ≤ 40% were recruited from 21 hospitals in Taiwan between 2013 and 2014. The criteria for SAC/VAL and ivabradine according to the different regulations were applied. RESULTS: Of 1,474 patients, 86.8%, 29.4%, and 9.5% met the EMA/FDA label criteria, TNHI-regulation, and ESC guidelines for SAC/VAL, compared to 47.1%, 37.2%, and 45.6% for ivabradine, respectively. Ineligible reasons for the TNHI regulations included LVEF > 35% (19.9%, for SAC/VAL and ivabradine) and sinus rate < 75 beats per minute (bpm) (29.9%, for ivabradine). Although not meeting the TNHI regulations, patients with LVEF 35-40% had a similar 1-year mortality rate (15.6% vs. 15.8%, p = 0.876) to those with LVEF ≤ 35%, whereas patients with a sinus rate 70-74 bpm had a similar 1-year mortality rate (15.3% vs. 16.1%, p = 0.805) to those with a sinus rate ≥ 75 bpm. CONCLUSIONS: Approximately 70% and 63% of TSOC-HFrEF registry patients were ineligible for SAC/VAL and ivabradine, respectively, according to current TNHI regulations. Regardless of the eligibility for novel HFrEF medications, the high incidence of adverse events suggests that all patients should be treated cautiously.

Prescription patterns of diabetes medications influencing clinical outcomes of heart failure patients with reduced ejection fraction.

AIMS: We collected the different prescription patterns of diabetes medications in a cohort of patients with heart failure with reduced ejection fraction (HFrEF) and analysed the impact of different prescription patterns on clinical outcomes. METHODS AND RESULTS: Consecutive diabetic patients with HFrEF from a heart failure referral centre were retrospectively analysed between 2015 and 2016. Exclusion criteria include being lost to follow-up, not receiving diabetes medications, and having severe renal impairment with a glomerular filtration rate < 30 mL/min/1.73 m2 . Prescription of diabetes medications and the respective clinical outcomes were collected between 2016 and 2018. Among 381 patients (mean age, 64.8 ± 12.8 years; 71.9% male; mean left ventricular ejection fraction, 27.6 ± 7.0%; mean body mass index, 26.1 ± 4.7 kg/m2 ), the prescription rates of sodium-glucose co-transporter 2 inhibitor (SGLT2i) increased from 10.3% in 2016 to 17.6% in 2017 and 26.5% in 2018 (P < 0.001); the prescription rates of metformin, sulfonylurea, insulin, and dipeptidyl peptidase-4 inhibitors did not change significantly over time. The prescription rates of metformin and SGLT2i were significantly higher in patients managed by cardiologists than non-cardiologists (in 2018, 71.1% vs. 44.2% for metformin, 45.4% vs. 9.9% for SGLT2i, both P < 0.001). During the study period, annualized event rates of cardiovascular death or first unplanned HF hospitalization were 19.0 per 100 patient-years. After a multivariate analysis, prescriptions of metformin {odds ratio (OR): 0.49 [95% confidence interval (CI) 0.27-0.51], P < 0.001} and SGLT2i [OR: 0.52 (95% CI 0.28-0.98), P = 0.042] were independently associated with lower annualized event rates of cardiovascular death or unplanned HF hospitalization. CONCLUSIONS: Prescription patterns of diabetes medications in diabetics with HFrEF were diverse among different specialists. Prescriptions of metformin and SGLT2i were associated with favourable clinical outcomes. Our finding indicates the importance of awareness of beneficial effect of different classes of diabetes medications and collaboration between specialists in the management of diabetic HFrEF patients.

Recovery of left ventricular dysfunction after sacubitril/valsartan: predictors and management.

BACKGROUND: Literature describing recovery of left ventricular (LV) function post sacubitril/valsartan treatment and the optimal management of heart failure (HF) patients receiving sacubitril/valsartan remain sparse. METHODS: We recruited 437 consecutive chronic HF patients with baseline left ventricular ejection fraction (LVEF) less than 40%, who were treated with sacubitril/valsartan. All patients underwent routine echocardiographic measurement. RESULTS: During treatment period, recovery of LVEF to 50% or greater was observed in 77 (17.6%) patients. After multivariate analysis, recovery of LV dysfunction was associated with non-ischemic etiology of HF, smaller baseline LV end-diastolic diameter (LVEDD), and higher initial dosage of sacubitril/valsartan. Compared to those without recovery of LV dysfunction, death from cardiovascular causes or first unplanned hospitalization for HF (CVD/HFH) were significantly lower in patients with LVEF recovery [11.7% vs. 24.4%, hazard ratio (HR) 0.42, p = 0.014]. Among patients with recovery of LVEF, 51 patients continued to receive the same dosage of sacubitril/valsartan had higher LVEF and were less likely to have deterioration of LVEF than the other 26 patients who received either tapering dose of sacubitril/valsartan or switching from sacubitril/valsartan to renin-angiotensin-system blockers (LVEF 56.4 ± 5.3% vs. 45.0 ± 12.8%, p < 0.001; ΔLVEF 1.2 ± 5.1% vs. -9.3 ± 12.0%, p < 0.001). CVD/HFH occurred more frequently in the taper group than the maintenance group (23.1% vs. 5.9%, HR 0.22, p = 0.035). CONCLUSIONS: Non-ischemic etiology of HF, smaller baseline LVEDD, and higher initial dosage of sacubitril/valsartan could predict better recovery of LV function. Among patients with functional recovery, tapering sacubitril/valsartan dose was associated with deterioration of recovered heart function and had less favorable prognosis during follow-up.

Sacubitril/valsartan in heart failure with reduced ejection fraction patients: Real world experience on advanced chronic kidney disease, hypotension, and dose escalation.

BACKGROUND: Angiotensin receptor and neprilysin inhibition (ARNI) has been shown to reduce cardiovascular mortality by 20% as compared with enalapril in a randomized controlled trial. However, there is a paucity of real-world data on the effects of ARNI in heart failure patients with reduced ejection fraction (HFrEF), especially those with concurrent renal impairment or hypotension. METHODS: Between 2016 and 2017, we recruited 466 HFrEF patients treated with sacubitril/valsartan (Group A) and 466 patients managed with standard HF treatment without ARNI (Group B) in a HF referral center. Baseline characteristics and clinical outcomes were collected between both groups. RESULTS: Baseline characteristics were comparable between the two groups. During a follow-up period of 15 months, death from cardiovascular causes or first unplanned hospitalization for HF occurred in 100 patients in Group A (21.5%) and 144 in Group B (30.9%, hazard ratio 0.66; 95% CI 0.51-0.85; p=0.001). The incidences of deaths from any causes, cardiovascular death, sudden death, and HF re-hospitalization were all significantly lower in Group A than Group B patients. Among patients with different chronic kidney disease stages and normotensive patients, treatment with sacubitril/valsartan showed more favorable outcomes than treatment with standard HF care without ARNI. However, in patients with baseline systolic blood pressure lower than 100mmHg, there were no significant differences of outcomes in both groups. Among Group A patients, escalation of sacubitril/valsartan was associated with better outcomes. CONCLUSIONS: Our study demonstrated the effectiveness of sacubitril/valsartan on HFrEF patients in real world practice, including those with advanced renal impairment.

Managements and outcomes of hospitalized heart failure patients with paroxysmal vs nonparoxysmal atrial fibrillation in Taiwan.

BACKGROUND: The prognostic significance and the optimal treatment strategy for patients with atrial fibrillation (AF) and heart failure (HF) remain controversial. METHODS: We extracted data from a large prospective national database involving Taiwanese patients with AF who were hospitalized for acute HF with reduced ejection fraction. Baseline characteristics, AF types, medications, and 1-year outcomes of the patients were analyzed. RESULTS: At baseline, 393 (26%) patients had AF, including 117 (29.8%) patients with paroxysmal AF (PAF) and 276 (70.2%) with nonparoxysmal AF (N-PAF). Patients with PAF were more likely to have ischemic cardiomyopathy (47.3% vs 29.7%, p = 0.021), chronic kidney disease (46.2% vs 29.0%, p = 0.001), and higher CHA2DS2-VASc score (4.0 vs 3.6, p = 0.033) compared with patients with N-PAF; however, patients with N-PAF had larger left atrial diameter (50.5 vs 47.3 mm, p = 0.004) than patients with PAF. Patients with PAF were more likely to receive treatment with amiodarone (31.6% vs 13.8%, p < 0.001) and antiplatelet agents (54.1% vs 42.5%, p = 0.041) but less likely to receive treatment with renin-angiotensin system blockers (52.3% vs 64.9%, p = 0.021) and anticoagulants (33.3% vs 50%, p = 0.003) compared with patients with N-PAF at discharge. The 1-year mortality (26.2% vs 16.5%, p = 0.024) and non-HF-related death rates (13.1% vs 5%, p = 0.005) were significantly higher in patients with PAF, whereas HF and arrhythmic death rates were similar in both groups (13.1% vs 11.5%). CONCLUSION: Among patients with HF complicated with AF, those with PAF were more likely to receive antiarrhythmic agents, less likely to receive guideline-recommended therapy, but developed worse 1-year outcome compared with patients with N-PAF. These findings further emphasize the importance of optimal guideline-recommended medical therapy in patients with HF.

Impact of Renal Denervation on Atrial Arrhythmogenic Substrate in Ischemic Model of Heart Failure.

BACKGROUND: Myocardial infarction increases the risk of heart failure (HF) and atrial fibrillation. Renal denervation (RDN) might suppress the development of atrial remodeling. This study aimed to elucidate the molecular mechanism of RDN in the suppression of atrial fibrillation in a HF model after myocardial infarction. METHODS AND RESULTS: HF rabbits were created 4 weeks after coronary ligation. Rabbits were classified into 3 groups: normal control (n=10), HF (n=10), and HF-RDN (n=6). Surgical and chemical RDN were approached through midabdominal incisions in HF-RDN. Left anterior descending coronary artery in HF and HF-RDN was ligated to create myocardial infarction. After electrophysiological study, the rabbits were euthanized and the left atrial appendage was harvested for real-time polymerase chain reaction analysis and Trichrome stain. Left atrial dimension and left ventricular mass were smaller in HF-RDN by echocardiography compared with HF. Attenuated atrial fibrosis and tyrosine hydroxylase levels were observed in HF-RDN compared with HF. The mRNA expressions of Cav1.2, Nav1.5, Kir2.1, KvLQT1, phosphoinositide 3-kinase, AKT, and endothelial nitric oxide synthase in HF-RDN were significantly higher compared with HF. The effective refractory period and action potential duration of HF-RDN were significantly shorter compared with HF. Decreased atrial fibrillation inducibility was noted in HF-RDN compared with HF (50% versus 100%, P<0.05). CONCLUSIONS: RDN reversed atrial electrical and structural remodeling, and suppressed the atrial fibrillation inducibility in an ischemic HF model. The beneficial effect of RDN may be related to prevention of the downregulation of the phosphoinositide 3-kinase/AKT/endothelial nitric oxide synthase signaling pathway.

Rhodiola Inhibits Atrial Arrhythmogenesis in a Heart Failure Model.

INTRODUCTION: Rhodiola, a popular plant in Tibet, has been proven to decrease arrhythmia. The aim of this study was to elucidate the molecular mechanism and electrophysiological properties of rhodiola in the suppression of atrial fibrillation. METHODS: This study consisted of 3 groups as follows: Group 1: normal control rabbits (n = 5); Group 2: rabbits with heart failure (HF) created by coronary ligation and who received 2 weeks of water orally as a placebo (n = 5); and Group 3: rabbits with HF who received 2 weeks of a rhodiola 270 mg/kg/day treatment orally (n = 5). The monophasic action potential, histology, and real-time polymerase chain reaction (RT-PCR) analysis of ionic channels and PI3K/AKT/eNOS were examined. RESULTS: Compared with the HF group, attenuated atrial fibrosis (35.4 ± 17.4% vs. 16.9 ± 8.4%, P = 0.05) and improved left ventricular (LV) ejection fraction (51.6 ± 3.4% vs. 68.0 ± 0.5%, P = 0.001) were observed in the rhodiola group. The rhodiola group had a shorter ERP (85.3 ± 6.8 vs. 94.3 ± 1.2, P = 0.002), APD90 (89.3 ± 1.5 vs. 112.7 ± 0.7, P < 0.001) in the left atrium (LA), and decreased AF inducibility (0.90 ± 0.04 vs. 0.42 ± 0.04, P < 0.001) compared with the HF group. The mRNA expressions of Kv1.4, Kv1.5, Kv4.3, KvLQT1, Cav1.2, and SERCA2a in the HF LA were up-regulated after rhodiola treatment. The rhodiola-treated HF LA demonstrated higher mRNA expression of PI3K-AKT compared with the HF group. CONCLUSIONS: Rhodiola reversed LA electrical remodeling, attenuated atrial fibrosis and suppressed AF in rabbits with HF. The beneficial electrophysiological effect of rhodiola may be related to upregulation of Kv1.4, Kv1.5, Kv4.3, KvLQT1, Cav1.2, SERCA2a, and activation of PI3K/AKT signaling.

Predictors of inappropriate atrial sensing in long-term VDD-pacing systems.

AIMS: The efficacy and stability of the atrial electrode sensing function is essential for maintaining atrioventricular (AV) synchrony. This study aimed to explore the long-term reliability and causes of the long-term sensing failure of VDD systems. METHODS AND RESULTS: We enrolled all the patients with complete or high-degree AV block who received VDD pacemakers between August 1994 to January 2006 and who were followed up for more than 12 months. The interrogation parameters, including the atrial potentials (APs) and AV-synchrony ratio were acquired immediately post-implantation and at 3-6 month intervals thereafter. An inappropriate atrial sensing efficacy was defined as an AV-synchrony ratio of <90%. Totally 157 patients (70 +/- 12 years, 103 males) were enrolled into the study with a follow-up for 4.9 +/- 2.5 years. Twenty-six patients (16.6%) suffered from inappropriate atrial sensing. According to a Kaplan-Meier analysis, the incidence of inappropriate atrial sensing was higher in the patients with an age > or =72 years old (P = 0.047), mean AP during the implantation of <3.0 mV (P = 0.015), concomitant use of non-dihydropyridine calcium channel blockers (CCBs) (P = 0.003), and atrial fibrillation (AF) (P < 0.001). A Cox regression analysis showed that non-dihydropyridine CCBs (hazard ratio, 3.255; 95% confidence interval, 1.148-9.227, P = 0.026) and AF (hazard ratio, 6.507; 95% confidence interval, 2.478-17.104, P < 0.001) predicted inappropriate atrial sensing. CONCLUSION: VDD pacing is a reliable pacing modality. However, we should monitor the pacemaker sensing function in the patients with the concomitant use of non-dihydropyridine CCBs and AF.

Glucose and non-glucose predictors of future onset of type 2 diabetes in newly diagnosed essential hypertensives.

BACKGROUND: Baseline fasting plasma glucose (FPG) level predicts the onset of type 2 diabetes mellitus (DM). Other predictors have been less investigated. This study aimed to investigate non-glucose predictors together with FPG for future onset of type 2 DM in fresh essential hypertensives. METHODS: Consecutive nondiabetic patients with newly diagnosed essential hypertension were prospectively evaluated for diurnal blood pressure (BP) change by ambulatory BP monitoring, vascular endothelial function by plethysmography, and biomarkers by blood biochemistry. They were then given guideline-based treatment and followed-up regularly for more than 5 years. RESULTS: During a mean follow-up period of 5.9 years, 6 of the 106 study patients developed DM. Baseline FPG, alanine aminotransferase (ALT) level, and day-night difference in diastolic BP were related to future onset of DM. FPG > 5.8 mmol/L (p = 0.034) and ALT > 31 U/L (p = 0.048) independently and day-night difference in diastolic BP < or = 2.9% potentially predicted new-onset DM (p = 0.089). Simultaneously having at least 2 of the indicators mentioned above at baseline is predictive of new-onset DM. Parameters of reactive hyperemia by plethysmography were not relevant. CONCLUSION: In addition to FPG, baseline serum ALT level independently and diurnal diastolic BP changes potentially predicted future onset of type 2 DM in newly diagnosed hypertensives. Both glucose and non-glucose indicators could be examined together for early risk stratification of future DM.

Coronary revascularization in a patient with immune thrombocytopenic purpura.

Immune thrombocytopenic purpura (ITP) is a bleeding disorder characterized by premature platelet destruction mediated by autoantibodies. We report a 71-year-old ITP patient with concomitant acute coronary syndrome. Cardiac catheterization was performed through the right radial artery and premedicated with immunoglobulin. Left anterior descending artery was stented, followed by clopidogrel treatment for 7 weeks without major bleeding complication. The patient has been observed for 2 years without clinical restenosis. We suggest that stent implantation is a safe treatment in this special condition. Treatment should be individualized, but it is still a challenge to balance bleeding and thrombosis complication.

An accurate electrocardiographic algorithm for differentiation of tremor-induced pseudo-ventricular tachycardia and true ventricular tachycardia.

Tremor-induced electrocardiographic artifacts could be misdiagnosed as ventricular tachycardia (VT). However, there has been no electrocardiographic algorithm effectively differentiating pseudo-VT. In this study, we used 3 electrocardiographic "signs": "Sinus" sign, "Spike" sign, and "Notch" sign, and created an electrocardiographic algorithm. The algorithm was prospectively tested in 98 electrocardiographs (37 tremor-induced pseudo-VT and 61 true VT) Thirty-six out of 37 (97.3%) tremor-induced pseudo-VTs could be accurately diagnosed. In conclusion, this is the first study to systemically analyze the tremor-induced pseudo-VT. Our new electrocardiographic algorithm provides a useful tool for a rapid and accurate diagnosis.