bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of pirfenidone on scar size and ventricular remodeling after myocardial infarction: a preclinical study
Authors: Aimo A , Burchielli S , Aquaro G D , Barison A , Musetti V , Masotti S , Pucci A , Modena M , Passino C , Emdin M
Published: November 2023

Background

An intense fibrotic response after myocardial infarction (MI) may lead to scar expansion and left ventricular (LV) remodeling, increasing the risk for ventricular arrhythmias and heart failure. Pirfenidone is a drug currently approved for the treatment of idiopathic pulmonary fibrosis, and reduces LV fibrosis in patients with heart failure and preserved ejection fraction. We aimed to characterize the different profiles or protein expression in the infarct zone in rats receiving or not receiving pirfenidone on top of standard therapy for MI.

Methods

Male Wistar rats were randomized to: sham procedure (group 1; n=13), reperfused MI induced by surgical ligation of the left anterior descending artery (LAD) for 45 minutes (group 2; n=17), reperfused MI plus standard therapy (aspirin, angiotensin-converting enzyme inhibitor, beta-blocker, and also mineralocorticoid receptor antagonist [MRA]) (group 3; n=17), reperfused MI plus pirfenidone alone (group 4; n=17), reperfused MI plus standard therapy and pirfenidone (group 5; n=17). Rats surviving LAD ligation and reperfusion underwent cardiac magnetic resonance (CMR) after 72 hours and 30 days from MI, and were sacrificed the day after the second CMR exam. The primary endpoint was the change in late gadolinium enhancement (LGE) mass as a percentage of LV mass.

Results

Forty-six rats survived until the second CMR. Percent changes in LV end-diastolic and end-systolic volume (p=0.370 and 0.423, respectively), ejection fraction (p=0.236) and mass (p=0.815) did not differ significantly between rats on pirfenidone plus standard therapy compared with those receiving standard therapy alone. The decrease in LGE mass was significantly greater in rats on pirfenidone plus standard therapy vs. those on standard therapy alone: -22.0% (interquartile range, -37.1 to -5.7, range -51.1 to +37.5) vs. +1.9% (-7.7 to +12.5, range -19.8 to +56.5), p=0.029.

Conclusions

Pirfenidone had additive effects to standard therapy for MI (including an MRA) in reducing LV fibrosis in a rat model of reperfused MI, while it did not further improve LV function, volumes or mass.
The power of optimal medical therapy in heart failure with secondary mitral regurgitation
Authors: Escabia Riera C , Codina P , Ruiz-Cueto M , Domingo M , Santiago-Vacas E , Cediel G , Zamora E , Borrellas A , Llibre C , Teis A , Ferrer E , Santesmases J , Delgado V , Lupon J , Bayes-Genis A
Published: November 2023

Background

Guideline-directed medical therapy (GDMT) for the management of heart failure (HF) may impact on the frequency of severe secondary mitral regurgitation (SMR).

Objective

To evaluate the impact of optimization of GDMT on the grade of SMR in a cohort of HF patients managed in a multidisciplinary HF clinic and to assess predictors and prognosis of deterioration of SMR.

Methods

In a prospective, consecutive, observational registry of HF patients, a 2-dimensional transthoracic echocardiography was performed at baseline and at 1 year of follow-up. Patients treated with surgical or interventional mitral valve repair were excluded. The primary endpoint was all-cause death.

Results

Of a total of 2.980 HF patients, 1814 patients had 2 echocardiograms performed 1 year apart. At baseline, 99 patients had a severe SMR (5.5%), 389 (21.4%) moderate and the remainder had mild, trace or none SMR. After 1-year, 80.8% of those with baseline severe SMR presented a regression to non-severe SMR, 66.6% of those with moderate SMR regressed to mild SMR and 1.1% of those with non-severe SMR at baseline worsened to severe SMR.

Older age (OR 1.42 per every decade; 95% CI 1.19-1.69, p<0.001), ischaemic aetiology of HF (OR 1.64; 95% CI 1.11-2.42, p<0.001) and baseline NTproBNP (OR 1.19; 95% CI 1.08-1.32, p<0.001) were independently associated with worsening of SMR at 1 year of follow-up.

Patients with baseline severe SMR that improved at 1 year had a similar risk of the primary endpoint to those with non-severe SMR at both time points (HR 0.93; 95% CI 0.62-1.42; p=0.75), even after adjusting for age, sex and LVEF (HR 0.99; 95% CI 0.65-1.52; p= 0.98). On the contrary, patients with non-severe SMR that worsen showed the worst prognosis (Figure 1).

Conclusions

Most of the patients with HF and severe SMR show a regression of SMR within 1 year of GDMT. Patients with baseline severe SMR that improved at 1 year have a similar prognosis than those with non-severe SMR at both time points. Older age, ischaemic aetiology and higher levels of NTproBNP were associated with deterioration of SMR.Table 1.Population characteristicsFigure 1.Survival curves
Cardiovascular safety of non-steroidal anti-inflammatory drug use for gout: A Danish nationwide case-crossover study
Authors: Drewes A M , Bonnesen K , Hauge E M , Schmidt M
Published: November 2023

Background

Gout is associated with increased cardiovascular risk through inflammation and shared risk factors. Gout attacks are treated with a uric-lowering drug, such as allopurinol, and an anti-inflammatory drug, such as a non-steroidal anti-inflammatory drug (NSAID). Thus, NSAIDs could be both cardiovascular beneficial, due to their anti-inflammatory actions, and cardiovascular hazardous, due to their prothrombotic, hypertensive, and proarrhythmic actions. Yet, no study has examined the cardiovascular safety of NSAIDs for the treatment of gout.

Purpose

To examine the risk of major adverse cardiovascular events (MACEs) associated with NSAID use in gout patients.

Methods

We conducted a nationwide, population-based case-crossover study of all Danes ≥18 years of age with first-time gout during 1997–2020, who experienced a MACE (myocardial infarction, ischemic stroke, congestive heart failure, atrial fibrillation or flutter, or all-cause death) (n=103,522). The patients were identified either via a hospital diagnosis for gout (12%) or via a filling of an allopurinol prescription (88%). The exposures were use of NSAIDs overall and according to subtype (ibuprofen, naproxen, or diclofenac). An individual was considered exposed from the time of a filled prescription until the end of a use period, estimated from average use of two tablets per day. In the case-crossover design, we used four reference dates at 120, 180, 240, and 300 days before the outcome. An individual was considered exposed if the use period covered a reference date or the outcome date. We used the Mantel-Haenszel method to calculate odds ratios (ORs) with 95% confidence intervals (CIs) of the association between NSAID use and MACE.

Results

NSAID use was overall associated with a 15% decreased risk of MACE (OR=0.85, 95% CI: 0.83–0.87). The ORs of the association between NSAID use and the individual cardiovascular events were 0.91 (95% CI: 0.84–0.99) for myocardial infarction, 0.88 (95% CI: 0.81–0.95) for ischemic stroke, 0.89 (95% CI: 0.83–0.94) for congestive heart failure, 0.80 (95% CI: 0.75–0.85) for atrial fibrillation or flutter, and 0.77 (95% CI: 0.75–0.80) for all-cause death. The decreased risk of MACE was observed for use of ibuprofen (OR=0.91, 95% CI: 0.88–0.95) and naproxen (OR=0.78, CI: 0.70–0.86), but not for use of diclofenac (OR=1.03, 95% CI: 0.97–1.09).

Conclusions

In patients with first-time gout, use of ibuprofen and naproxen was associated with a slightly decreased cardiovascular risk, whereas diclofenac was not.
Long-term serial changes in left atrial volume and function after catheter ablation for atrial fibrillation
Authors: Okada T , Kobori A , Sano M , Murai R , Sasaki Y , Toyota T , Taniguchi T , Kim K , Ehara N , Kinoshita M , Furukawa Y
Published: November 2023

Background

Catheter ablation for atrial fibrillation (AF) is an effective method to restore and maintain sinus rhythm. The value of left atrial (LA) volume and reservoir function at short-term after ablation have been shown to associate with clinical outcomes. However, data regarding serial changes in LA size and function after the ablation remain scarce.

Purpose

The purpose of this study was to investigate the serial changes in LA volume and function, and their relationship to the AF recurrence in patients who underwent primary ablation for AF and had preserved left ventricular ejection fraction (LVEF).

Methods

We retrospectively reviewed 1,204 patients (age: 72±10 years, male: 72%, LVEF: 62±4%, paroxysmal AF: 66%) for whom both pre- and post-procedural serial echocardiographic data were available. Echocardiography was performed at pre-, 1-year, 2-year and 3-year after the ablation procedure. The association between AF recurrence and changes in echocardiographic parameters were evaluated by A repeated measures ANOVA with a Greenhouse-Geisser correction and Bonferroni tests. The AF recurrence was defined as any documented atrial arrhythmia of > 30 seconds after a single ablation procedure.

Results

During the mean follow-up of 1725±713 days, AF recurrence was observed in 418 patients (34.7%) and persistent AF at last follow-up was 41 patients (3.4%). Patients with AF recurrence had significantly larger LA volume index (LAVI) and lower LA emptying fraction (LAEF) at baseline than those without (50.0±15.5 vs 41.4±14.4 mL/m2, P<0.001, and 31.2±14.9 vs 37.7±14.0 %, P<0.001, respectively) and these differences were maintained thereafter during the follow-up. The trend of LAVI decreased until 6 months later and then remained unchanged regardless of the AF recurrence. These trends were maintained in patients divided into initial paroxysmal and persistent AF. The trend of LAEF increased until 6 months later and then gradually decreased regardless of the AF recurrence. These trends were maintained in patients with persistent AF, however, LAEF continued to decline in patients with paroxysmal AF. (Figure)

Conclusions

The catheter ablation was associated with significant reduction in LAVI and improvement of LAEF in patients with persistent AF regardless of recurrent AF. In contrast, LAEF decreased gradually in patients with paroxysmal AF. These findings may suggest LA function in patients with AF declines gradually, even when they are maintained in sinus rhythm. However, both LAVI and LAEF in paroxysmal AF were better than persistent AF, suggesting that catheter ablation may be more effective in the paroxysmal AF stage.
First clinical experiences with inclisiran in real world setting
Authors: Galema-Boers J M H , Mulder J W C M , Steward K , Roeters Van Lennep J E
Published: November 2023

Background

Inclisiran is the first-in-class small interfering RNA (siRNA) PCSK9 inhibitor. In clinical trials, inclisiran showed effective and sustained LDL-C reduction of approximately 50%. However, data about the efficacy and safety in clinical setting are scarce. We aim to investigate the efficacy and safety in clinical practice.

Methods

Registry of all consecutive patients who started with inclisiran at a lipid clinic of a university hospital. Patients were eligible if they fulfilled reimbursement criteria in the Netherlands; very high risk patients with FH and/or ASCVD and not on target LDL-C levels despite maximally tolerated oral lipid lowering medication. Patients were included if they started with inclisiran as first line (group 1) or switched from PCSK9 monoclonal antibody (mAbs) to inclisiran (group 2). LDL-C levels were measured 3 months after administration of inclisiran initiation. Median change of LDL-C levels was calculated on an individual and group level.

Results

We analysed 50 patients (26 women, 33 patients with FH), median [25th percentile; 75th percentile] age of 64 [52; 68] years. Patients who newly started Inclisiran (group 1) showed a LDL-C decrease of 39 [-50; -33]%. Patients who used statins as co-medication had a higher median LDL-C decrease compared to those without statin use (45% vs. 38%). However, patients who switched from mAbs to Inclisiran (group 2) had an increase in LDL-C of +41 [+3; +97]% (figure 1).

Almost half of the patients (42%) experienced a mild burning sensation. During follow-up 6 patients (12%) reported side effects as abdominal complains, dizziness, fatigue and flu-like symptoms in the first week after administration. One patient stopped treatment because of perceived side effects like fatigue and myalgia.

Conclusions

Our initial experience of inclisiran in a clinical setting showed slightly less reduction in LDL-C levels compared to clinical trials but a similar safety profile. Moreover, patients who switched from PCSK9 mAbs to inclisiran showed an increase in LDL-C levels implying that inclisiran is less potent in LDL-C reduction compared to PCSk9 mAbs.Figure 1Waterfallplot LDL-C change
Association between preeclampsia and long-term risk of arrhythmias
Authors: Havers-Borgersen E , Stahl A , Johansen M , Joens C , Koeber L , Fosboel E L
Published: November 2023

Background

Preeclampsia (PE), a pregnancy-induced hypertensive disorder, affects 4-5% of pregnancies worldwide. It is well known that hypertension is associated with increased risk of arrhythmias; however, data on the association between PE and arrhythmias are sparse and there is a lack of knowledge on the long-term risk of arrhythmias.

Purpose

To compare the incidence of arrhythmias following preeclamptic and normotensive pregnancies.

Methods

In this observational cohort study, we identified all primiparous women without history of arrhythmias who gave birth in Denmark from 1997 to 2016 using Danish nationwide registries. The women were stratified on whether they developed PE during their primiparous pregnancy and were followed from primiparous pregnancy to incident arrhythmia, emigration, death, or end of study (December 31, 2018). The comparative risks of arrhythmias were assessed in cause-specific Cox regression analyses adjusted for known arrhythmogenic risk factors including obesity, smoking, hypertension, coronary artery disease, cardiomyopathy, congenital heart disease, thyroid disease, diabetes, and alcohol abuse.

Results

A total of 521,517 primiparous women with a median age of 28 years were included and 23,523 (4.5%) were diagnosed with PE. Women with versus without PE were of similar age but had a higher burden of comorbidities. During a median follow-up period of 10.2 years, women with PE were associated with higher absolute incidences of arrhythmias (Figure 1). No statistically significant association was found for the composite of cardiac arrest, ventricular arrhythmias, or ICD-implantation nor for the composite of advanced 2nd or 3rd degree atrioventricular block, sinoatrial dysfunction, or pacemaker-implantation. However, women with PE were associated with a significant increased risk of the composite of supraventricular tachyarrhythmias and extrasystoles (p<0.01) and the composite of all included arrhythmias (p<0.01). Factors associated with arrhythmias among women with PE included obesity (HR 1.40 (95%CI 1.03-1.91), coronary artery disease (HR 2.39 (95%CI 1.14-5.00), cardiomyopathy (HR 9.65 (95%CI 3.46-26.92), and congenital heart disease (HR 5.86 (95%CI 2.59-13.28).

Conclusion

Preeclamptic women were associated with a significantly higher rate of arrhythmias - mainly driven by supraventricular tachyarrhythmias and extrasystoles - than normotensive women. For the purpose of primary and secondary prevention, this finding suggests that women with a history of PE may benefit from evaluation of cardiovascular risk factors, screening of and education in prevention of cardiovascular disease.Figure 1
Therapeutic gaps in low-density lipoprotein cholesterol management have narrowed over time but remain wide: a wide study of 40,141 acute coronary syndrome patients from 2016 to 2021
Authors: Sun H , Lai A , Tan G M , Yan B
Published: November 2023

Background

There are significant therapeutic gaps in ‘real-word’ low-density lipoprotein cholesterol (LDL-C) management in very-high risk patients. Understanding these gaps is important for developing strategies to bridge these gaps.

Purpose

We aimed to evaluate trends and identify therapeutic gaps in LDL-C management in very-high risk patients.

Methods

We retrospectively analyzed consecutive patients admitted with a diagnosis of acute coronary syndrome (ACS) to 16 public hospitals in between 2016 and 2021. Baseline and 12-month lipid-lowering therapy (LLT) including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor and LDL-C levels were recorded. We evaluated trends-over-time in percentage achievement of guideline Class I recommendations including (i) in-hospital initiation of high-intensity LLT; (ii) lipid-profile at follow-up post discharge; (iii) achieve at least 50% reduction in LDL-C from baseline with a goal of (iv) LDL-C <1.4 mmol/L.

Results

Of 40,141 ACS patients (mean age 71, male 66.5%), 61.2% were statin-naïve on admission. Baseline average LDL-C was 2.35 mmol/L (IQR 1.74 to 3.13 mmol/L). LLT prescription on discharge increased over time from 63.8% in 2016 to 96.2% in 2021. The use of high-intensity statins on discharge also increased over time from 24.7% to 53.7% but still suboptimal. The use of high-intensity statins increased significantly at 12-months (29.4% in 2016 and 59% in 2021) compared to on discharge (44.1% vs. 40.9% overall, p<0.001). The use of combination LLT was very low (1.3%-3.8%). Up to 22% of patients did not have repeated lipid profile after discharge. Of patients who had follow-up lipid profile, the median LDL-C was 1.74 mmol/L with a median LDL-C reduction of 29%. Only 27.5% reached the LDL-C goal of <1.4 mmol/L and 22.5% achieved at least 50% of LDL-C reduction. LDL-C reduction improved over time from 25.8% in 2016 to 31% in 2021, proportion of patients who reached LDL-C goal of <1.4 mmol/L improved over time from 20.8% in 2016 to 28.7% in 2021, and proportion of patients who achieved at least 50% of LDL-C reduction improved over time from 18.5% in 2016 to 24.6% in 2021, respectively.

Conclusion

Despite an increasing trend in the use of high-intensity statins and combination LLT over time, most patients did not reach guideline-recommended LDL-C target. Early up-titration of statin and addition of non-statin LLT may be required in the majority of patients.
Strike Early and Strike Strong: application of a strategy comprising first-line combination of high-intensity statins and ezetimibe for patients with acute myocardial infarction in routine practice
Authors: Schiele F , Monnin C , Bettinger C , Guillon B , Besutti M , Chatot M , Chopard R , Meneveau N
Published: November 2023

Aim

Rapid and intense LDL-c reduction for patients with acute myocardial infarction (AMI) using a systematic combination of high intensity statins and ezetimibe, dubbed "Strike Early and Strike Strong" (SESS), has been proposed in a position paper endorsed by ESC. The applicability of this strategy in routine practice, and the tolerance and biological efficacy of such lipid lowering treatment (LLT) are poorly documented.

Methods

Single-center, prospective, observational study including 500 consecutive patients admitted for AMI. Unless there was known intolerance, a SESS policy was advocated at admission for AMI, irrespective of baseline LDL-c. Actual discharge LLT, LDL-c level during follow-up (3 to 8 months) and the rate of patients at ESC LDL-c target were recorded. We considered LLT to be maintained when observed LDL-c level at follow-up (FU) was not 20% higher than that expected from baseline LDL- and LLT intensity at discharge.

Results

Between January 2020 and July 2021, 527 patients were included, 387(75%) were male, 110(22%) had diabetes, mean age was 63±12 years. Admission LDL-c was 127±44mg/dL, 431(78%) had no previous LLT. At discharge, 456 (97%) a high intensity statin, and combined with ezetiibe in 430/456(92%). The mean capacity of the discharge LLT to decrease LDL-c was 63±10%. 12-month FU with biology was available for 273 randomly selected patients. The combination of high intensity statins and ezetimibe was maintained in 87%, although ezetimibe was stopped in 9% and the statin dose was reduced in 15% (mainly reduction from atorvastatin 80 to 40 mg/day). As a result, capacity of the LLT to decrease LDL-c was reduced to 59±11%. Mean LDL-c was 53±33 mg/dL. ESC LDL-c therapeutic goals were reached in 53%: LDL-c<55mg/dL in 62% and >50% decrease in baseline LDL-c in 74%. Regarding the need for PCSK9 inhibitors, the rate was 14% for a threshold for prescription set at a LDL-c≥ 70mg/dL, and 7% for a threshold set at ≥100mg/dL. An LDL-c level <30mg/dL was observed in 19%.

Conclusion

The SESS strategy before discharge after ACS is feasible in routine practice. At 12 months, LLT intensity was maintained in the majority of cases, yielding an average LDL-c level of 53±33 mg/dL, and 53% of patients at LDL-c goals.
The impact of statin intensity on long-term outcomes in elderly patients with acute myocardial infarction who have undergone percutaneous coronary intervention
Authors: Choe J , Lee S H , Ahn J H , Park J S , Lee H W , Oh J H , Choi J H , Lee H C , Cha K S , Jeong M H
Published: November 2023

Background

The data regarding long-term clinical outcomes according to statin intensity in elderly patients who have undergone percutaneous coronary intervention (PCI) for acute myocardial infarction (MI) is unclear.

Purpose

We aimed to investigate the long-term clinical benefit of high intensity statin versus moderate to low intensity statin in elderly patients underwent PCI for acute MI.

Methods

Among 13104 patients with acute MI who have undergone PCI in a nationwide, prospective, and real-world registry, 4294 elderly (defined as ≥70 years) patients prescribed statin at discharge were included. 1136 patients were prescribed with high intensity statin, and 3158 patients were prescribed with moderate to low intensity statin. The major adverse cardiac events (MACE; all-cause death, recurrent MI, any revascularization, stroke, readmission due to heart failure [HF], or definite/probable stent thrombosis [ST]) and the components of MACE were compared in multivariable Cox regression, propensity score (PS) matched, and underwent PS-adjusted analyses.

Results

During a median follow-up of 998 days, MACE, all-cause death, and cardiac death occurred in 1297 patients (30.2%), 737 patients (17.2%), and 460 patients (10.7%), respectively. The risks of MACE (entire: 26.9% vs. 31.4%, hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.73-0.95, p=0.005; PS-matched: n=2186, 25.3% vs. 30.8%, HR 0.79, 95% CI 0.67-0.94, p=0.008), all-cause death (entire: 14.4% vs. 18.1%, HR 0.78, 95% CI 0.65-0.93, p=0.005; PS-matched: 13.8% vs. 18.9%, HR 0.69, 95% CI 0.57-0.92, p=0.002), cardiac death (entire: 9.5% vs. 11.4%, HR 0.81, 95% CI 0.67-0.97, p=0.042; PS-matched: 8.7% vs. 11.3%, HR 0.77, 95% CI 0.61-0.96, p=0.031), and readmission due to HF (entire: 5.5% vs. 7.5%, HR 0.72, 95% CI 0.55-0.95, p=0.021; PS-matched: 5.7% vs. 8.1%, HR 0.78, 95% CI 0.59-0.96, p=0.017) were significantly decreased in the patients received high intensity statin compared to in those received moderate to low intensity statin. There were no significant differences in the risks of recurrent MI, any revascularization, stroke, and definite/probable ST between the groups. In patients ≥80 years, compared to the moderate to low intensity statin group, high intensity statin group had the reduced rates of MACE, all-cause death, cardiac death, recurrent MI, any revascularization, stroke, readmission due to HF, or definite/probable ST, but insignificantly.

Conclusions

From the nationwide registry, we noted that in elderly patients after PCI for acute MI the administration of high intensity statin versus moderate to low intensity statin was contributed to the improved long-term clinical outcomes.
The effect of proprotein convertase subtilisin/kexin type 9 inhibition on the plasma proteome: a SPIRE sub-study
Authors: Kraaijenhof J , Cornel J H , Opstal T S J , Gill D , Hovingh G K , Stroes E S G , Catapano A L , Koenig W , Ridker P M , Nurmohamed N S
Published: November 2023

Background

The plasma proteome is an intermediate phenotype for disease and is a tool to inform on pharmacological mechanisms of effect. For selective low-density lipoprotein cholesterol (LDL-C) lowering by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, multiple studies have demonstrated that its potent LDL-C lowering effect coincides with marked reductions in both cellular and arterial plaque inflammation, despite unaltered high-sensitivity C-reactive protein (hs-CRP) levels.

Purpose

In the present study, we set out to investigate potential anti-inflammatory effects of PCSK9 inhibition using plasma proteomics.

Methods

In 190 patients participating in the SPIRE-1/2 trials, 184 targeted proteins were measured at baseline and after 12 months of bococizumab treatment using the Cardiovascular II and III panels (Sweden). Of the included patients, 96 patients received placebo and 94 received 150mg of bococizumab, once every two weeks. Considering the development of auto-antibodies in some patients, patients with LDL-C reduction below 15% were excluded. The primary outcome was the fold change in protein levels after 12 months compared to baseline. The Benjamini-Hochberg method was used to adjust for multiple comparisons with a false discovery rate (FDR) of 5%. The findings were compared to the LoDoCo2 sub-study which used the same proteomic panels.

Results

In the placebo group, there was no significant change in any of the proteins. In the bococizumab group (n=77, mean age 62.2±9.7 years and 70 [91%] male), LDL-C levels were reduced from 114±41 mg/dL to 47±34 mg/dL (mean reduction 66±29 mg/dL) on top of statin therapy while there was a neutral effect on hs-CRP (median change 0.0 mg/L IQR [-0.8,1.1]). PCSK9 was the only protein with change upon treatment with bococizumab (24.4±11.0 vs. 15.0±10.7; PFDR=0.033; Figure 1A). In comparison, treatment of colchicine in the LoDoCo2 sub-study was associated with a significant change in 60 proteins (Figure 1B).

Conclusion

Here, we show that PCSK9 inhibition with bococizumab resulted in a highly selective reduction of PCSK9 plasma levels without robustly affecting other circulating proteins in the measured panels, implying PCSK9 inhibition lowers ASCVD risk via pure lipid lowering pathways. Our study reinforces the neutral systemic inflammatory effect of PCSK9 inhibition on top of statin therapy. The local effects on cellular and vascular inflammation by PCSK9 inhibition observed in earlier studies most likely reflect a direct consequence of a reduced cholesterol content in inflammatory cells and plaques, subsequently leading to a local anti-inflammatory effect. These findings support the combination of targeted anti-inflammatory therapies on top of potent LDL-C lowering in order to further reduce the residual inflammatory risk.
Efficacy, safety, adherence and persistence of PCSK9 inhibitors in clinical practice: a single country, multicenter, observational study (AT-TARGET-IT)
Authors: Gargiulo P , Basile C , Calabro' P , Catalano A , Merlini P A , Iannuzzo G , Ciccone M M , Paloscia L , Varbella F , Brunetti N D , Paolillo S , Marzano F , Indolfi C , Perrone-Filardi P
Published: November 2023

Background

PCSK9 inhibitors (PCSK9i) significantly decrease LDL cholesterol (LDL-C), either as monotherapy or in addition to the maximally tolerated dose of statin and/or ezetimibe. Yet, few data are available on efficacy and background lipid-lowering therapy (LLT) adjustment in patients treated with PCSK9i in real-world observations.

Purpose

AT-TARGET-IT is an Italian multicenter registry involving 9 Italian centers, designed to assess efficacy, adherence, and persistence of PCSK9i, as well as prescribing doctors’ behavior in patients with atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia (FH).

Methods

From June through November 2021, we enrolled patients with PCSK9i first prescription from 6 months before inclusion through starting of PCSK9i use. Clinical and demographic characteristics, concomitant therapies, blood chemistry, were recorded at the time of first prescription and at the latest observation preceding inclusion in the study. Background therapy was assessed at baseline and during follow-up, evaluating treatment withdrawal, reduction of doses, or changes from statin-ezetimibe association to single drug therapy.

Results

798 patients were enrolled. The median reduction in LDL-C levels was 64.9%. After stratification for CV risk, 63.8% achieved LDL-C target; of them, 83.3% took LLTs at PCSK9i initiation and 16.7% did not (Figure 1). 760 patients (95.2%) showed high adherence to therapy, 13 (1.6%) partial adherence, and 25 (3.1%) poor adherence (Figure 2). At 6 months, 99.7% of patients enrolled in the study remained on therapy; there were 519 and 423 patients in the study with a follow-up of at least 12 and 18 months, respectively. Persistence in these groups was 98.1% and 97.5%, respectively. Overall, 3.5% of patients discontinued therapy. No differences in efficacy, adherence, and persistence were found between alirocumab and evolocumab.

Conclusion

PCSK9i are safe and effective in clinical practice, leading to very high adherence and persistence to therapy, and achievement of recommended LDL-C target in most patients, especially when used as combination therapy.Stratified LDL-C target achievementAdherence and persistence status
Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular outcomes in patients with atrial fibrillation and type 2 diabetes mellitus
Authors: Oh Y S , Choi Y , Kim S H , Kim S H , Park S Y , Kim H J
Published: November 2023

Background

A sodium-glucose cotransporter-2 inhibitor (SGLT2i) improves clinical outcomes in patients with type 2 diabetes (T2DM) and cardiovascular disease. Also use of SGLT2i was associated with a reduction of atrial fibrillation (AF) burden. We investigated the effect of SGLT2is on clinical outcomes in patients with T2DM and AF.

Methods

This was a retrospective study using a clinical data warehouse (CDW) constructed from 7 medical centers. We analyzed 11,043 patients with AF and T2DM. The patients were classified to the SGLT2i group and the control group according to the SGLT2i use. We performed 1:2 propensity score matching analysis. The primary endpoint was a composite of all-cause death or hospitalization due to heart failure events. The secondary endpoints were acute myocardial infarction, stroke, renal function decline and an initiation of dialysis.

Results

The propensity score matched population consisted of 467 patients in the SGLT2i group and 848 patients in the control group. During a mean follow up of 31.8 (± 21.0) months, the incidence of the primary endpoint was significantly lower in the SGLT2i group (9.6% vs. 16.9%, hazard ratio [HR] 0.624 [0.446 – 0.873]). SGLT2i was associated with reduced all-cause death (HR 0.292 [0.144 – 0.591]) and non-significantly lower risk of heart failure hospitalization (HR 0.734 [0.509 – 1.060]). There was no significant difference in the incidence of myocardial infarction, ischemic stroke, renal function decline and an initiation of dialysis between the two groups. In multivariate analysis, age, renal dysfunction, prior heart failure, and the absence of SGLT2i were independent predictors for the worse outcome.

Conclusion

SGLT2 inhibitor was associated with a lower incidence of all-cause mortality or heart failure hospitalization in patients with AF and T2DM.Freedom from the primary endpoint in the
Prescribing trends of sodium-glucose cotransporter 2 Inhibitors in patients with heart failure with preserved, mildly reduced and reduced ejection fraction
Authors: Hofer F , Hammer A , Steinacher E , Baumer U , Kazem N , Koller L , Richter B , Hengstenberg C , Sulzgruber P , Niessner A
Published: November 2023

Background

Numerous randomized controlled trials have evaluated the efficacy of SGLT2i and demonstrated decreased hospitalization rates for HF and a better cardiorenal outcome in diverse heart failure (HF) populations comprising HF patients with reduced (HFrEF), mildly reduced (HFmrEF) and preserved (HFpEF) ejection fraction. Since the beneficial effects of SGLT2i in HF patients are well known, real-world data on the clinical implementation of these agents following availability of CV outcome trial data seems of utmost importance.

Methods

We identified patients presenting with HF who were hospitalized at a university affiliated tertiary care center, between 01/2017 and 10/2022. All prescriptions of SGLT2i (dapagliflozin and empagliflozin) – including marketed fixed-dose combinations with other glucose-lowering drugs – were identified.

Results

In total, 2,673 patients with HF (median age 75, 39.9% female, 23.1% with diabetes) were included in the present analyses. Among the 2,637 patients with signs and symptoms suggestive of HF, 1086 (40.6%) had a documented left ventricular ejection fraction (LVEF) ≤ 40% (HFrEF), 445 (16.6%) a LVEF between 40-50% (HFmrEF) and 1142 (42.7%) a LVEF > 50% (HFpEF). In the overall cohort, 382 (14.3%) patients received an SGLT2i. As shown in Figure 1, the prescription of SGLT2i significantly increased from the beginning to the end of the inclusion period. In detail, it climbed from 6.8% in 2017 to 56.6% in 2022 in the HFrEF group (p-trend <0.001), from 3.3% to 49.2% in the HFmrEF group (p-trend <0.001) and from 1.9% to a still very low 26.4% in the HFpEF group (p-trend <0.001). While prescription of SGLT2i in HFrEF patients started to increase after the presentation of the DAPA-HF trial, the SGLT2i prescription in HFmrEF and HFpEF patients showed a marked rise after the presentation of the new HF ESC guidelines (2021) and the EMPEROR-Preserved trial.

Conclusion

The prescription of SGLT2i is constantly rising due to greater awareness among cardiologists and other specialists in internal medicine. Nevertheless, despite a growing evidence on the reduction of CV events by SGLT2i, our data show that there is still room for improvement in prescribing of these cardioprotective agents, especially in patients with HFpEF.Prescription trend of SGLT2i.
GLP1-RA versus metformin as first-line therapy for achieving glycemic control and risk-factor management - a one-year nationwide cohort study
Authors: Soerensen K K , Torp-Pedersen C , Pedersen-Bjerregaard U , Zareini B
Published: November 2023

Background

Glucagon-like peptide 1 receptor agonist (GLP1-RA) reduces cardiovascular events in patients with long standing diabetes. We hypothesized that treatment early during diabetes could be beneficial.

Purpose

The aim was to compare one-year effects of GLP1-RA and metformin as first-line glucose-lowering therapy on glycemic control, adherence, kidney function, and cholesterol levels.

Methods

Using the Danish nationwide registers, we included all first-line users of monotherapy with GLP1-RA or metformin between 2018-2021, who had information on glycated hemoglobin (HbA1c) maximum one year prior to baseline and a measured HbA1c level above 41 mmol/mol. The outcomes were one-year change in HbA1c category, adherence to therapy, avoidance of add-on glucose lowering drugs, as well as absolute change in HbA1c, creatinine, and cholesterol levels. Targeted likelihood maximum estimation with ensemble Superlearning was used to estimate the average treatment effects.

Results

A total of 40,987 individuals were included, of which 870 were prescribed GLP1-RA and 40,117 were prescribed metformin. After adjusting for age, sex, income, education, degree of urbanization, baseline HbA1c levels, comorbidities, and concomitant medication, GLP1-RA users had an one-year absolute decrease in HbA1c (ATE: -3.84 mmol/mol, 95% CI: -5.36;.-2.33), and HDL (ATE: -0.03 mmol/L, 95% CI: -0.06;-0.01), an absolute increase in creatinine (ATE: 2.89 μmol/L, 95% CI: 0.07;4.82), and no difference in low-density lipoprotein cholesterol (ATE: 0.11 mmol/L [95% CI: -0.03;0.24]), total lipoprotein cholesterol (ATE: 0.13 mmol/L [95% CI: -0.03;0.29]), triglycerides (ATE: 0.02 mmol/L [95% CI: -0.25;0.30]), non-adherence (RR: 1.05 [95% CI: 0.75;1.46]), and add-on therapy (RR: 1.04 [95% CI: 0.75;1.44]), compared to metformin users.

Conclusion

First line use of GLP1-RA was associated with a clear one-year reduction of HbA1c and a very small increase in creatinine. Future studies are needed to show whether this translates to a clinical benefit.
Duration of type 2 diabetes mellitus is associated with third-degree atrioventricular block - A Danish nationwide registry study
Authors: Haxha S , Soerensen K K , Haugaard S B , Ruwald M H , Halili A , Philbert B T , Koeber L , Gislason G H , Torp-Pedersen C , Bang C N
Published: November 2023

Introduction

Type 2 diabetes mellitus (T2DM) is associated with third-degree atrioventricular block, but whether duration of T2DM is an important factor of the association is unknown.

Aim

To investigate the association between duration of T2DM and third-degree atrioventricular block.

Method

This nested case–control study, based on nation-wide Danish cohort registries, included patients older than 18 years, diagnosed with third-degree atrioventricular block between 1 July 1995 and 31 December 2018. Five controls, from the risk set of each case of third-degree atrioventricular block, were matched on age and sex to fit a conditional logistic regression with time-dependent exposure and time-dependent covariates. Duration of T2DM was split into four groups: 0–5 years, 6–10 years, 11–15 years, and >15 years.

Results

We included 24 177 cases with third-degree atrioventricular block who were matched 1:5 on sex and birth year with 120 915 controls without third-degree atrioventricular block. Median age was 73.8 years, 62% were males in both cases and controls, whereas 19% of cases and 9.7% of controls had T2DM respectively. After adjusting for atrioventricular nodal blocking agents and comorbidities known to be associated with third-degree atrioventricular block, patients with T2DM duration 0–5 years, 6–10 years, 11-15 years, and >15 years had a higher hazard ratio of third-degree atrioventricular block of 1.24 (95% CI 1.16-1.33), 1.41 (95% CI 1.31-1.52), 1.79 (95% CI 1.64-1.95), and 2.20 (95% CI 2.01-2.40), respectively, compared to patients with no T2DM (Figure 1).

Conclusion

This study shows a stepwise increase in the hazard ratio of third-degree atrioventricular block along with duration of T2DM, which is independent of atrioventricular nodal blocking agents and comorbidities known to be associated with third-degree atrioventricular block.Figure 1
The gender gap in prescription pattern of Sodium-Glucose Cotransporter 2 inhibitors in patients with Type 2 Diabetes and Coronary Artery Disease
Authors: Hammer A , Hofer F , Kazem N , Koller L , Steinacher E , Baumer U , Niessner A , Sulzgruber P
Published: November 2023

Background

Type 2 diabetes mellitus (T2DM) is a major risk factor for the development of coronary artery disease (CAD), which is the leading cause of morbidity and mortality in T2DM patients. In this regard, sodium-glucose 2 cotransporter (SGLT2) inhibitors have been proven to not only reduce the glycemic burden but additionally lower the risk of major adverse cardiovascular events in T2DM patients with established CAD or at high risk for CAD. However, previous studies have not dealt with SGLT2 inhibitor prescription under real-world conditions, especially if SGLT2 inhibitor therapy is sex-independently utilized in such patients.

Methods

Patients with T2DM and CAD admitted to a tertiary academic center between 01/2014 and 04/2020 were identified by searching electronic health records. Patient characteristics and data on antidiabetic therapy at discharge were assessed.

Results

The present analysis included 1498 patients, with a median age of 70 years and 36.3% of them being female. Overall, only 17.2% of the entire cohort received an SGLT2 inhibitor, with an increasing prescription trend during the observation period. Interestingly, the prescription rate of SGLT2 inhibitors showed significant differences between males and females with a significantly lower intention for prescription in women (18.7% vs. 13.3%, p=0.008), despite having comparable patient characteristics. Women who did not receive an SGLT2 inhibitor tended to present more frequently with chronic kidney disease, however only 43 women presented with an estimated glomerular filtration rate of <30ml/min/1.73m2, which does not explain the observed general gender gap. Furthermore, in a regression analysis male participants were found to have a significantly higher probability of SGLT2i prescription, illustrated as an adjusted odds ratio of 1.44 (CI 95% 1.022-2.022; p =0.037) compared to women.

Conclusion

SGLT2i are potentially underutilized in female patients with CAD and T2DM, despite an overall increasing prescription trend during the observation period. Reasons for withholding therapy could not be objectified. The present data indicate a major need to increase awareness of guideline-directed therapy, especially in female T2DM patients with established CAD.
Biochemical profiles and risk of cardiovascular events in patients withType 2 Diabetes: implications for choice of novel antihyperglycemic therapy
Authors: Malik M E , Zahir D , Garred C H , Jensen J , Holt A , Andersson C , Fosboel E , Koeber L , Schou M
Published: November 2023

Background

Guidelines on type 2 diabetes (T2D) recommend targeting patients at greater risk of heart failure with sodium-glucose cotransporter-2 inhibitors (SGLT2-i) and patients at greater risk of cardiovascular ischemic events with glucagon-like peptide-1 receptor agonists (GLP1-RA) or SGLT2-i. It is currently unclear whether distinct biochemical profiles are more or less associated with the occurrence of heart failure or a cardiovascular ischemic event.

Purpose

To investigate the risk of the first occurring event of either heart failure or a cardiovascular ischemic event associated with different biochemical profiles in newly diagnosed T2D patients without cardiovascular disease.

Methods

From Danish nationwide registers, we identified all patients newly diagnosed with T2D who were free of cardiovascular disease (heart failure, ischemic heart disease, peripheral artery disease, and previous stroke), from 2013-2021. Patients <40 years, and patients without a registered blood test within three months prior to the T2D diagnosis, were excluded. The absolute 5-year risk of the first occurring event of either heart failure or a cardiovascular ischemic event, was calculated for patients with different levels of three biochemical markers that are known to be associated with cardiovascular disease: 1) HbA1c 2) low-density lipoprotein (LDL); and 3) estimated glomerular filtration rate (eGFR) calculated from serum creatinine.

Results

Of the 81,095 patients included in the study, 53% were male and the median age was 60 years [interquartile range 52-69]. For all pre-defined biochemical profiles—HbA1c below or above 8%, LDL below or above 4 mmol/L, and eGFR below or above 60ml/min/1.73m2—the absolute 5-year risk of a cardiovascular ischemic event was greater than the risk of heart failure (risk ratio ranging from 2.3–4.2), as the first occurring event following the diagnosis of T2D. The highest risk of heart failure was observed in those with moderately to severely reduced eGFR (<60 ml/min/1.73m2).

Conclusions

Among patients newly diagnosed with T2D and free of cardiovascular disease, different biochemical profiles of HbA1c, LDL, and eGFR, were all associated with a higher risk of an ischemic cardiovascular event as the first occurring event following T2D diagnosis, as opposed to heart failure.Flowchart of patient selectionCumulative incidence of CIE Vs. HF
GLP1 receptor agonists exhibit antioxidant and anti-inflammatory properties in human heart tissue via the canonical GLP1 receptor expression through a AMPK-mediated pathway
Authors: Cordeanu E M , Qureshi A W , Mroueh A , Mazzucotelli J P , Stephan D , Schini-Kerth V
Published: November 2023

Background

Clinical research has demonstrated that glucagon-like peptide-1 receptor (GLP1R) agonists (GLP1RA) can decrease the occurrence of major cardiovascular events in diabetic patients, regardless of their glycemic control. However, a significant challenge in understanding the positive effects of GLP1RA has been the lack of knowledge regarding the specific cellular types that express GLP1R. Despite the established cardiovascular benefits of GLP1RA, previous studies have been unable to confirm the expression of GLP1R in the heart.

Aim

The study aimed to investigate the expression and function of GLP1R in heart tissue.

Methods

We collected human cardiac tissue samples from 30 patients who underwent left ventricle (LV) biopsies (n=21) or right atrial (RA) appendage closure (n=9) at a university hospital. Gene expression levels were assessed using RT-qPCR, protein levels by Western blot analysis, in situ tissue localization of proteins by immunofluorescence (IF) staining, and the level of oxidative stress using dihydroethidium.

Results

LV biopsies and RA appendages showed a substantial heterogeneity in GLP1R mRNA levels. GLP1R mRNA levels exhibited a positive correlation with IL1B, IL6, TNFα, CCL2, CD68, ACE1, AT1R, and VCAM1 mRNA levels, but a negative correlation with NOS3 mRNA levels. High GLP1R expression in both RA appendages and LV biopsies was associated with increased oxidative stress levels, which were mitigated by the antioxidant N-acetylcysteine (NAC), NADPH oxidase inhibitor (VAS-2870), ACE inhibitor (perindoprilat), AT1R antagonist (losartan), TNF-α receptor neutralizing antibody (infliximab) and by GLP1R agonists (liraglutide and semaglutide) with inhibitory effects amounting to about 50-60 %. Exendin, a GLP1R antagonist reversed the effect of liraglutide and semaglutide which accounted for a receptor-mediated antioxidant effect. H-89, a PKA inhibitor equally reversed liraglutide and semaglutide effect on ROS generation suggesting a canonical GLP1R mediated effect involving the AMPK pathway.

Conclusion

These findings indicate that human cardiac GLP1R expression levels are correlated to low-grade inflammation and endothelial dysfunction. Increased expression levels of GLP1R were associated with higher levels of oxidative stress sensitive to GLP1RA in a canonical GLP1R AMPK-mediated manner. Therefore, the cardiovascular beneficial effects of GLP1RA might be attributable to their antioxidant and anti-inflammatory properties, specifically within the cardiac system.
Lower risks of new-onset hip fracture risks in users of sodium glucose cotransporter 2 (SGLT2) inhibitors versus users of dipeptidyl peptidase-4 (DPP4) inhibitors: a propensity score-matched analysis
Authors: Chou O H I , Zhou J , Satti D I , Lin K , Lee S , Wong W T , Wai A K C , Liu T , Cheung B M Y , Jing F , Tse G
Published: November 2023

Purpose

This study aimed to compare the effects of sodium glucose cotransporter 2 inhibitors (SGLT2I) and dipeptidyl peptidase-4 inhibitors (DPP4I) on new-onset hip fractures.

Methods

This was a retrospective population-based cohort study including type-2 diabetes mellitus patients treated with either SGLT2I or DPP4I between January 1st 2015 and December 31st 2020 in Hong Kong. The primary outcome was new-onset hip fracture and the secondary outcome was all-cause mortality. Propensity score matching (1:1 ratio) using the nearest neighbour search was performed. Univariable and multivariable Cox regression were applied to identify significant predictors. Competing risks models and multiple approaches using the propensity score were performed.

Results

This cohort included 56393 patients with type-2 diabetes mellitus (median age: 62.1 years old [interquantile range, IQR]: 54.2-71.1; 57.45% males), of which 20432 patients ([incidence rate, IR]: 36.23%) used SGLT2I and 35961 patients (IR: 63.77%) used DPP4I. After the 1:1 propensity score matching, 449 (IR: 1.09%) patients had hip fractures, and 2012 patients (IR: 4.92%) died. SGLT2I was associated with significantly lower risks of hip fractures after adjusting for the demographics, past comorbidities, non-SGLT2I/DPP4I medications and laboratory results (hazard ratio: 0.55; 95% confidence interval: 0.42-0.89; P=0.0036). The results were consistent in the competing risk models and the different propensity matching approaches.

Conclusions

SGLT2I was associated with lower risks of new-onset hip fractures after propensity score matching and adjustments.Figure 1