bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unraveling immune checkpoint inhibitors effects on atherosclerosis: mechanisms and preventive approaches
Authors: Nardi Agmon I , Leshem-Lev D , Shavit R , Gurevitz C , Rahat O , Gueta T , Hochhauser E , Eisen A , Kornowski R 
Published: October 2024

Abstract

Background
Immune checkpoint inhibitors (ICIs) represent a novel and rapidly evolving field in cancer treatment. Despite increasing reports of accelerated atherosclerosis and ICI-related atherosclerotic cardiovascular (CV) events in clinical studies and case reports, there is a notable lack of data concerning the underlying mechanisms, appropriate monitoring, and potential interventions.

Objectives
To explore the role of ICIs in triggering and/or accelerating the atherosclerotic process, with a specific focus on the involvement of CD8+ T-cells. Additionally, we aimed to evaluate and compare the potential beneficial effects of statins and Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors on atherosclerosis under ICIs treatment.

Methods
Thirty 8-week-old C57BL mice were divided into six groups as follows: (1) Control, normal diet; (2) Control, atherogenic diet; (3) Atherogenic diet + anti PD-1; (4) Atherogenic diet + statins + anti-PD1; (5) Atherogenic diet + PCSK9-i + anti PD-1; (6) Atherogenic diet + PCSK9 inhibitors. At 16 weeks, the carotid arteries and heart were removed for histological examination, and serum was withdrawn for blood work and further analysis.

Results
Anti-PD1 treatment resulted in extensive lymphocytic infiltration of the carotid intima, primarily constituted of CD8+ T cells. This infiltration was significantly attenuated when statins or PCSK-9 inhibitors were used in conjunction with anti-PD1 treatment. Serum analysis for CD4+ and CD8+ T cells by ELISA revealed no difference in CD4+ abundance between the groups. However, plasma CD8+ T cells were significantly increased with anti-PD1 treatment, and furthermore, when PCSK9 inhibitors were used in combination; but not when statins were used.

Conclusion
The induction of CD8+ T cell infiltration in the arterial carotid walls by anti-PD-1 was prevented with the use of either statins or PCSK9 inhibitors. In the plasma, while statins reduced the hyper-expression of CD8+ T cells observed under PD-1 treatment, PCSK9 inhibitors enhanced this expression. This may provide a first indication of the potential benefit of PCSK9 inhibitor treatment for both preventing arterial inflammation and enhancing the desired anti-tumor immune response under ICIs treatment.
Figure legend:
1A. A cross-section of the carotid artery after 16 weeks of treatment, stained with H&E. Magnification is X100.
1B. A cross-section of the carotid artery after 16 weeks of treatment, stained with anti-CD8 Ab. Magnification is X100.
1C. quantitative CD8+ T cells staining in the carotid arteries.
1D. quantitative results of ELISA for plasma CD8+ T cells.
The predictive value of coronary artery calcium deposit for cardiovascular events in patients treated with immune checkpoint inhibitor therapy
Authors: Soleman M S , Rozenbaum Z R , Gvili Perelman M G V , Topilsky Y T , Banai S B , Carver J C , Laufer-Perl M 
Published: October 2024

Abstract

Background
Immune checkpoint inhibitors (ICIs) are now a standard of care for the treatment of wide variety of cancers, due to their dramatically improved patient's outcomes. Nevertheless, their use may lead to significant cardiovascular immune-related adverse events (CV irAEs).

Objectives
We aimed to assess whether pre-treatment coronary artery calcium (CAC) deposit may play as a risk factor for CV irAEs development in patients treated with ICIs therapy.

Methods
A retrospective single center cohort of patients treated with ICIs therapy, who performed pre-treatment chest computed tomography. Visual CAC assessment was performed, categorized to positive or negative calcium deposit in the coronary arteries. Patients with pre-existing ischemic heart disease were excluded. The primary endpoint was to evaluate the association between positive CAC deposit and the composite CV irAEs, including myocarditis, acute coronary syndrome, heart failure, and arrhythmias. The secondary endpoint was to evaluate its association to all-cause mortality.

Results
The cohort included 238 patients, with mean age 65±13 years and 53% male representative. The most prevalent type of cancer was lung (36%) and the prominent ICIs regimen was pembrolizumab (54%). High incidence of cardiac risk factors was observed, including hypertension (39%), hyperlipidemia (35%) and diabetes (23%). Overall, 145 (61%) patients were included in the positive CAC deposit group. No significant differences were observed between the positive and negative groups regarding cancer type, ICIs therapy and baseline cardiac risk factors or medical therapy. Over a 12-months follow-up period, positive CAC deposit was not associated with the development of CV irAEs (p=0.139), or increased all-cause mortality (p=0.884).

Conclusion
The presence of pre-treatment positive CAC deposit did not demonstrate a predictive role in assessing the risk of CV irAEs or all-cause mortality in patients treated with ICIs.
Pregnancy and inherited aortopathies: insights from specialized care
Authors: Sola Garcia E , Garcia Garcia A M , Casian M , Cauldwell M , Watt-Coote I , Sharma R , Marciniak A , Tome Esteban M 
Published: October 2024

Abstract

Background
Genetic counselling, pregnancy follow-up and delivery planning in women with aortopathy should be conducted by a multidisciplinary team in an expert centre.

Purpose
Our objective was to analyze the impact of pregnancy on aortopathy outcomes in a centre specialized in inherited cardiovascular conditions in the United Kingdom.

Methods
All women with aortopathy referred to our centre due to pregnancy between 2016 and 2023 were retrospectively analyzed. Demographic, clinical, obstetric, genetic, electrocardiographic, and multimodal imaging variables were collected.

Results
Between 2016 and 2023, 22 women with aortopathy were referred to our centre for pregnancy follow-up and delivery planning. Among them, 14 (63.6%) had Marfan syndrome (FBN1+), 4 (18.2%) family history of aortic dissection without known genetic mutations, 2 (9.1%) bicuspid aortic valve with aortic dilation and 2 (9.1%) Loeys-Dietz syndrome (SMAD3+). The average number of births per patient was 1.55. Among those with an identified mutation, 4 (25%) underwent preimplantation diagnosis. In total, there were 40 pregnancies resulting in 34 live births. 15 women (68.2%) had an aortic root dimension &lt;40mm and 7 (31.8%) ≥40mm. There were 4 (26.7%) and 5 (71.4%) patients in each group under beta-blockers. Out of the total 40 pregnancies, there were 6 (15%) miscarriages, all in the first trimester, 2 (5%) cases of preeclampsia and 1 (2.5%) case of gestational diabetes. There were no statistically significant differences between these complications and the aortic root dimension (8 (20%) &lt;40mm vs 1 (2.5%) ≥40mm; p = 0.160) or the absence or presence of treatment (3 (7.5%) vs 6 (15%); p = 0.769). Regarding delivery, 16 patients (72.7%) underwent vaginal delivery and 6 (27.3%) has a caesarean section. After delivery, there were 6 cases of major bleeding, 4 (10%) after vaginal delivery and 2 (5%) after caesarean (p=0.376). One patient had a subacute type A aortic dissection in the context of Marfan syndrome with an aortic root of 40mm before pregnancy. No significant differences were observed in the occurrence of these complications based on the aortic root dimension (5 (12.5%) &lt;40mm vs 2 (5%) ≥40mm; p = 0.928) or the absence or presence of treatment (2 (5%) vs 5 (12.5%) respectively; p = 0.591). 100% of the patients survived pregnancy and the postpartum period.

Conclusions
Our findings underscore the complexity of managing aortopathy during pregnancy. This highlights the importance of a comprehensive risk assessment for precise pregnancy and delivery planning.
Worse ischemic symptoms and cardiac function in women with suspected ischemia with no obstructive coronary artery disease and adverse pregnancy outcomes history
Authors: Quesada O Q , Oneglia A O , Lauzon M L , Tapp D T , Maughan J M , Wei J W , Shufelt C S , Tamarappoo B T , Pepine C P , Nelso M N , Bairey Merz N B M 
Published: October 2024

Abstract

Background
Adverse pregnancy outcomes (APO) are associated with increased maternal risk of cardiovascular disease (CVD) and mortality. Ischemia with no obstructive coronary artery disease (INOCA) is predominant in women, however the association of APO history with INOCA is poorly understood.

Purpose
To compare clinical characteristics, symptoms, cardiac structure and function and coronary microvascular dysfunction in women suspected to have INOCA with or without a history of APO.

Methods
Women’s Ischemia Syndrome Evaluation (WISE) CVD (NCT00832702) and WISE pre-HFpEF (NCT02582021) prospective cohorts of women with suspected INOCA were merged and utilized to determine among women with at least 1 prior pregnancy whether a history of APO was associated with ischemic symptoms, and to characterize CMRI measured left ventricle (LV) structure and function, myocardial deformation (systolic and diastolic strain) and coronary microvascular dysfunction on invasive coronary functional testing (CFT). Self-reported APO was defined as hypertensive disorder of pregnancy (HDP), gestational diabetes, preterm birth (&lt;37-week gestation), low birth weight (&lt;5lbs).

Results
In a cohort of 469 women with suspected INOCA, (mean average age 55 [SD 10.2] years) and at least 1 prior pregnancy, 138 (29%) had history of at least 1 APO. Among women with history of APO, 78 reported HDP, 50 gestational diabetes, 27 pre-term birth, 8 low birth weight. Women with a history of APO were younger, had higher rates of hypertension and diabetes, higher BMI and lower SAQ and DASI scores compared to those with no history of APO (Table). LV ejection fraction (EF) was lower and early diastolic strain rate/LVEDP was higher in women with APO history compared to those without APO history.

Conclusion(s)
In cohort of women with INOCA, history of APO was highly prevalent. Despite younger age, women with history of APO had higher rates of CVD risk factors, worse ischemic symptoms and functional capacity, lower EF, and higher filling pressures. Our findings suggest a potential for APO history to better identify women with worse prognosis that warrants further investigation and aggressive management.
Subclinical myocardial disfunction detected by left ventricle myocardial work impairment in patients with long standing human inmmunodeficiency virus infection
Authors: Gascuena R , Gomez Diego J , Cervero M , Torres R , Morales T , Jimenez Azzaoui B , Ayllon J , Ruesgas R , Esteban A 
Published: October 2024

Abstract
Heart failure is a known complication in patients living with human inmmunodeficiency virus (HVI) infection. Detection of subclinical disfunction is nowadays possible by echocardiographic strain techniques. Myocardial work is a novel technique based on global longitudinal strain (GLS) that measures global work efficiency of left ventricle (GWE) and would allow early detection of subclinical myocardial damage.

Methods
We performed a cross sectional echocardiographic study of patients with long standing HIV infection, and no previous cardiopathy, assessing GLS of left ventricle (LV), left atrium (LA) and free wall of right ventricle (RV-FW GLS). We identified patients with subclinical disfunction expressed by an impaired GWE , and studied its determinants by lineal regression.

Results
110 patients, 78.2% male, median age 53.3 (51.2-55.4) were included. Time from diagnosis was 20.5 (18.6-22.3) years. Myocardial work strain analysis showed an impaired GWE: 91.9% (90.9-92.9);p&lt;0.001) and a GW index of 1840.8 mmHg%(1758.7-1922.9):p&lt;0.001. The rest of deformation parameters laid into normal range: LV GLS was -19.5% (-19.0- -20.0) GLS dispersion 55.1 (50.1-60.1), LA GLS (reservoir) 32.8% (31.2-34.5), and RV free wall GLS -22.3% (-21.4 - -23.2).
By univariate analysis, determinants of impaired GWE were age, Score2 risk, time from HIV diagnosis, QRS Interval duration, long QTc Interval, LV ejection fraction (LVEF),diastolic disfunction by doppler tissue imaging, CD4 count nadir, initial and maximun viral load, and exposure to didanosine treatment. After adjustment by cardiovascular risk and diastolic function (Ea velocity by tissue Doppler) , GWE impaired depended on duration of infection (Beta 0.3;95%CI:0.04-0.56;p=0.023), initial viral load (Beta -1.1;95%CI:-2.1- -0.02;p=0.046) and exposure to stavudine (Beta -6.3;95%IC: -11.5- -1.1;p=0.019).

Conclusions
Subclinical myocardial disfunction is prevalent in long standing HIV infection. Global work efficiency is a very sensitive parameter for detection, even in patients with normal GLS values, and it was related to duration of infection, initial viral load, and exposure to stavudine in our patients.Determinants of Global Work Efficiency
Prognostic value of C-reactive protein / albumin ratio for amputation and/or mortality after lower extremity revascularization in haemodialysis patients with peripheral artery disease
Authors: Takahashi H , Kumada Y , Kawai N , Ishida N , Nakamura Y , Ito R , Oshima S , Izawa H , Ozaki Y , Murohara T , Ishii H 
Published: October 2024

Abstract

Background
Hypoalbuminemia, a manifestation of protein-energy wasting (PEW) or malnutrition, which is commonly observed in patients with chronic kidney disease, is associated with increasing cardiovascular risk. Recently, C-reactive protein (CRP) / albumin ratio has been developed as a newly surrogate marker of the PEW because the PEW seems to result not only from an inadequate diet but also rather be induced by chronic inflammatory status. The aim of this study was to clarify whether pre-procedural CRP/albumin ratio levels could predict amputation and/or mortality after lower extremity revascularization for peripheral artery disease (PAD) in patients on haemodialysis (HD).

Methods
A total of consecutive 1,850 HD patients successfully undergoing lower extremity revascularization (494 bypass surgery and 1,356 endovascular therapy) were enrolled in this study. Patients were divided into tertiles according to pre-procedural CRP/albumin ratio levels; low (&lt;0.6, n=619), middle (0.6-3.7, n=609) and high tertile (&gt;3.7, n=622). They were followed up for up to 8-year. The primary endpoint was defined as amputation and/or mortality.

Results
During follow-up period (median of 53 months), 162 major amputation (8.8%) was performed and 508 patients (27.5%) died. Cumulative incidence rates of amputation and/or mortality at 8-year were 47.4%, 56.2% and 70.0% in low, middle and high tertile of CRP/albumin ratio, respectively (p&lt;0.0001). After adjustment for male, age, traditional risk factors, body mass index, history of coronary artery disease or stroke, procedure (bypass vs. endovascular therapy), infrapopliteal disease and ulcer/gangrene, the CRP/albumin ratio was identified as an independent predictor for amputation and/or mortality [adjusted hazard ratio (aHR) 1.39, 95% confidence interval (CI) 1.12-1.72, p=0.0028 for middle vs. low tertile, and aHR 2.53, 95% CI 2.07-3.09, p&lt;0.0001 for high vs. low tertile, respectively]. Similar results were also observed even for major amputation and mortality, respectively (aHR 2.73, 95% CI 1.77-4.31 for amputation and aHR 2.32, 95% CI 1.82-2.97 for mortality with p&lt;0.0001 for high vs. low tertile in both, respectively, Figure).

Conclusion
Pre-procedural CRP/albumin ratio could predict both of amputation and mortality after lower extremity revascularization, and could stratify the risk in HD patients with PAD. Measurement of CRP/albumin ratio in such high-risk population may be useful because this newly surrogate marker of the PEW is simple and can be easily obtained in daily practice.
Surgical reduction of a high-flow dialysis fistula has long-term positive effects of the heart
Authors: Valerianova A , Buryskova Salajova K , Malik J 
Published: October 2024

Abstract

Introduction
Part of chronic haemodialysis patients develop a high-flow arteriovenous fistula (AVF). The volume overload caused by the presence of a high-flow AVF leads to increased cardiac output, dilation of cardiac chambers, increased pulmonary artery pressure or even to the development of high-output heart failure. Our previous data showed a positive effect of AVF flow-reducing surgery in 6 weeks follow-up.

Purpose
The purpose of this study was to analyse the long-term effect of AVF blood flow (Qa) reduction on cardiac structure and function.

Methods
We included patients with high-flow AVFs (defined as Qa over 1500 mL/min) indicated for blood flow reduction surgery for heart failure symptoms or pre-defined echocardiographic changes (left ventricular hypertrophy, severe secondary valvular regurgitations, or pulmonary hypertension). Echocardiography was performed one day before the surgery, the 6 weeks, 6 months, and 12 months thereafter. Qa was measured by ultrasound during the same visits.

Results
27 patients were included, 20 men and 7 women, aged 57 ± 13 years. The procedure led to an immediate decrease in Qa. However, we observed failure of the procedure within 1 year in 8 (= 30%) patients defined by increased Qa back to pre-surgery values. Detailed results are displayed in Table 1. Estimated pulmonary arterial systolic pressure and left atrial volume remained significantly lower after 1 year despite the Qa rise. Effective cardiac output (= difference of cardiac output and Qa) rose immediately and remained increased during the follow-up period despite the increase in AVF blood flow.

Conclusions
We observed a long-time positive effect of AVF blood flow reduction surgery on the heart despite a significant Qa rise. The effective cardiac output remained increased despite the gradual increase of Qa, probably due to the adaptation of systemic arterioles.
Plasma statin concentrations do not correlate with statin-induced myalgia
Authors: Ritvos M , Mombelli G , Ramste M , Laaperi M , Kauhanen D , Sinisalo J , Sirtori C , Thompson P D , Dube M P , Tardif J C , Laaksonen R 
Published: October 2024

Abstract

Aims
Statins are essential in cardiovascular prevention. Although well-tolerated, patient adherence is often suboptimal due to experienced musculoskeletal symptoms ranging from mild myalgia to rare life-threatening rhabdomyolysis. This study aimed to investigate the relationship between plasma concentrations of statin metabolites in patients experiencing myalgia without rhabdomyolysis.

Methods and results
Plasma concentrations of statin metabolites were quantitatively assessed using mass spectrometry across three case-control cohorts evaluating statin-induced myalgia. The analysis included a total of 373 patients from the MILANO study (N=85 with self -reported myalgia), the MONTREAL study (N=248 with clinically verified myalgia) and the STOMP study (N=40 with rechallenge-verified statin-induced myalgia). STOMP found no significant difference in the plasma concentrations of statin metabolites between statin naïve patients with myalgia (N=12) taking atorvastatin 80 mg daily and asymptomatic controls (N=28), including upon subsequent statin rechallenge. Both the MILANO and MONTREAL studies showed lower plasma concentrations of statin metabolites in patients with myalgias compared to controls. MILANO showed a significant difference in rosuvastatin lactone concentration in patients with myalgias compared to asymptomatic controls (P = 0.025). Similarly, MONTREAL showed significantly lower mean atorvastatin metabolite concentrations in affected patients versus controls (P values ranging from 0.0073 to 0.037). Atorvastatin dosages in MONTREAL ranged from 5 to 80 mg daily, the most frequent regimens being 20 mg (27% in cases; 24% in controls) and 40 mg (33% in cases; 37% in controls). Creatine kinase levels were measured in all cohorts and were not different between cases and controls.

Conclusion
Development of myalgias in patients with normal creatine kinase levels is not associated with higher statin metabolite plasma concentrations. Myalgias during statin therapy are not caused by pharmacokinetic abnormalities.
Glutathione s-transferase pi is a marker of loop diuretic resistance in patients with congestive heart failure exacerbation
Authors: Imiela T , Poplawski P , Zaborska B , Pilichowska - Paszkiet E , Bednarczyk T , Piszcz K , Budaj A 
Published: October 2024

Abstract

Background
Loop diuretic resistance (LDR) in patients with heart failure (HF) exacerbation is associated with worse clinical outcomes, greater symptom burden and mortality. Diagnosis and treatment of LDR remains a significant clinical dilemma.

Purpose
To assess the ability of different urine biomarkers to predict LDR in patients with HF exacerbation.

Methods
Consecutive patients with congestive HF exacerbation were prospectively included in the study. HF was diagnosed according to ESC 2021 HF Guidelines definition. Congestion was defined as a presence of one or more of the following signs: edema, ascites, pleural effusion. LDR was defined as persistent congestion on the 4th day of hospital stay despite high i.v. loop diuretic dose. Urine biomarkers released from different parts of the nephron (Kidney Injury Molecule-1 - KIM-1, N-acetyl-β-D-glucosaminidase - NAG, uromodulin, glutathione S-transferase Pi - pi-GST, aquaporin-2), transthoracic echo, clinical and biochemical parameters were evaluated on the 1st and 4th day of hospital stay. Results are presented as mean ±standard deviation or median (interquartile range).

Results
40 patients were included in the study with median age 84 (72,8; 86) years, median left ventricle ejection fraction (EF) 35.3 (26,5; 49) %, median NT-proBNP 8967.5 (3024; 15241) pg/ml. LDR was found in 14 (35%) patients. Univariate analysis identified the following risk factors for LDR: urine pi-GST concentration on admission and on the 4th day, right ventricle to pulmonary circulation coupling index (TAPSE/PASP ratio), presence of mitral regurgitation, serum creatine concentration, serum urea concentration, serum LDL concentration. Logistic regression analysis identified pi-GST concentration as a significant independent risk factor for LDR in this population: odds ratio (OR) 5.75 [95% confidence interval (CI) 1.271–25.990].

Conclusions
Urine pi-GST on admission and after 4 days of treatment might be a marker for a development of LDR in patients with congestive HF exacerbation.