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Anatolian Journal of Cardiology Jul 2024Myocardial ischemia-reperfusion injury (I/R) has been improved with drugs and effective reperfusion, but it still cannot be prevented.
BACKGROUND
Myocardial ischemia-reperfusion injury (I/R) has been improved with drugs and effective reperfusion, but it still cannot be prevented.
METHODS
To investigate whether renal denervation (RDN) reduces cardiomyocyte apoptosis by ameliorating endoplasmic reticulum stress, 60 male specific pathogen-free (SPF) Wistar rats were randomly divided into 6 groups (n = 6). We established the I/R rat model by ligating the left anterior descending artery. The I/R+ angiotensin receptor neprilysin inhibitors (ARNI) group received ARNIs for 2 weeks until euthanasia.
RESULTS
The I/R+RDN and I/R+ARNI groups have significantly ameliorated left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) and reversed expansion of the left ventricular end-systolic diameter (LVSD) and left ventricular end diastolic diameter (LVDD) compared to the I/R group. The levels of norepinephrine (NE), angiotensin II, and aldosterone (ALD) increased significantly in the I/R group, but decreased significantly after RDN and ARNI intervention. In the I/R+RDN and I/R+ARNI groups, the myocardial tissue edema was alleviated. The infarct size was smaller in the I/R+RDN and I/R+ARNI groups compared to the I/R group. Apoptosis of cardiomyocytes and fibroblasts in myocardial tissue increased significantly in the I/R group, which was greatly diminished by RDN and ARNI. The expression of Bax, caspase-3, CHOP, PERK, and ATF4 protein was significantly increased in the I/R group, which compared to other groups, and the level of CHOP, PERK, and ATF4 gene expression increased. After RDN intervention, these expression levels recovered to varying degrees.
CONCLUSION
The effect of RDN may be associated with regulating the endoplasmic reticulum stress PERK/ATF4 signaling pathway.
Topics: Animals; Male; Rats; Rats, Wistar; Apoptosis; Myocardial Reperfusion Injury; Myocytes, Cardiac; Kidney; Disease Models, Animal; Endoplasmic Reticulum; Mitochondria; Denervation; Random Allocation; Endoplasmic Reticulum Stress; Mitochondria Associated Membranes
PubMed: 38940410
DOI: 10.14744/AnatolJCardiol.2024.3579 -
JACC. Advances May 2024
PubMed: 38939634
DOI: 10.1016/j.jacadv.2024.100926 -
JACC. Advances May 2024Persistent left ventricular hypertrophy after transcatheter aortic valve replacement (TAVR) has been associated with poor outcomes. Angiotensin-converting enzyme...
BACKGROUND
Persistent left ventricular hypertrophy after transcatheter aortic valve replacement (TAVR) has been associated with poor outcomes. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), due to their favorable effects on ventricular remodeling, have been hypothesized to improve outcomes post-TAVR, yet there are no recommendations regarding their use.
OBJECTIVES
This study aimed to compare the outcomes of patients receiving ACEIs/ARBs with those not receiving ACEIs/ARBs after TAVR.
METHODS
We performed a literature search on PubMed and Cochrane Library until June 14, 2023, and included all studies comparing clinical outcomes between patients given ACEIs/ARBs and those not given ACEIs/ARBs after TAVR. All-cause mortality was the primary outcome. We used a random effects model with appropriate corrections to calculate relative risk (RR) and CIs, with all analyses carried out using R v4.0.3.
RESULTS
We included ten studies on the use of ACEIs/ARBs post-TAVR. Patients on ACEIs/ARBs had lower risk of all-cause mortality (RR: 0.74, 95% CI: 0.65-0.86, I = 62%, chi-square < 0.01), cardiovascular mortality (RR: 0.70, 95% CI: 0.56-0.88, I = 0%, chi-square = 0.54), and new-onset atrial fibrillation (RR: 0.71, 95% CI: 0.52-0.96, I = 0%, chi-square = 0.59). Patients on ACEIs/ARBs had a similar risk of myocardial infarction, heart failure, stroke, new permanent pacemaker implantation, acute kidney injury, major bleeding, vascular complications, aortic regurgitation, and mitral regurgitation.
CONCLUSIONS
We found that patients receiving ACEIs/ARBs had a lower risk of all-cause mortality, cardiovascular mortality, and new-onset atrial fibrillation. Risk of other outcomes was similar to patients not receiving ACEIs/ARBs. Randomized clinical trials are needed to explore the benefits of ACEIs/ARBs post-TAVR, so that definitive guidelines can be developed.
PubMed: 38939627
DOI: 10.1016/j.jacadv.2024.100927 -
Discriminative Ability of Left Ventricular Strain in Mildly Reduced Ejection Fraction Heart Failure.JACC. Advances Nov 2023Left ventricular (LV) systolic strain is presumably a more sensitive myocardial indicator than LV ejection fraction (LVEF). Data regarding the use of LV strain in...
BACKGROUND
Left ventricular (LV) systolic strain is presumably a more sensitive myocardial indicator than LV ejection fraction (LVEF). Data regarding the use of LV strain in clinical risk stratification and in identifying angiotensin receptor-neprilysin inhibitor (ARNi) responders remain scarce in heart failure with mildly reduced ejection fraction (HFmrEF).
OBJECTIVES
The authors aimed to examine whether assessing LV strain may provide prognostic insight beyond LVEF and help discriminate the therapeutic efficacy of ARNi in HFmrEF patients.
METHODS
LVEF and LV strain were quantified among 1,075 first-time hospitalized HFmrEF patients (mean age: 68.1 ± 15.1 years, 40% female). The MAGGIC (Meta-analysis Global Group in Chronic Heart Failure) risk score and its components were calculated. A Cox proportional hazard model was constructed for time-to-event analysis. Restrictive cubic spline curves were used to model the therapeutic effects of ARNi against renin-angiotensin system inhibitor according to baseline LVEF or LV strain.
RESULTS
LV strain showed a statistically significant inverse association with MAGGIC cardiac risk (coefficient: -0.14, < 0.001). LV strain was independently associated with clinical outcomes after accounting for LVEF. MAGGIC-LV strain strata outperformed MAGGIC-LVEF strata in overall survival (Harrell's C-index: 0.71 and 0.56, for difference <0.001; category-free net reclassification index: 0.44, < 0.001). Lower LV strain but not LVEF consistently showed the beneficial therapeutic effects of ARNi against renin-angiotensin system inhibitor by Cox models and restrictive cubic spline (all <0.05).
CONCLUSIONS
Among HFmrEF patients, LV strain may serve as an attractive systolic marker and provide a better prognostic and therapeutic discriminative measure for ARNi treatment than conventional LVEF.
PubMed: 38938730
DOI: 10.1016/j.jacadv.2023.100654 -
JACC. Advances Jun 2023
PubMed: 38938244
DOI: 10.1016/j.jacadv.2023.100388 -
JACC. Advances Jun 2023Recent trial data refute concerns about neurocognitive off-target effects of neprilysin inhibition with sacubitril and suggest benefit in patients with heart failure and...
BACKGROUND
Recent trial data refute concerns about neurocognitive off-target effects of neprilysin inhibition with sacubitril and suggest benefit in patients with heart failure and ejection fraction >40%. We hypothesized that sacubitril/valsartan is associated with improved cognitive outcomes in patients with heart failure and reduced ejection fraction (HFrEF).
OBJECTIVES
The purpose of this study was to compare 3-year cognitive outcomes in patients with HFrEF who receive sacubitril/valsartan vs angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs).
METHODS
Retrospective cohort study of: 1) 11,313 adults with HFrEF (International Classification of Diseases-10th Revision-Clinical Modification [ICD-10-CM] codes: I50.2 or I50.4) started on sacubitril/valsartan between 1/1/2015 and 12/31/2019; and 2) 11,313 propensity matched patients receiving ACEI/ARB during that time. Data were obtained from the TriNetX Research Network, encompassing 41 health care organizations in the United States. Primary endpoint was the composite of cognitive decline (ICD-10-CM: R41.8), dementia (ICD-10-CM: F01-F03), and Alzheimer's disease (ICD-10-CM: G30).
RESULTS
At 3 years, 858 patients on sacubitril/valsartan met the primary endpoint vs 1,209 on ACEI/ARB (3-year incidence: 10.7% vs 15.0%; HR: 0.69; 95% CI: 0.63-0.75; < 0.001), with consistently lower rates of cognitive decline (9.5% vs 13.3%; HR: 0.69; 95% CI: 0.63-0.76; < 0.001), dementia (3.4% vs 5.0%; HR: 0.65; 95% CI: 0.57-0.77; < 0.001), and Alzheimer's disease (0.6% vs 1.3%; HR: 0.48; 95% CI: 0.35-0.66; < 0.001) in the sacubitril/valsartan cohort. Results were consistent in matched sex and race subgroups. Three-year mortality was 22.0% on sacubitril/valsartan vs 24.6% on ACEI/ARB (HR: 0.89; 95% CI: 0.84-0.94; < 0.001).
CONCLUSIONS
Sacubitril/valsartan was associated with lower 3-year rates of neurocognitive disorders when compared to ACEI/ARBs in patients with HFrEF.
PubMed: 38938237
DOI: 10.1016/j.jacadv.2023.100372 -
BMC Nephrology Jun 2024Sarcoidosis is a multisystemic inflammatory disease, characterized by the presence of non-caseating, epithelioid granulomas. Glomerular disease in patients with...
BACKGROUND
Sarcoidosis is a multisystemic inflammatory disease, characterized by the presence of non-caseating, epithelioid granulomas. Glomerular disease in patients with sarcoidosis is rare and membranous nephropathy (MN) is cited as the most common. The association between the two diseases remained unclear. This article reported a case of co-occurrence of sarcoidosis and anti-PLA2R-associated MN, to provide a possible relationship between these two entities.
CASE PRESENTATION
A 61-year-old Chinese Han woman with a history of sarcoidosis was admitted to our hospital for nephrotic syndrome. Her sarcoidosis was diagnosed according to the adenopathy observed on the computed tomography scan and the biopsy of lymph nodes. The MN presented with nephrotic syndrome with a PLA2R antibody titer of 357RU/ml, and the final diagnosis was based on a renal biopsy. The patient's sarcoidosis was remitted after treatment with prednisone. One year later MN was diagnosed, and she was treated with prednisone combined with calcineurin inhibitors, based on a full dose of renin-angiotensin system (RAS) inhibitor. The patient's sarcoidosis had been in remission while the MN was recurrent, and her renal function deteriorated to end-stage renal disease 6 years later due to discontinuation of immunosuppression. A genetic test led to the identification of the HLA-DRB1*0301 and HLA-DRB1*150 genes associated with both sarcoidosis and MN, which provides a new possible explanation of the co-occurrence of these two diseases.
CONCLUSION
This case suggested for the first time a potential genetic connection between idiopathic MN and sarcoidosis which needs further studies in the future.
Topics: Humans; Glomerulonephritis, Membranous; Female; Middle Aged; Receptors, Phospholipase A2; Sarcoidosis; Genetic Predisposition to Disease; Autoantibodies
PubMed: 38937663
DOI: 10.1186/s12882-024-03649-0 -
Scientific Reports Jun 2024There is no treatment for acute aortic dissection (AAD) targeting inflammatory cells. We aimed to identify the new therapeutic targets associated with inflammatory...
There is no treatment for acute aortic dissection (AAD) targeting inflammatory cells. We aimed to identify the new therapeutic targets associated with inflammatory cells. We characterized the specific distribution of myeloid cells of both human type A AAD samples and a murine AAD model generated using angiotensin II (ANGII) and β-aminopropionitrile (BAPN) by single-cell RNA sequencing (scRNA-seq). We also examined the effect of an anti-interleukin-1β (IL-1β) antibody in the murine AAD model. IL1B inflammatory macrophages and classical monocytes were increased in human AAD samples. Trajectory analysis demonstrated that IL1B inflammatory macrophages differentiated from S100A8/9/12 classical monocytes uniquely observed in the aorta of AAD. We found increased infiltration of neutrophils and monocytes with the expression of inflammatory cytokines in the aorta and accumulation of inflammatory macrophages before the onset of macroscopic AAD in the murine AAD model. In blocking experiments using an anti-IL-1β antibody, it improved survival of murine AAD model by preventing elastin degradation. We observed the accumulation of inflammatory macrophages expressing IL-1β in both human AAD samples and in a murine AAD model. Anti-IL-1β antibody could improve the mortality rate in mice, suggesting that it may be a treatment option for AAD.
Topics: Aortic Dissection; Interleukin-1beta; Animals; Humans; Macrophages; Mice; Disease Models, Animal; Male; Aminopropionitrile; Angiotensin II; Inflammation; Monocytes; Aorta; Mice, Inbred C57BL; Female
PubMed: 38937528
DOI: 10.1038/s41598-024-65931-3 -
Cell Death & Disease Jun 2024SARS-CoV-2 infection is initiated by Spike glycoprotein binding to the human angiotensin-converting enzyme 2 (ACE2) receptor via its receptor binding domain. Blocking...
SARS-CoV-2 infection is initiated by Spike glycoprotein binding to the human angiotensin-converting enzyme 2 (ACE2) receptor via its receptor binding domain. Blocking this interaction has been proven to be an effective approach to inhibit virus infection. Here we report the discovery of a neutralizing nanobody named VHH60, which was directly produced from an engineering nanobody library based on a commercialized nanobody within a very short period. VHH60 competes with human ACE2 to bind the receptor binding domain of the Spike protein at S, Sand S as determined by structural analysis, with an affinity of 2.56 nM. It inhibits infections of both ancestral SARS-CoV-2 strain and pseudotyped viruses harboring SARS-CoV-2 wildtype, key mutations or variants at the nanomolar level. Furthermore, VHH60 suppressed SARS-CoV-2 infection and propagation 50-fold better and protected mice from death for twice as long as the control group after SARS-CoV-2 nasal infections in vivo. Therefore, VHH60 is not only a powerful nanobody with a promising profile for disease control but also provides evidence for a highly effective and rapid approach to generating therapeutic nanobodies.
Topics: SARS-CoV-2; Single-Domain Antibodies; Humans; Animals; COVID-19; Spike Glycoprotein, Coronavirus; Mice; Angiotensin-Converting Enzyme 2; Antibodies, Neutralizing; COVID-19 Drug Treatment; Antibodies, Viral; HEK293 Cells; Mice, Inbred BALB C; Protein Binding; Female
PubMed: 38937437
DOI: 10.1038/s41419-024-06802-7 -
Circulation Jun 2024Results from the COORDINATE-Diabetes trial demonstrated that a multifaceted, clinic-based intervention increased prescription of evidence-based medical therapies to...
Effects of an Intervention to Improve Evidence-Based Care for People With Diabetes and Cardiovascular Disease Across Sex, Race, and Ethnicity Subgroups: Insights From the COORDINATE-Diabetes Trial.
BACKGROUND
Results from the COORDINATE-Diabetes trial demonstrated that a multifaceted, clinic-based intervention increased prescription of evidence-based medical therapies to participants with type 2 diabetes and atherosclerotic cardiovascular disease. This secondary analysis assessed whether intervention success was consistent across sex, race, and ethnicity.
METHODS
COORDINATE-Diabetes, a cluster randomized trial, recruited participants from 43 US cardiology clinics (20 randomized to intervention and 23 randomized to usual care). The primary outcome was the proportion of participants prescribed all 3 groups of evidence-based therapy (high-intensity statin, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and sodium-glucose cotransporter-2 inhibitor or glucagon-like peptide 1 receptor agonist) at last trial assessment (6 to 12 months). In this prespecified analysis, mixed-effects logistic regression models were used to assess the outcome by self-reported sex, race, and ethnicity in the intervention and usual care groups, with adjustment for baseline characteristics, medications, comorbidities, and site location.
RESULTS
Among 1045 participants with type 2 diabetes and atherosclerotic cardiovascular disease, the median age was 70 years, 32% were female, 16% were Black, and 9% were Hispanic. At the last trial assessment, there was an absolute increase in the proportion of participants prescribed all 3 groups of evidence-based therapy in women (36% versus 15%), Black participants (41% versus 18%), and Hispanic participants (46% versus 18%) with the intervention compared with usual care, with consistent benefit across sex (male versus female; =0.44), race (Black versus White; =0.59), and ethnicity (Hispanic versus Non-Hispanic; = 0.78).
CONCLUSIONS
The COORDINATE-Diabetes intervention successfully improved delivery of evidence-based care, regardless of sex, race, or ethnicity. Widespread dissemination of this intervention could improve equitable health care quality, particularly among women and minority communities who are frequently underrepresented in clinical trials.
REGISTRATION
URL: https://clinicaltrials.gov. Unique identifier: NCT03936660.
PubMed: 38934111
DOI: 10.1161/CIRCULATIONAHA.124.068962