Tag: Cardiomyopathy

Inflammatory responses fuel cardiovascular complications

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In a recent study published in the journal Circulation, researchers investigate the inflammatory response to acute respiratory distress syndrome (ARDS) within the heart.

Study: Virus-Induced Acute Respiratory Distress Syndrome Causes Cardiomyopathy Through Eliciting Inflammatory Responses in the Heart. Image Credit: Kateryna Kon / Shutterstock

The link between respiratory viral infections and CVD

Seasonal viral infections can range in severity from mild flu-like symptoms to potentially lethal ARDS. For example, despite being primarily a respiratory tract infection, coronavirus disease of 2019 (COVID-19) can lead to ARDS and other severe cardiovascular disease outcomes with high mortality rates.

Circulating immune cells may respond to COVID-19 by upregulating cytokine release, which can lead to myocardial injury. Cardiac macrophages, immune cells responsible for the myocardial inflammatory response, are increasingly being investigated for their role in ARDS. Recent evidence indicates that macrophage expansion, which can be accompanied by changes in the population size and relative abundances of various cardiac macrophages, is a characteristic feature of ARDS.

The main two types of cardiac macrophages include C-C chemokine receptor type 2 negative (CCR2^–) and CCR2⁺ macrophages. Further research is needed to determine the viral-induced contributions of these macrophages to adverse cardiac outcomes.

These data would allow clinicians to make informed intervention decisions and elucidate whether these outcomes are COVID-19-induced or if observed inflammation is a systemic immune response to viral infection. Furthermore, this information could support the development of future therapies to prevent cardiovascular disease (CVD) following recovery from COVID-19.

About the study

In the present study, researchers investigate the role of viral- and non-viral-induced ARDS-associated immune signals in altering cardiac macrophage populations, thereby impacting CVD parameters, including systemic inflammation.

This study was conducted at Massachusetts General Hospital and involved 33 control samples obtained from patients who died between September and December 2019, prior to the onset of COVID-19, as well as 21 samples obtained between May and July 2020 from patients who died from COVID-19-associated complications. Samples consisted of autopsy tissue excised from the left ventricular or septal region.

Simultaneously, in vivo studies involved a daily intratracheal administration of an ARDS cocktail of immunostimulatory agents to mice, which included resiquimod, imiquimod, lipopolysaccharide (LPS), and angiotensin-converting enzyme 2 (ACE2) inhibitor MLN-4760. This model allowed the researchers to reproduce clinical ARDS features in mice without the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Patient data included results obtained from electrocardiogram (ECG), echocardiography, lung computed tomography (CT) scan, blood gas analyses, body temperature evaluation, bronchoalveolar lavage fluid (BALF) characterization, blood pressure measurements, and flow cytometry. Both human and murine autopsy samples were processed using ribonucleic acid (RNA) isolation, real-time polymerase chain reaction (PCR) assay, and enzyme-linked immunosorbent assays (ELISAs) for protein and gene expression determinations.

Similar immune responses in non-viral- and SARS-CoV-2-associated ARDS

In the absence of viral infection, mice treated with the ARDS cocktail exhibited significant weight loss over the five-day cocktail treatment period. This was accompanied by hypothermia, a common feature of both ARDS and septic shock, as well as a mortality rate of over 40% by day five.

Mice with ARDS exhibited bilateral opacities and immune cell infiltrations within their lungs, as well as reduced blood oxygenation. Furthermore, increased D-dimer, neutrophil, and monocyte levels were observed, as well as reduced blood pressure and lower heart rates in ARDS mice. Other inflammatory pathways that were activated in ARDS mice included increased levels of interleukin 6 (IL-6), IL-1ß, tumor-necrosis factor α (TNF-α), and interferon y (IFN-y), all of which are also associated with SARS-CoV-2 infection.

In both non-infected ARDS and SARS-CoV-2-infected mice, an increased infiltration of interstitial macrophages and reduced levels of alveolar macrophages were observed. Although both mouse models exhibited increased levels of cardiac macrophages, this immune response was more pronounced in infected mice. Nevertheless, both models’ subsets of cardiac macrophages were altered to similar levels.

Upon comparison of control and COVID-19 patient myocardium samples, SARS-CoV-2 infection recruited a more significant number of CCR2+ CD68+ macrophages, thus indicating that a robust immune response is elicited after severe infection compared to other life-threatening diseases.

“Our findings indicate that systemic and myocardial inflammatory signals elicited by virally induced ARDS may contribute to the cardiovascular complications and high mortality rates of this condition. In addition, our study confirms previous reports that SARS-CoV-2 infection increases overall macrophage numbers in hearts.”

The cardiac benefits of TNF-α immune therapy

TNF-α neutralizing antibodies were also administered to mice to evaluate their effects on immune activation during ARDS. To this end, TNF-α immune therapy reduced weight loss, improved body temperature, increased blood oxygenation, and led to better survival rates. Histological analysis indicated that ARDS mice receiving anti-TNF-α therapy exhibited reduced macrophages, Cxcl2, IL-1ß, and IL-6 expression within the lungs.

TNF-α therapy also improved systolic dysfunction, cardiomyocyte apoptosis, and monocyte infiltration in ARDS mice. Total cardiac macrophage counts and reduced expression of IL-1ß, IL-6, and TNF-α within the myocardium were also observed, thus demonstrating the anti-inflammatory benefits associated with TNF-α immune therapy in the lungs and hearts of mice with ARDS.

Conclusions

The study findings demonstrate that SARS-CoV-2 infection leads to significant alterations in cardiac macrophage subset levels, particularly increased levels of CCR2+ macrophages, in both mice and humans. Even in the absence of SARS-CoV-2 or another virus, the immune response to ARDS-like injury is capable of inducing significant alterations in heart macrophage levels, which may increase the risk of cardiovascular complications and mortality associated with ARDS.

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March 24, 2024
SARS-CoV-2-associated ARDS can damage the heart without direct infection

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SARS-CoV-2, the virus that causes COVID-19, can damage the heart even without directly infecting the heart tissue, a National Institutes of Health-supported study has found. The research, published in the journal Circulation, specifically looked at damage to the hearts of people with SARS-CoV2-associated acute respiratory distress syndrome (ARDS), a serious lung condition that can be fatal. But researchers said the findings could have relevance to organs beyond the heart and also to viruses other than SARS-CoV-2.

Scientists have long known that COVID-19 increases the risk of heart attack, stroke, and Long COVID, and prior imaging research has shown that over 50% of people who get COVID-19 experience some inflammation or damage to the heart. What scientists did not know is whether the damage occurs because the virus infects the heart tissue itself, or because of systemic inflammation triggered by the body’s well-known immune response to the virus.

This was a critical question and finding the answer opens up a whole new understanding of the link between this serious lung injury and the kind of inflammation that can lead to cardiovascular complications. The research also suggests that suppressing the inflammation through treatments might help minimize these complications.”

Michelle Olive, Ph.D., Associate Director, Basic and Early Translational Research Program at the National Heart, Lung, and Blood Institute (NHLBI)

To reach their findings, the researchers focused on immune cells known as cardiac macrophages, which normally perform a critical role in keeping the tissue healthy but can turn inflammatory in response to injury such as heart attack or heart failure. The researchers analyzed heart tissue specimens from 21 patients who died from SARS-CoV-2-associated ARDS and compared them with specimens from 33 patients who died from non-COVID-19 causes. They also infected mice with SARS-CoV-2 to follow what happened to the macrophages after infection.

In both humans and mice, they found the SARS-CoV-2 infection increased the total number of cardiac macrophages and also caused them to shift from their normal routine and become inflammatory.

When macrophages are no longer doing their normal jobs, which includes sustaining the metabolism of the heart and clearing out harmful bacteria or other foreign agents, they weaken the heart and the rest of the body, said Matthias Nahrendorf, M.D., Ph.D., professor of Radiology at Harvard Medical School and senior author on the study.

The researchers then designed a study in mice to test whether the response they observed happened because SARS-CoV-2 was infecting the heart directly, or because the SARS-CoV-2 infection in the lungs was severe enough to render the heart macrophages more inflammatory. This study mimicked the lung inflammation signals, but without the presence of the actual virus. The result: even in the absence of a virus, the mice showed immune responses strong enough to produce the same heart macrophage shift the researchers observed both in the patients who died of COVID-19 and the mice infected with SARS-CoV-2 infection.

“What this study shows is that after a COVID infection, the immune system can inflict remote damage on other organs by triggering serious inflammation throughout the body – and this is in addition to damage the virus itself has directly inflicted on the lung tissue,” said Nahrendorf. “These findings can also be applied more generally, as our results suggest that any severe infection can send shockwaves through the whole body.”

The research team also found that blocking the immune response with a neutralizing antibody in the mice stopped the flow of inflammatory cardiac macrophages and preserved cardiac function. While they have yet to test this in humans, Nahrendorf said a treatment like this could be used as a preventive measure to help COVID-19 patients with pre-existing conditions, or people who are likely to have more severe outcomes from SARS-CoV-2 associated ARDS.

Source:

NIH/National Heart, Lung and Blood Institute

Journal reference:

Grune, J., et al. (2024) Virus-induced ARDS causes cardiomyopathy through eliciting inflammatory responses in the heart. Circulation. doi.org/10.1161/CIRCULATIONAHA.123.066433.

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March 20, 2024
The efficacy of the Mediterranean diet on health outcomes in adults with cancer

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Cancer treatment is often associated with undue weight gain, mostly due to fat deposition. The Mediterranean diet (MED diet) may help support such patients during this period. A new study published in the European Journal of Clinical Nutrition explores the safety and benefits of this diet in adults with cancer, in addition to its feasibility in this population.

Study: Mediterranean-style dietary interventions in adults with cancer: a systematic review of the methodological approaches, feasibility, and preliminary efficacy. Image Credit: Marian Weyo/Shutterstock.com

Background

Almost 20 million people today have received a cancer diagnosis, making it the leading cause of illness and death globally. The treatment of cancer is also associated with multiple adverse effects that cause rapid aging, trigger chronic metabolic aberrations, and reduce the quality of life.

These side effects include early menopause, cognitive impairment, and cardiomyopathy, with persistent fatigue and weight loss. Such long-term ill effects could be mitigated by nutrition and exercise. Yet, there is little evidence to support the right nutritional pattern for such issues arising during or after cancer treatment.

About the Mediterranean diet

The MED diet has been long recognized as among the healthiest eating patterns. Compliance with this diet has been associated with reduced risk of many chronic illnesses, including type 2 diabetes and cardiovascular harm.

This dietary pattern is characterized by a high consumption of fish, vegetables, legumes, nuts, fruits, and extra virgin olive oil, a moderate intake of dairy and red wine, with little added sugar, processed foods, and red meat. The antioxidant and anti-inflammatory profile of this diet have been thought to mediate its beneficial effects on cardiac and metabolic health.

Previous evidence indicates that those on a MED diet have 22% and 13% lower odds of dying from prostate and breast cancer, respectively. This is very significant since the hormone treatment typically used in these cancers adversely affects the metabolic and body composition profile, increasing the risk of cardiometabolic disease.

This group of patients has been shown to benefit from nutritional manipulation with exercise by reducing body fat and body weight. Yet, there is little systematic evidence to support the recommendation of a MED diet for adults with cancer. This prompted the current study.

About the study

A systematic review was undertaken, including 15 articles covering the MED diet intervention among this group of patients. Of these, ten included breast cancer patients, all women, and one mostly female breast cancer patients. The remaining included prostate cancer, acute myeloid leukemia, and lung cancer.

In five of the studies, patients were being actively treated, while five were post-treatment studies. Three included patients who either had been or were being treated, with one starting within five years from the diagnosis.

In most studies, the aim was to lose weight, but a few were aimed at lessening fatigue, reducing inflammatory mediator levels, enhancing the diet, or maintaining a stable weight. Energy restrictions at varying levels were applied for those who were obese or overweight. Others used strategies such as reduced portion size or consuming more satiating foods.

What changes were observed?

Most participants adhered closely to the MED diet compared to controls, at 64% to 96% completion rates. In six studies, the body weight of the MED diet participants decreased compared to that of the control group. In seven studies, the body mass index (BMI) decreased in the intervention group vs controls.

A similar favorable change was reported in the body fat mass, though three also reported loss of lean mass.

Multiple metabolic biomarkers and inflammatory markers were favorably affected, including decreased glucose markers, reduced cardiovascular markers including triglycerides and total cholesterol, increased high-density lipoprotein (HDL, ‘good cholesterol’), higher albumin levels, and reduced interleukin-8 (IL-8).

The intervention was also associated with a higher quality of life and reduction in fatigue, as well as better emotional, physical, and cognitive health.

What are the conclusions?

The studies included in this review had widely varying study designs and MED diet content, making it difficult to provide a definitive recommendation to achieve these favorable outcomes. However, the safety and feasibility, as well as acceptability, of the MED diet as a nutritional intervention is established.

The positive role of nutritionists in this type of intervention, with accompanying advice on nutritional value, cooking demos, and recipes tailored to individual clients, appears from the significantly higher adherence seen in such studies.

Body weight reduction is particularly well supported by this diet with energy restriction, with overweight or obese subjects on hormone therapy or post-treatment for prostate or breast cancer losing up to 4 kg. Currently, evidence of the benefit of the MED diet is available only for women who have completed breast cancer treatment.

Further studies need to be done to confirm that the MED diet will help prevent and manage chronic disease in this population of cancer survivors who are at high risk for such conditions. Approaches that protect or increase muscle mass but are compatible with this dietary pattern need to be explored.

Confounding factors that may have mediated the improvement in cardiometabolic status and quality of life include frequent interactions with healthcare providers and other dietary components like green tea that have anti-inflammatory and antioxidant activity themselves. Careful documentation of the diet, adherence, and outcomes is necessary to rule out the role of such factors in preventing or managing chronic disease in future studies.

“Future longer term RCTs should focus on reducing the risk of, or managing, cardiovascular or metabolic disease after cancer treatment to improve the potential clinical implications of the MED-diet.”

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March 15, 2024
Major study of 59 million Americans finds fine particulate matter from air pollution increases heart disease risks

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In a recent study published in BMJ, researchers assessed exposure-response relationships between chronic fine-size particulate matter (PM2.5) exposure and the probability of first-time hospitalization for cardiovascular disease (CVD) subgroups.

Study: Exposure-response associations between chronic exposure to fine particulate matter and risks of hospital admission for major cardiovascular diseases: population based cohort study. Image Credit: Kzenon/Shutterstock.com

Background

PM2.5, a minor component of air pollution, contributes considerably to CVD by inducing inflammation, vasoconstriction, cardiac electrical abnormalities, and blood clot formation.

Chronic exposure raises the risk of CVD-related hospitalization and death. Studies frequently focus on one or two CVD subtypes, neglecting to detect susceptible ones.

Comparing effect sizes across subtypes might help us understand processes and advise targeted strategies to lessen the impact of PM2.5.

About the study

In the present population-based cohort study, researchers evaluated exposure-response correlations between chronic PM_2.5 exposure and the probability of initial hospitalization for seven main CVD subtypes and their composite.

The study covered Medicare beneficiaries aged 65 years and above in the continental United States (US) from 2000 to 2016. The team linked calibrated fine particulate matter estimations to each participant’s residence postal code as a proxy for exposure assessment.

The primary outcome measures were the initial hospitalization risks for cerebrovascular diseases, ischemic heart diseases, cardiomyopathy, heart failure, valvular heart diseases, abdominal and thoracic aortic aneurysms, arrhythmia, or a combination of these cardiovascular disease subtypes.

The researchers created a causal-type framework resistant to confounding effects and bias caused by inaccuracies in exposure-response estimations.
The study included Medicare beneficiaries aged 65 years and above residing in the United States (US) and registered with the fee-for-service program from 2000 to 2016.

The researchers created a distinct cohort for each CVD subtype by tracking each beneficiary annually till the initial hospitalization for that CVD subtype, death, or study termination, whichever came first.

They created another study cohort by monitoring each beneficiary year till the initial hospitalization for the examined CVDs, mortality, or study termination, whichever occurred first, to investigate the risk of the initial hospitalization for the composite CVD outcome.

The researchers utilized spatially weighted logistic regressions to estimate ambient PM2.5 values daily at 1.0 km2 grids across the United States from 2000 to 2016.

They blended predictions from machine-learning-based algorithms and incorporated information sources such as weather, satellite imagery, land use factors, monitoring information, and chemical model simulations.

They used regression calibrations to improve grid-level particulate matter estimations and eliminate biases in health-effect estimations caused by exposure errors.

Results

The research included 59,761,494 individuals with 476,953,892 follow-up years; the majority were white (84%), with a higher number of female beneficiaries (55%). Most participants (75%) were between the ages of 65 and 74 when they began the research.

During the trial, 18% of participants registered with Medicaid. 22% required hospitalization due to a combination of cardiovascular diseases. The most frequent CVD subtype was ischemic heart illness, which affected 8.8% of recipients.

Other common illnesses were cerebrovascular disease (7.7%), heart failure (6.6%), and arrhythmia (6.5%). Three-year mean exposure to PM2.5 was related to an increase in the relative risk of initial hospitalization for cerebrovascular illnesses, ischemic heart diseases, cardiomyopathy, heart failure, abdominal and thoracic aortic aneurysms, and arrhythmia.

Exposure-response curves for composite cardiovascular disease showed a monotonically elevated risk related to fine particulate matter exposure.

Compared to exposures ≤5.0 µg m-3 [air quality standard issued by the World Health Organization], the relative risks at exposures ranging from 9.0 to 10 µg m-3, encompassing the United States mean of 9.70 µg m-3 during the analysis, was 1.3.

Composite CVD-related hospitalization risk rose from 2.6% with exposures of less than or equal to 5.0 µg m-3 to 3.4% with exposures ranging from 9.0 to 10 µg m-3.

The effects lasted for ≥3.0 years following PM2.5 exposure. Education, age, healthcare access, and neighborhood socioeconomic deprivation influenced PM2.5 sensitivity.

The highest risk for composite cardiovascular disease and the most common cardiovascular disease CVD subtypes (cerebrovascular disease, ischemic heart disease, and cardiac failure) was related to immediate PM2.5 exposure at lag 0, and a significantly reduced impact at lag 1.0 followed by a decrease at lag 2.0.

Female beneficiaries were more likely to develop composite cardiovascular disease, heart failure, and ischemic heart disease, although cardiomyopathy risk was lower.

Younger beneficiaries and individuals aged between 65 and 74 years are more likely to be admitted to the hospital for CVD and subtypes. Those living in areas with lower high school graduation rates, higher deprivation levels, or longer hospital distances likely experienced the most outcomes.

Conclusion

The study findings showed that chronic exposure to fine-sized particulate matter increases the risk of cerebrovascular illnesses, ischemic heart diseases, cardiomyopathy, heart failure, arrhythmia, and abdominal and thoracic aortic aneurysms.

Exposure-response curves for several CVD subtypes shifted, indicating a lack of a safe threshold for cardiovascular health.

Adhering to the WHO’s air quality standards of ≤5 µg/m3 can provide considerable advantages. Susceptibility varied by participant age, healthcare access, educational achievement, and neighborhood deprivation.

Cardiac arrhythmia and heart failure are among the most vulnerable CVD subtypes in patients exposed to PM2.5.

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February 22, 2024