Lipid Use and Misuse by the Heart Schulze, P Christian; Drosatos, Konstantinos; Goldberg, Ira J
Circulation research,
2016-May-27, Letnik:
118, Številka:
11
Journal Article
Recenzirano
Odprti dostop
The heart utilizes large amounts of fatty acids as energy providing substrates. The physiological balance of lipid uptake and oxidation prevents accumulation of excess lipids. Several processes that ...affect cardiac function, including ischemia, obesity, diabetes mellitus, sepsis, and most forms of heart failure lead to altered fatty acid oxidation and often also to the accumulation of lipids. There is now mounting evidence associating certain species of these lipids with cardiac lipotoxicity and subsequent myocardial dysfunction. Experimental and clinical data are discussed and paths to reduction of toxic lipids as a means to improve cardiac function are suggested.
The heart has both the greatest caloric needs and the most robust oxidation of fatty acids (FAs). Under pathological conditions such as obesity and type 2 diabetes, cardiac uptake and oxidation are ...not balanced and hearts accumulate lipid potentially leading to cardiac lipotoxicity. We will first review the pathways utilized by the heart to acquire FAs from the circulation and to store triglyceride intracellularly. Then we will describe mouse models in which excess lipid accumulation causes heart dysfunction and experiments performed to alleviate this toxicity. Finally, the known relationships between heart lipid metabolism and dysfunction in humans will be summarized.
Accumulating data support a role for bioactive lipids as mediators of lipotixicity in cardiomyocytes. One class of these, the ceramides, constitutes a family of molecules that differ in structure and ...are synthesized by distinct enzymes, ceramide synthase (CerS)1‐CerS6. Data support that specific ceramides and the enzymes that catalyze their formation play distinct roles in cell function. In a mouse model of diabetic cardiomyopathy, sphingolipid profiling revealed increases in not only the CerS5‐derived ceramides but also in very long chain (VLC) ceramides derived from CerS2. Overexpression of CerS2 elevated VLC ceramides caused insulin resistance, oxidative stress, mitochondrial dysfunction, and mitophagy. Palmitate induced CerS2 and oxidative stress, mitophagy, and apoptosis, which were prevented by depletion of CerS2. Neither overexpression nor knockdown of CerS5 had any function in these processes, suggesting a chain‐length de‐ pendent impact of ceramides on mitochondrial function. This concept was also supported by the observation that synthetic mitochondria‐targeted ceramides led to mitophagy in a manner proportional to N‐acyl chain length. Finally, blocking mitophagy exacerbated cell death. Taken together, our results support a model by which CerS2 and VLC ceramides have a distinct role in lipotoxicity, leading to mitochondrial damage, which results in subsequent adaptive mitophagy. Our data reveal a novel lipotoxic pathway through CerS2.—Law, B. A., Liao, X., Moore, K. S., Southard, A., Roddy, P., Ji, R., Szulc, Z., Bielawska, A., Schulze, P. C., Cowart, L. A. Lipotoxic very‐long‐chain ceramides cause mito‐ chondrial dysfunction, oxidative stress, and cell death in cardiomyocytes. FASEB J. 32,1403‐1416 (2018). www.fasebj.org
The sodium-glucose cotransporter 2 inhibitor empagliflozin reduces the risk of cardiovascular death or heart failure hospitalization in patients with chronic heart failure, but whether empagliflozin ...also improves clinical outcomes when initiated in patients who are hospitalized for acute heart failure is unknown. In this double-blind trial (EMPULSE; NCT04157751 ), 530 patients with a primary diagnosis of acute de novo or decompensated chronic heart failure regardless of left ventricular ejection fraction were randomly assigned to receive empagliflozin 10 mg once daily or placebo. Patients were randomized in-hospital when clinically stable (median time from hospital admission to randomization, 3 days) and were treated for up to 90 days. The primary outcome of the trial was clinical benefit, defined as a hierarchical composite of death from any cause, number of heart failure events and time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, as assessed using a win ratio. More patients treated with empagliflozin had clinical benefit compared with placebo (stratified win ratio, 1.36; 95% confidence interval, 1.09-1.68; P = 0.0054), meeting the primary endpoint. Clinical benefit was observed for both acute de novo and decompensated chronic heart failure and was observed regardless of ejection fraction or the presence or absence of diabetes. Empagliflozin was well tolerated; serious adverse events were reported in 32.3% and 43.6% of the empagliflozin- and placebo-treated patients, respectively. These findings indicate that initiation of empagliflozin in patients hospitalized for acute heart failure is well tolerated and results in significant clinical benefit in the 90 days after starting treatment.
Phytosterols and Cardiovascular Disease Makhmudova, Umidakhon; Schulze, P. Christian; Lütjohann, Dieter ...
Current atherosclerosis reports,
11/2021, Letnik:
23, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Purpose of Review
Coronary heart disease is the leading cause of mortality worldwide. Elevated blood cholesterol levels are not only the major but also the best modifiable cardiovascular risk factor. ...Lifestyle modifications which include a healthy diet are the cornerstone of lipid-lowering therapy. So-called functional foods supplemented with plant sterols lower blood cholesterol levels by about 10–15%.
Recent Findings
In the recent revision of the ESC/EAS dyslipidemia guideline 2019, plant sterols are recommended for the first time as an adjunct to lifestyle modification to lower blood cholesterol levels. However, the German Cardiac Society (DGK) is more critical of food supplementation with plant sterols and calls for randomized controlled trials investigating hard cardiovascular outcomes. An increasing body of evidence suggests that plant sterols per se are atherogenic.
Summary
This review discusses this controversy based on findings from in vitro and in vivo studies, clinical trials, and genetic evidence.
Aims
To assess the impact of the lockdown due to coronavirus disease 2019 (COVID-19) on key quality indicators for the treatment of ST-segment elevation myocardial infarction (STEMI) patients.
...Methods
Data were obtained from 41 hospitals participating in the prospective Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction (FITT-STEMI) study, including 15,800 patients treated for acute STEMI from January 2017 to the end of March 2020.
Results
There was a 12.6% decrease in the total number of STEMI patients treated at the peak of the pandemic in March 2020 as compared to the mean number treated in the March months of the preceding years. This was accompanied by a significant difference among the modes of admission to hospitals (
p
= 0.017) with a particular decline in intra-hospital infarctions and transfer patients from other hospitals, while the proportion of patients transported by emergency medical service (EMS) remained stable. In EMS-transported patients, predefined quality indicators, such as percentages of pre-hospital ECGs (both 97%, 95% CI = − 2.2–2.7,
p
= 0.846), direct transports from the scene to the catheterization laboratory bypassing the emergency department (68% vs. 66%, 95% CI = − 4.9–7.9,
p
= 0.641), and contact-to-balloon-times of less than or equal to 90 min (58.3% vs. 57.8%, 95%CI = − 6.2–7.2,
p
= 0.879) were not significantly altered during the COVID-19 crisis, as was in-hospital mortality (9.2% vs. 8.5%, 95% CI = − 3.2–4.5,
p
= 0.739).
Conclusions
Clinically important indicators for STEMI management were unaffected at the peak of COVID-19, suggesting that the pre-existing logistic structure in the regional STEMI networks preserved high-quality standards even when challenged by a threatening pandemic.
Clinical trial registration
NCT00794001
Remote patient management in patients with heart failure might help to detect early signs and symptoms of cardiac decompensation, thus enabling a prompt initiation of the appropriate treatment and ...care before a full manifestation of a heart failure decompensation. We aimed to investigate the efficacy of our remote patient management intervention on mortality and morbidity in a well defined heart failure population.
The Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial was a prospective, randomised, controlled, parallel-group, unmasked (with randomisation concealment), multicentre trial with pragmatic elements introduced for data collection. The trial was done in Germany, and patients were recruited from hospitals and cardiology practices. Eligible patients had heart failure, were in New York Heart Association class II or III, had been admitted to hospital for heart failure within 12 months before randomisation, and had a left ventricular ejection fraction (LVEF) of 45% or lower (or if higher than 45%, oral diuretics were being prescribed). Patients with major depression were excluded. Patients were randomly assigned (1:1) using a secure web-based system to either remote patient management plus usual care or to usual care only and were followed up for a maximum of 393 days. The primary outcome was percentage of days lost due to unplanned cardiovascular hospital admissions or all-cause death, analysed in the full analysis set. Key secondary outcomes were all-cause and cardiovascular mortality. This study is registered with ClinicalTrials.gov, number NCT01878630, and has now been completed.
Between Aug 13, 2013, and May 12, 2017, 1571 patients were randomly assigned to remote patient management (n=796) or usual care (n=775). Of these 1571 patients, 765 in the remote patient management group and 773 in the usual care group started their assigned care, and were included in the full analysis set. The percentage of days lost due to unplanned cardiovascular hospital admissions and all-cause death was 4·88% (95% CI 4·55–5·23) in the remote patient management group and 6·64% (6·19–7·13) in the usual care group (ratio 0·80, 95% CI 0·65–1·00; p=0·0460). Patients assigned to remote patient management lost a mean of 17·8 days (95% CI 16·6–19·1) per year compared with 24·2 days (22·6–26·0) per year for patients assigned to usual care. The all-cause death rate was 7·86 (95% CI 6·14–10·10) per 100 person-years of follow-up in the remote patient management group compared with 11·34 (9·21–13·95) per 100 person-years of follow-up in the usual care group (hazard ratio HR 0·70, 95% CI 0·50–0·96; p=0·0280). Cardiovascular mortality was not significantly different between the two groups (HR 0·671, 95% CI 0·45–1·01; p=0·0560).
The TIM-HF2 trial suggests that a structured remote patient management intervention, when used in a well defined heart failure population, could reduce the percentage of days lost due to unplanned cardiovascular hospital admissions and all-cause mortality.
German Federal Ministry of Education and Research.
Mitochondrial homeostasis is critical for tissue health, and mitochondrial dysfunction contributes to numerous diseases, including heart failure. Here, we have shown that the transcription factor ...Kruppel-like factor 4 (KLF4) governs mitochondrial biogenesis, metabolic function, dynamics, and autophagic clearance. Adult mice with cardiac-specific Klf4 deficiency developed cardiac dysfunction with aging or in response to pressure overload that was characterized by reduced myocardial ATP levels, elevated ROS, and marked alterations in mitochondrial shape, size, ultrastructure, and alignment. Evaluation of mitochondria isolated from KLF4-deficient hearts revealed a reduced respiration rate that is likely due to defects in electron transport chain complex I. Further, cardiac-specific, embryonic Klf4 deletion resulted in postnatal premature mortality, impaired mitochondrial biogenesis, and altered mitochondrial maturation. We determined that KLF4 binds to, cooperates with, and is requisite for optimal function of the estrogen-related receptor/PPARγ coactivator 1 (ERR/PGC-1) transcriptional regulatory module on metabolic and mitochondrial targets. Finally, we found that KLF4 regulates autophagy flux through transcriptional regulation of a broad array of autophagy genes in cardiomyocytes. Collectively, these findings identify KLF4 as a nodal transcriptional regulator of mitochondrial homeostasis.
Effective diuretic regimens using loop diuretics in patients with acute decompensated heart failure are often limited by the development of worsening kidney function. Sodium-glucose cotransporter-2 ...inhibitors induce glucosuria and sodium excretion with nephroprotective effects in patients with stable heart failure but their role in acute decompensated heart failure is unclear.
In this single-center, prospective, double-blind, placebo-controlled, randomized study, we randomly assigned patients with acute decompensated heart failure to empagliflozin 25 mg daily or placebo in addition to standard decongestive treatments that included loop diuretics. The primary end point was cumulative urine output over 5 days. Secondary end points included diuretic efficiency, dynamics in markers of kidney function and injury, and NT-proBNP (N-terminal pro-B-type natriuretic peptide).
Sixty patients were randomized within 12 hours of hospitalization for acute decompensated heart failure. Addition of empagliflozin daily to standard medical treatment of acute decompensated heart failure resulted in a 25% increase in cumulative urine output over 5 days (median 10.8 versus 8.7 L mL in placebo, group difference estimation 2.2 L 95% CI, 8.4 to 3.6;
=0.003). Empagliflozin increased diuretic efficiency compared with placebo (14.1 mL urine per milligram furosemide equivalent 95% CI, 0.6-27.7;
=0.041) without affecting markers of renal function (estimated glomerular filtration rate, 51±19 versus 54±17 mL/min per 1.73 m²;
=0.599) or injury (total urinary protein, 492±845 versus 503±847 mg/g creatinine;
=0.975; and urinary α1-microglobulin, 55.4±38.6 versus 31.3±33.6 mg/g creatinine;
=0.066) with more pronounced decrease in NT-proBNP in the empagliflozin group compared with placebo (-1861 versus -727.2 pg/mL after 5 days; quotient in slope, 0.89 95% CI, 0.83-0.95;
<0.001). There were no differences in the incidence of safety events between groups.
Early addition of empagliflozin to standard diuretic therapy increases urine output without affecting renal function in patients with acute decompensated heart failure.
URL: https://www.
gov; Unique identifier: NCT04049045.
Heart failure (HF) is associated with high morbidity and mortality and its incidence is increasing worldwide. MicroRNAs (miRNAs) are potential markers and targets for diagnostic and therapeutic ...applications, respectively. We determined myocardial and circulating miRNA abundance and its changes in patients with stable and end-stage HF before and at different time points after mechanical unloading by a left ventricular assist device (LVAD) by small RNA sequencing. miRNA changes in failing heart tissues partially resembled that of fetal myocardium. Consistent with prototypical miRNA–target-mRNA interactions, target mRNA levels were negatively correlated with changes in abundance for highly expressed miRNAs in HF and fetal hearts. The circulating small RNA profile was dominated by miRNAs, and fragments of tRNAs and small cytoplasmic RNAs. Heart- and muscle-specific circulating miRNAs (myomirs) increased up to 140-fold in advanced HF, which coincided with a similar increase in cardiac troponin I (cTnI) protein, the established marker for heart injury. These extracellular changes nearly completely reversed 3 mo following initiation of LVAD support. In stable HF, circulating miRNAs showed less than fivefold differences compared with normal, and myomir and cTnI levels were only captured near the detection limit. These findings provide the underpinning for miRNA-based therapies and emphasize the usefulness of circulating miRNAs as biomarkers for heart injury performing similar to established diagnostic protein biomarkers.
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