Inhibition of carnitine palmitoyl-transferase 1 is a potential target in a mouse model of Parkinson's disease.

Glucose metabolism is dysregulated in Parkinson's disease (PD) causing a shift toward the metabolism of lipids. Carnitine palmitoyl-transferase 1A (CPT1A) regulates the key step in the metabolism of long-chain fatty acids. The aim of this study is to evaluate the effect of downregulating CPT1, either genetically with a Cpt1a P479L mutation or medicinally on PD using chronic rotenone mouse models using C57Bl/6J and Park2 knockout mice. We show that Cpt1a P479L mutant mice are resistant to rotenone-induced PD, and that inhibition of CPT1 is capable of restoring neurological function, normal glucose metabolism, and alleviate markers of PD in the midbrain. Furthermore, we show that downregulation of lipid metabolism via CPT1 alleviates pathological motor and non-motor behavior, oxidative stress, and disrupted glucose homeostasis in Park2 knockout mice. Finally, we confirm that rotenone induces gut dysbiosis in C57Bl/6J and, for the first time, in Park2 knockout mice. We show that this dysbiosis is alleviated by the downregulation of the lipid metabolism via CPT1.

Temporal trends in patient characteristics, presumed causes, and outcomes following cardiogenic shock between 2005 and 2017: a Danish registry-based cohort study.

AIMS: Most cardiogenic shock (CS) studies focus on acute coronary syndrome (ACS). Contemporary data on temporal trends in patient characteristics, presumed causes, treatments, and outcomes of ACS- and in particular non-ACS-related CS patients are sparse. METHODS AND RESULTS: Using nationwide medical registries, we identified patients with first-time CS between 2005 and 2017. Cochrane-Armitage trend tests were used to examine temporal changes in presumed causes of CS, treatments, and outcomes. Among 14 363 CS patients, characteristics remained largely stable over time. As presumed causes of CS, ACS (37.1% in 2005 to 21.4% in 2017), heart failure (16.3% in 2005 to 12.0% in 2017), and arrhythmias (13.0% in 2005 to 10.9% in 2017) decreased significantly over time; cardiac arrest increased significantly (11.3% in 2005 to 24.5% in 2017); and changes in valvular heart disease were insignificant (11.5% in 2005 and 11.6% in 2017). Temporary left ventricular assist device, non-invasive ventilation, and extracorporeal membrane oxygenation use increased significantly over time; intra-aortic balloon pump and mechanical ventilation use decreased significantly. Over time, 30-day and 1-year mortality were relatively stable. Significant decreases in 30-day and 1-year mortality for patients presenting with ACS and arrhythmias and a significant increase in 1-year mortality in patients presenting with heart failure were seen. CONCLUSION: Between 2005 and 2017, we observed significant temporal decreases in ACS, heart failure, and arrhythmias as presumed causes of first-time CS, whereas cardiac arrest significantly increased. Although overall 30-day and 1-year mortality were stable, significant decreases in mortality for ACS and arrhythmias as presumed causes of CS were seen.

Association between vectorcardiographic QRS area and incident heart failure diagnosis and mortality among patients with left bundle branch block: A register-based cohort study.

BACKGROUND: QRS duration and morphology including left bundle branch block (LBBB) are the most widely used electrocardiogram (ECG) markers for assessing ventricular dyssynchrony and predicting heart failure (HF). However, the vectorcardiographic QRS area may more accurately identify delayed left ventricular activation and HF development. OBJECTIVE: We investigated the association between QRS area and incident HF risk in patients with LBBB. METHODS: By crosslinking data from Danish nationwide registries, we identified patients with a first-time digital LBBB ECG between 2001 and 2015. The vectorcardiographic QRS area was derived from a 12­lead ECG using the Kors transformation method and grouped into quartiles. The endpoint was a composite of HF diagnosis, filled prescriptions for loop diuretics, or death from HF. Cause-specific multivariable Cox regression was used to compute hazard ratios(HR) with 95% confidence intervals(CI). RESULTS: We included 3316 patients with LBBB free from prior HF-related events (median age, 72 years; male, 40%). QRS area quartiles comprised Q1, 36-98 µVs; Q2, 99-119 µVs; Q3, 120-145 µVs; and Q4, 146-295 µVs. During a 5-year follow-up, 31% of patients reached the composite endpoint, with a rate of 39% in the highest quartile Q4. A QRS area in quartile Q4 was associated with increased hazard of the composite endpoint (HR:1.48, 95%CI:1.22-1.80) compared with Q1. CONCLUSIONS: Among primary care patients with newly discovered LBBB, a large vectorcardiographic QRS area (146-295 µVs) was associated with an increased risk of incident HF diagnosis, filling prescriptions for loop diuretics, or dying from HF within 5-years.

Downregulating carnitine palmitoyl transferase 1 affects disease progression in the SOD1 G93A mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by death of motor neurons. The etiology and pathogenesis remains elusive despite decades of intensive research. Herein, we report that dysregulated metabolism plays a central role in the SOD1 G93A mouse model mimicking ALS. Specifically, we report that the activity of carnitine palmitoyl transferase 1 (CPT1) lipid metabolism is associated with disease progression. Downregulation of CPT1 activity by pharmacological and genetic methods results in amelioration of disease symptoms, inflammation, oxidative stress and mitochondrial function, whereas upregulation by high-fat diet or corticosterone results in a more aggressive disease progression. Finally, we show that downregulating CPT1 shifts the gut microbiota communities towards a protective phenotype in SOD1 G93A mice. These findings reveal that metabolism, and specifically CPT1 lipid metabolism plays a central role in the SOD1 G93A mouse model and shows that CPT1 might be a therapeutic target in ALS.

Dysregulation of metabolic pathways by carnitine palmitoyl-transferase 1 plays a key role in central nervous system disorders: experimental evidence based on animal models.

The etiology of CNS diseases including multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis remains elusive despite decades of research resulting in treatments with only symptomatic effects. In this study, we provide evidence that a metabolic shift from glucose to lipid is a key mechanism in neurodegeneration. We show that, by downregulating the metabolism of lipids through the key molecule carnitine palmitoyl transferase 1 (CPT1), it is possible to reverse or slowdown disease progression in experimental models of autoimmune encephalomyelitis-, SOD1G93A and rotenone models, mimicking these CNS diseases in humans. The effect was seen both when applying a CPT1 blocker or by using a Cpt1a P479L mutant mouse strain. Furthermore, we show that diet, epigenetics, and microbiota are key elements in this metabolic shift. Finally, we present a systemic model for understanding the complex etiology of neurodegeneration and how different regulatory systems are interconnected through a central metabolic pathway that becomes deregulated under specific conditions.