Abdominal congestion may play an important role in the cardiorenal syndrome and has been demonstrated to drive disease progression. An animal model for abdominal congestion, without other culprit mechanisms that are often present in patients such as low cardiac output or chronic kidney disease, might be interesting to allow a better study of the pathophysiology of the cardiorenal syndrome. The objective of this study was to develop a clinically relevant and valid rat model with abdominal venous congestion and without pre-existing heart and/or kidney dysfunction. To do so, a permanent surgical constriction (20 Gauge) of the thoracic inferior vena cava (IVC) was applied in male Sprague Dawley rats (IVCc, n = 7), which were compared to sham-operated rats (SHAM, n = 6). Twelve weeks after surgery, abdominal venous pressure (mean: 13.8 vs 4.9 mmHg, p < 0.01), plasma creatinine (p < 0.05), plasma cystatin c (p < 0.01), urinary albumin (p < 0.05), glomerular surface area (p < 0.01) and width of Bowman’s space (p < 0.05) of the IVCc group were significantly increased compared to the SHAM group for a comparable absolute body weight between groups (559 vs 530g, respectively, p = 0.73). Conventional cardiac echocardiographic and hemodynamic parameters did not differ significantly between both groups, indicating that cardiac function was not compromised by the surgery. In conclusion, we demonstrate that constriction of the thoracic IVC in adult rats is feasible and significantly increases the abdominal venous pressure to a clinically relevant level, thereby inducing abdominal venous congestion.

Congestion (i.e., backward failure) is an important culprit mechanism driving disease progression in heart failure. Nevertheless, congestion remains often underappreciated and clinicians underestimate the importance of congestion on the pathophysiology of decompensation in heart failure. In patients, it is however difficult to study how isolated congestion contributes to organ dysfunction, since heart failure and chronic kidney disease very often coexist in the so-called cardiorenal syndrome. Here, we review the existing relevant and suitable backward heart failure animal models to induce congestion, induced in the left-(i.e., myocardial infarction, rapid ventricular pacing) or right-sided heart (i.e., aorta-caval shunt, mitral valve regurgitation, and monocrotaline), and more specific animal models of congestion, induced by saline infusion or inferior vena cava constriction. Next, we examine critically how representative they are for the clinical situation. After all, a relevant animal model of isolated congestion offers the unique possibility of studying the effects of congestion in heart failure and the cardiorenal syndrome, separately from forward failure (i.e., impaired cardiac output). In this respect, new treatment options can be discovered.

Venous congestion is an important contributor to worsening renal function in heart failure and the cardiorenal syndrome. In patients, it is difficult to study the effects of isolated venous congestion on organ function. In this study, the consequences of isolated abdominal venous congestion on morphology and function of the kidneys, liver and heart were studied in a rat model. Twelve sham-operated (SHAM) male Sprague Dawley rats were compared to eleven inferior vena cava-constricted (IVCc) rats for twenty-one weeks. Abdominal venous pressure was significantly higher in the IVCc versus SHAM group (p < 0.0001). Indices of liver and kidney weight, function and morphology, inflammation as well as collagen deposition were significantly increased in the IVCc compared to SHAM group, (p < 0.05). Echocardiographic and hemodynamic parameters were largely unaffected by abdominal venous congestion. In this rat model of isolated abdominal venous congestion, retrogradely conducted glomerular hypertension without a concomitant change in glomerular filtration rate was observed. Adverse short-term hepatic morphological alterations were developed which explain the observed organ function dysfunction. Importantly, cardiac function remained comparable between both groups. This study provides relevant insight in the pathophysiology of abdominal congestion on organ function.

Worldwide, cytoreductive surgery (CRS) and hyperthermic intraperitoneal perioperative chemotherapy (HIPEC) are used in current clinical practice for colorectal peritoneal surface malignancy (PSM) treatment. Although, there is an acknowledged standardization regarding the CRS, we are still lacking a much-needed standardization amongst the various intraperitoneal (IP) chemotherapy protocols, including the HIPEC dosing regimen. We should rely on pharmacologic evidence building towards such a standardization. The current IP chemotherapy dosing regimens can be divided into body surface area (BSA)-based and concentration-based protocols. A preclinical animal study was designed to evaluate pharmacologic advantage (PA), efficacy and survival. WAG/Rij rats were IP injected with the rat colonic carcinoma cell line CC-531. Animals were randomized into three groups: CRS alone or CRS combined with oxaliplatin-based HIPEC (either BSA- or concentration-based). There was no difference in PA between the two groups (p=0.283). Platinum concentration in the tumor nodule was significantly higher in the concentration-based group ( p <0.001). Median survival did not differ between the treatment groups ( p <0.250). This preclinical study, in contrast to previous thinking, clearly demonstrates that the PA does not provide any information about the true efficacy of the drug and emphasizes the importance of the tumor nodule as pharmacologic endpoint.

Background: Oxidative/carbonyl stress is elevated in lower-limb muscles of patients with Chronic Obstructive Pulmonary Disease (COPD). Carnosine is a skeletal muscle antioxidant particularly present in fast-twitch fibers. Aims: To compare muscle carnosine, oxidative/carbonyl stress, antioxidants and fiber characteristics between patients with COPD and healthy controls (HCs), and between patients after stratification for airflow limitation (mild/moderate vs. severe/very-severe). To investigate correlates of carnosine in patients with COPD. Methods: A vastus lateralis muscle biopsy was obtained from 40 patients with stable COPD and 20 age/sex matched HCs. Carnosine, oxidative/carbonyl stress, antioxidants, fiber characteristics, quadriceps strength and endurance (QE), VO2peak (incremental cycle test) and physical activity (PA) were determined. Results: Patients with COPD had a similar carnosine concentration (4.16 mmol/kg wet weight (WW) (SD 1.93)) to HCs (4.64 mmol/kgWW (SD 1.71)) and significantly higher percentage of fast-twitch fibers and lower QE, VO2peak and PA vs. HCs. Patients with severe/very-severe COPD had a 30% lower carnosine concentration (3.24 mmol/kgWW (SD 1.79); n=15) vs. patients with mild/moderate COPD (4.71 mmol/kgWW (SD 1.83); n=25; P=0.02) and significantly lower VO2peak and PA vs. patients with mild/moderate COPD. Carnosine correlated significantly with QE (rs=0.427), VO2peak (rs=0.334), PA (rs=0.379) and lung function parameters in patients with COPD. Conclusion: Despite having the highest proportion of fast-twitch fibers, patients with severe/very-severe COPD displayed a 30% lower muscle carnosine concentration compared to patients with mild/moderate COPD. As no oxidative/carbonyl stress markers, nor antioxidants were affected, the observed carnosine deficiency is thought to be a possible first sign of muscle redox balance abnormalities.