Terminal heart failure (HF) is the most prevalent cause of death in the Western world and the implantation of a left ventricular assist device (LVAD) has become the gold standard therapy today. Most of the actually implanted devices are driven at a constant speed (CS) regardless of the patient’s physiological demand. A new physiological controller [power ratio (PR) controller], which keeps a constant ratio between LVAD power and left ventricular power, a previous concept [preload responsive speed (PRS) controller], which adds a variable LVAD power to reach a defined stroke work, and a CS controller were compared with an unimpaired ventricle in a full heart computer simulation model. The effects of changes in preload, afterload and left ventricular contractility are displayed by global hemodynamics and ventricular pressure-volume loops. Both physiological controllers demonstrated the desired load dependency, whereas the PR controller exceeded the PRS controller in response to an increased load and contractility. Response was inferior when preload or contractility was decreased. Thus, the PR controller might lead to an increased exercise tolerance of the patient. Additional studies are required to evaluate the controllers

The linearity and load insensitivity of the end-systolic pressure–volume-relationship (ESPVR), a parameter that describes the ventricular contractile state, are controversial. We hypothesize that linearity is influenced by a variable overlay of the intrinsic mechanism of autoregulation to afterload (shortening deactivation) and preload (Frank-Starling mechanism). To study the effect of different short-term loading alterations on the shape of the ESPVR, experiments on twenty-four healthy pigs were executed. Preload reductions, afterload increases and preload reductions while the afterload level was increased were performed. The ESPVR was described either by a linear or a bilinear regression through the end-systolic pressure volume (ES-PV) points. Increases in afterload caused a biphasic course of the ES-PV points, which led to a better fit of the bilinear ESPVRs (r²0.929 linear ESPVR vs. r²0.96 and 0.943 bilinear ESPVR). ES-PV points of a preload reduction on a normal and augmented afterload level could be well described by a linear regression (r²0.974 linear ESPVR vs. r²0.976 and 0.975 bilinear ESPVR). The intercept of the second ESPVR (V0) but not the slope demonstrated a significant linear correlation with the reached afterload level (effective arterial elastance Ea). Thus, the early response to load could be described by the fixed slope of the ESPVR and variable V0, which was determined by the actual afterload. The ESPVR is only apparently nonlinear, as its course over several heartbeats was affected by an overlay of SDA and FSM. These findings could be easily transferred to cardiovascular simulation models to improve their accuracy.

Cirrhotic patients often suffer from cirrhotic cardiomyopathy (CCM). Previous animal models of CCM were inconsistent concerning the time and mechanism of injury; thus, the temporal dynamics and cardiac vulnerability were studied in more detail. Rats underwent bile duct ligation (BDL) and a second surgery 28 days later. Cardiac function was assessed by conductance catheter and echocardiography. Histology, gene expression, and serum parameters were analyzed. A chronotropic incompetence (P_d31 < 0.001) and impaired contractility at rest and a reduced contractile reserve (P_d31 = 0.03, P_dob-d31 < 0.001) were seen 31 days after BDL with increased creatine (P_d35, P_d42, and P_d56 < 0.05) and transaminases (P_d31 < 0.001). A total of 56 days after BDL, myocardial fibrosis was seen (P_d56 < 0.001) accompanied by macrophage infiltration (CD68: P_group < 0.001) and systemic inflammation (TNFα: P_group < 0.001, white blood cell count: P_group < 0.001). Myocardial expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) was increased after 31 (P_d31 < 0.001) and decreased after 42 (P_d42 < 0.001) and 56 days (P_d56 < 0.001). Caspase-3 expression was increased 31 and 56 days after BDL (P_d31 = 0.005; P_d56 = 0.005). Structural changes in the myocardium were seen after 8 weeks. After the second surgery (second hit), transient myocardial insufficiency with secondary organ dysfunction was seen, characterized by reduced contractility and contractile reserve.

To elucidate the adaptation of the right ventricle to acute and intermittently sustained afterload elevation, targeted preload reductions and afterload increases were implemented in a porcine model involving 12 pigs. Preload reduction was achieved via balloon occlusion of the inferior vena cava before, immediately and 5 min after acute afterload elevation induced by pulmonary artery occlusion or thromboxane A2 analog (U46619) infusion. Ventricular response was monitored by registration of pressure–volume (PV) loops using a conductance catheter. The end-systolic pressure–volume relationship (ESPVR) during pure preload reduction was adequately described by linear regression (mean and SEM slope of ESPVR (Ees) 0.414 ± 0.064 mmHg/ml), reflecting the classical Frank-Starling mechanism (FSM). The ESPVR during acute afterload elevation exhibited a biphasic trajectory with significantly distinct slopes (mean and SEM Ees bilin1: 1.256 ± 0.066 mmHg ml; Ees bilin2: 0.733 ± 0.063 mmHg ml, p < 0.001). The higher slope during the first phase in the absence of ventricular dilation could be explained by a reduced amount of shortening deactivation (SDA). The changes in PV-loops during the second phase were similar to those observed with a preload intervention. The persistent increase in afterload resulted in an increase in the slopes of ESPVR and preload recruitable stroke work (PRSW) with a slight decrease in filling state, indicating a relevant Anrep effect. This effect became more pronounced after 5 min or TXA infusion. This study demonstrates, for the first time, the relevance of intrinsic mechanisms of cardiac autoregulation in the right ventricle during the adaptation to load. The SDA, FSM, and Anrep effect could be differentiated and occurred successively, potentially with some overlap. Notably, the Anrep effect serves to prevent ventricular dilation.

The implantation of a left ventricular assist device (LVAD) is often the only therapy in terminal heart failure (HF). However, despite technical advancements, the physical fitness of the patients is still limited. One strategy to improve the benefits of ventricular assist device therapy might be the implementation of load adaptive control strategies. Two control strategies and a constant speed controller (CS) were implemented in an acute animal model where four healthy pigs received LVAD implantations. In the first strategy (preload recruitable stroke work [SW] controller, PRS), the desired pump work was computed in relation to the end-diastolic volume. In the second strategy, the controller was programmed to keep a fixed ratio of the mean hydraulic power of the assist device to the mean hydraulic power of the left ventricle (power relation controller, PR). Preload reduction, afterload increase experiments and short-term coronary artery occlusions were conducted to test the behavior of the control strategies under variable conditions. Within the experiments, the PR controller demonstrated the best preload sensitivity. The PRS controller had the best response to an increased afterload and to a reduced ventricular contractility in terms of effectively preventing ventricular overloading and increasing VAD support. No significant differences in systemic flow were observed.

Severity assessment in animals is an ongoing field of research. In particular, the question of objectifiable and meaningful parameters of score-sheets, as well as their best combination, arise. This retrospective analysis investigates the suitability of a score-sheet for assessing severity and seeks to optimise it for predicting survival in 89 male Sprague Dawley rats (Rattus norvegicus), during an experiment evaluating the influence of liver cirrhosis by bile duct ligation (BDL) on vascular healing. The following five parameters were compared for their predictive power: (i) overall score; (ii) relative weight loss; (iii) general condition score; (iv) spontaneous behaviour score; and (v) the observer’s assessment whether pain might be present. Suitable cut-off values of these individual parameters and the combination of multiple parameters were investigated. A total of ten rats (11.2%; 10/89) died or had to be sacrificed at an early stage due to pre-defined humane endpoints. Neither the overall score nor any individual parameter yielded satisfactory results for predicting survival. Using retrospectively calculated cut-off values and combining the overall score with the observer’s assessment of whether the animal required analgesia (dipyrone) for pain relief resulted in an improved prediction of survival on the second post-operative day. This study demonstrates that combining score parameters was more suitable than using single ones and that experienced human judgement of animals can be useful in addition to objective parameters in the assessment of severity. By optimising the score-sheet and better understanding the burden of the model on rats, this study contributes to animal welfare.