Techniques are provided for use with an implantable medical device for detecting and assessing heart failure and for controlling cardiac resynchronization therapy (CRT) based on impedance signals obtained using hybrid impedance configurations. The hybrid configurations exploit right atrial (RA)-based impedance measurement vectors and/or left ventricular (LV)-based impedance measurement vectors. In one example, current is injected between the device case and a ring electrode in the right ventricle (RV) or RA. RA-based impedance values are measured along vectors between the device case and an RA electrode. LV-based impedance values are measured along vectors between the device case and one or more electrodes of the LV. Heart failure and other cardiac conditions are detected and tracked using the measured impedance values. CRT delay parameters are also optimized based impedance. In this manner, multiple hybrid impedance measurement configurations are exploited whereby different vectors are used to inject current and measure impedance.