Large-scale modeling allows for a broad mechanistic view of a cardiopulmonary disease, often beyond what can be observed clinically. Our group has developed a large-scale model of the human cardiovascular-respiratory system (H-CRS) that integrates heart mechanics, hemodynamics, circulatory and gas transport aspects of the lung, brain and whole body tissue, and nervous system control of the cardiovascular and respiratory systems into a single model that can be used to analyze the dynamic behavior of the normal and deranged cardiopulmonary system. The model is a composite model based on data from multiple sources, developed over the years, and has been able to mimic responses to cardiovascular, respiratory, and nervous system activity, and accurately predict changes to environmental or diseased conditions. The ability of a large-scale model to portray many aspects of the cardiopulmonary system simultaneously is beyond the scope of clinical procedures, as providing such data becomes overly invasive, expensive, and risky. However, clinical questions can be pursued in virtual mode using modeling as a tool, and the hope is that modeling might also point to novel avenues to explore in disease diagnosis. In this work, we have advanced new conceptual framework of pericardial constraint, respiratory modulation, and septal pumping in the H-CRS model to address three important clinical topics. The first is cardiac tamponade (CT) which results from fluid accumulation in the pericardial sac; the second is left ventricular diastolic dysfunction (LVDD) which leads to congestive heart failure; the third is a hemodynamic analysis of the use of left ventricular rotary assist devices in systolic heart failure due to left ventricular systolic dysfunction (LVSD). These topics are highly relevant in the clinical setting, employ advanced methods for clinical diagnosis (with sufficient clinical data available for model validation), yet contain unanswered physiological questions for our modeling to explore. For example, the proposed modeling studies show that detailed mechanistic characterization of the diseases CT, LVDD, and LVSD exhibit model-generated results of known disease signs, but also reveal the significance of unexplored right heart symptoms and the important role of septal mechanics in these disease states. Left ventricular assist device (LVAD) modeling demonstrates improvement in cardiac output and reduced left heart work, but at the expense of septal functionality and right heart work. Our work in demonstrating the ability of a large-scale model to portray many complex aspects of the cardiopulmonary system simultaneously suggests that modeling might provide novel avenues to explore disease diagnosis, physiology, and management.