[8] Kass' first research work was during undergraduate studies in applied mathematics in the laboratory of Martin Moore-Ede, a circadian rhythm biologist at Harvard's Physiology Department.

[5] Kass showed that the volume sensing mechanism, which was coupled to atrial stretch (later shown to relate to natriuretic peptide), was blunted during the nighttime by central circadian regulation.

Kass applied pressure-volume analysis to the intact mouse heart in situ[11] and shortly thereafter in human patients,[12][13] advancing the understanding of cardiac disease pathophysiology.

[14] His work established the factors regulating pressure-volume relations in the intact heart and in particular its maximal elastance, an index of contractility, and the role of external constraints on measures of diastolic function.

[23] While the Kass Laboratory was exploring the mechanisms for CRT, he discovered that a relative of nitric oxide (NO), termed nitroxyl (HNO), conferred positive contractile changes differently from NO and could improve the function of the failing heart.

[24][25][26] This led to founding the pharmaceutical company Cardioxyl Inc., which developed room stable HNO donor molecules that were ultimately advanced to Phase II clinical trials.

[36] PDE9A was later reported by his laboratory to stimulate fatty acid oxidation and lipolysis in fat and cardiac muscle, and improve disease related to diet-induced obesity and cardiometabolic syndrome.

[38] In the late 2010s and early 2020s, Kass' research has shifted towards investigating heart failure with preserved ejection fraction (HFpEF), with a focus on the role of obesity and metabolic defects in this condition.