David Kass, M.D. is the Abraham and Virginia Weiss Professor of Cardiology at Johns Hopkins University. He also serves as a Professor of Medicine, Pharmacology, Molecular Sciences, and Biomedical Engineering. He obtained a Bachelor of Arts degree from Harvard College in 1975, majoring in Applied Physics and Engineering, and a Doctor of Medicine degree from Yale University in 1980. Following his medical studies, he completed an Internal Medicine residency at George Washington University in Washington, DC before joining the Cardiology Division at Johns Hopkins University. Kass' research has ranged from fundamental molecular and cellular studies to human clinical research. His publication record includes over 550 original papers, with more than 55,000 citations.
Kass is the Director of the Institute of CardioScience and co-directs a post-doctoral NIH-training program in Cardiovascular Disease. He has received honors including awards from the American Heart Association. the Inaugural Janice Pfeffer Award from the International Society for Heart Research, and an Outstanding Investigator Award from the National Institutes of Health. In 2020, he received the Louis and Artur Lucien Prize in Cardiovascular Diseases and the Inaugural NAS-International Society of Heart Research Innovator Award. He received two Outstanding Investigator Awards from the National Heart Lung and Blood Institute in 2017 and 2023.
Kass is a member of professional societies such as the American Society for Clinical Investigation, American Heart Association, and Association of American Physicians. He has served on the editorial board for journals like Circulation Research and as an Associate Editor the American Journal of Physiology.https://www.ahajournals.org/res/editorial-board
Early career 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. He merged understanding of bio-oscillatory mathematics with the biology of diurnal biological behavior, focusing on regulation of renal excretion of both sodium and potassium. 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 DA, Sulzman FM, Fuller CA, and Moore-Ede MC. Renal responses to central vascular expansion are suppressed at night in conscious primates. Am J Physiol. 1980;239:F343-f351. doi: 10.1152/ajprenal.1980.239.4.F343Kass DA and Moore-Ede MC. Renal responses to prolonged central volume expansion in conscious primates. Am J Physiol. 1982;242:F649-56. doi: 10.1152/ajprenal.1982.242.6.F649
Kass completed medical residency with the Internal Medicine Department at the George Washington University then a Fellowship in Cardiology at the Johns Hopkins University, working with Kiichi Sagawa in the Bioengineering Department in cardiac systemic engineering and mechanics pressure-volume relationships in the heart. Kass applied pressure-volume analysis to the intact mouse heart in situKass DA, Maughan WL, Guo ZM, Kono A, Sunagawa K and Sagawa K. Comparative influence of load versus inotropic states on indexes of ventricular contractility: experimental and theoretical analysis based on pressure-volume relationships. Circulation. 1987;76:1422-36. doi: 10.1161/01.cir.76.6.1422 and shortly thereafter in human patients,Kass DA, Midei M, Brinker J and Maughan WL. Influence of coronary occlusion during PTCA on end-systolic and end-diastolic pressure-volume relations in humans. Circulation. 1990;81:447-460Kelly RP, Ting CT, Yang TM, Liu CP, Maughan WL, Chang MS and Kass DA. Effective arterial elastance as index of arterial vascular load in humans. Circulation. 1992;86:513-521 advancing the understanding of cardiac disease pathophysiology.Dauterman K, Pak PH, Nussbacher A, Arie S, Liu CP and Kass DA. Contribution of external forces to left ventricle diastolic pressure: Implications for the Clinical Use of the Frank-Starling Law. Annals Int Med. 1995;122:737-742. 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.Kass DA. Assessment of diastolic dysfunction. Invasive modalities. CardiolClin. 2000;18:571-586Kass DA, Bronzwaer JG and Paulus WJ. What mechanisms underlie diastolic dysfunction in heart failure? Circ Res. 2004;94:1533-1542
In the latter 1990’s Kass began research into applying pacing stimuli to both sides of a failing heart. This approach was later called cardiac resynchronization therapy (CRT). His work showed that with CRT net systolic function was enhanced without commensurate increases in oxygen consumption,Kass DA, Chen CH, Curry C, Talbot M, Berger R, Fetics B and Nevo E. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation. 1999;99:1567-1573 that is, the heart became more mechanically efficient.Nelson GS, Berger RD, Fetics BJ, Talbot M, Hare JM, Spinelli JC and Kass DA. Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block. Circulation. 2000;102:3053-3059 He also showed how to predict which patients were most likely to benefit from the treatment.Nelson GS, Curry CW, Wyman BT, Kramer A, Declerck J, Talbot M, Douglas MR, Berger RD, McVeigh ER and Kass DA. Predictors of systolic augmentation from left ventricular preexcitation in patients with dilated cardiomyopathy and intraventricular conduction delay. Circulation. 2000;101:2703-2709
Kass also explored a canine model of heart failure with dyssynchronous contraction and studied cellular and molecular mechanisms relevant to the improvement from resynchronizing contraction. Among the studies from this work was the discovery of how CRT altered adrenergic signaling to improve contractile reserve,. Chakir K, Daya SK, Aiba T, Tunin RS, Dimaano VL, Abraham TP, Jaques-Robinson KM, Lai EW, Pacak K, Zhu WZ, et al. Mechanisms of enhanced beta-adrenergic reserve from cardiac resynchronization therapy. Circulation. 2009;119:1231-40Chakir K, Depry C, Dimaano VL, Zhu WZ, Vanderheyden M, Bartunek J, Abraham TP, Tomaselli GF, Liu SB, Xiang YK, et al. Galphas-biased beta2-adrenergic receptor signaling from restoring synchronous contraction in the failing heart. Sci Transl Med. 2011;3:100ra88 and improved sarcomere force-calcium dependence.Kirk JA, Holewinski RJ, Kooij V, Agnetti G, Tunin RS, Witayavanitkul N, de Tombe PP, Gao WD, Van Eyk J and Kass DA. Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3beta. J Clin Invest. 2014;124:129-38
Kass later developed a novel pacing therapy for heart failure where a normally contracting heart (not affected by a conduction delay to induce dyssynchrony) could be treated by temporarily making it contract dyssynchronously by means of right ventricular pacing, but then restored to normal contraction within 6 hours. The approach improved failing canine heart function, adrenergic signaling, and contractile function at the sarcomere level.Kirk JA, Chakir K, Lee KH, Karst E, Holewinski RJ, Pironti G, Tunin RS, Pozios I, Abraham TP, de Tombe P, et al. Pacemaker-induced transient asynchrony suppresses heart failure progression. Sci Transl Med. 2015;7:319ra207
Major contributions to cardiology 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.Paolocci N, Saavedra WF, Miranda KM, Martignani C, Isoda T, Hare JM, Espey MG, Fukuto JM, Feelisch M, Wink DA, et al. Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo by calcitonin gene-related peptide signaling. ProcNatlAcadSciUSA. 2001Paolocci N, Katori T, Champion HC, St John ME, Miranda KM, Fukuto JM, Wink DA and Kass DA. Positive inotropic and lusitropic effects of HNO/NO- in failing hearts: independence from beta-adrenergic signaling. ProcNatlAcadSciUSA. 2003;100:5537-5542Tocchetti CG, Wang W, Froehlich JP, Huke S, Aon MA, Wilson GM, Di Benedetto G, O'Rourke B, Gao WD, Wink DA, et al. Nitroxyl improves cellular heart function by directly enhancing cardiac sarcoplasmic reticulum Ca2+ cycling. Circ Res. 2007;100:96-104 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. The company was acquired by Bristol Meyers Squibb in 2015.
In the early 2000s, Kass began to incorporate molecular and cellular biology along with traditional bioengineering to better study heart failure mechanisms and novel therapies. The lab discovered that inhibiting phosphodiesterase type 5A(PDE5A), which degraded Cyclic guanosine monophosphate(cGMP) and was inhibited by the drug sildenafil (Viagra®), blunted heart contractility from adrenergic stimuli in animal and human hearts,Senzaki H, Smith CJ, Juang GJ, Isoda T, Mayer SP, Ohler A, Paolocci N, Tomaselli GF, Hare JM and Kass DA. Cardiac phosphodiesterase 5 (cGMP-specific) modulates beta-adrenergic signaling in vivo and is down-regulated in heart failure. FASEB J. 2001;15:1718-1726Takimoto E, Champion HC, Belardi D, Moslehi J, Mongillo M, Mergia E, Montrose DC, Isoda T, Aufiero K, Zaccolo M, et al. cGMP catabolism by phosphodiesterase 5A regulates cardiac adrenergic stimulation by NOS3-dependent mechanism. Circ Res. 2005;96:100-109Borlaug BA, Melenovsky V, Marhin T, Fitzgerald P and Kass DA. Sildenafil inhibits beta-adrenergic-stimulated cardiac contractility in humans. Circulation. 2005;112:2642-2649 and when chronically administered to animals, it improved their heart function and heart disease in response to pressure-stress.Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y and Kass DA. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. NatMed. 2005;11:214-222. Subsequent studies identified various mechanisms underlying this benefit.Takimoto E, Koitabashi N, Hsu S, Ketner EA, Zhang M, Nagayama T, Bedja D, Gabrielson KL, Blanton R, Siderovski DP, et al. RGS2 mediates cardiac compensation to pressure-overload and anti-hypertrophic effects of PDE5 inhibition. J Clin Invest. 2009;53(2)Koitabashi N, Aiba T, Hesketh GG, Rowell J, Zhang M, Takimoto E, Tomaselli GF and Kass DA. Cyclic GMP/PKG-dependent inhibition of TRPC6 channel activity and expression negatively regulates cardiomyocyte NFAT activation Novel mechanism of cardiac stress modulation by PDE5 inhibition. J Mol Cell Cardiol. 2010;48:713-24.counter adverse cardiac stress. Nature. 2019;566:264-269. Ranek MJ, Oeing C, Sanchez-Hodge R, Kokkonen-Simon KM, Dillard D, Aslam MI, Rainer PP, Mishra S, Dunkerly-Eyring B, Holewinski RJ, et al. CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury. Nat Commun. 2020;11:5237.