Combining renin-angiotensin system blockade and sodium-glucose cotransporter-2 inhibition in experimental diabetes results in synergistic beneficial effects.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibition exerts cardioprotective and renoprotective effects, often on top of renin-angiotensin system (RAS) blockade. We investigated this in diabetic hypertensive (mREN2)27 rats. METHODS: Rats were made diabetic with streptozotocin and treated with vehicle, the angiotensin receptor blocker valsartan, the SGLT2 inhibitor empagliflozin, or their combination. Blood pressure (BP) was measured by telemetry. RESULTS: Diabetes resulted in albuminuria, accompanied by glomerulosclerosis, without a change in glomerular filtration rate. Empagliflozin did not lower BP, while valsartan did, and when combined the BP drop was largest. Only dual blockade reduced cardiac hypertrophy and prevented left ventricular dilatation. Valsartan, but not empagliflozin, increased renin, and the largest renin rise occurred during dual blockade, resulting in plasma angiotensin II [but not angiotensin-(1-7)] upregulation. In contrast, in the kidney, valsartan lowered angiotensin II and angiotensin-(1-7), and empagliflozin did not alter this. Although both valsartan and empagliflozin alone tended to diminish albuminuria, the reduction was significant only when both drugs were combined. This was accompanied by reduced glomerulosclerosis, no change in glomerular filtration rate, and a favorable expression pattern of fibrosis and inflammatory markers (including SGLT2) in the kidney. CONCLUSION: RAS blockade and SGLT2 inhibition display synergistic beneficial effects on BP, kidney injury and cardiac hypertrophy in a rat with hypertension and diabetes. The synergy does not involve upregulation of angiotensin-(1-7), but may relate to direct RAS-independent effects of empagliflozin in the heart and kidney.

Guiding Interventions for Secondary Tricuspid Regurgitation: Follow the Intricate Interplay Between Form and Function.

Secondary tricuspid regurgitation (TR) has long been considered a benign and well-tolerated valvular lesion that resolves after treatment of the underlying disease. This view has been challenged by data indicating that long-standing TR can be a progressive disorder, contributing to right ventricular failure and end-organ damage, despite adequate treatment of the underlying disease. Surgical correction is curative, but infrequently performed and historically associated with poor outcomes. This may be due to delayed diagnosis, lack of well-defined surgical indications, and, consequently, late intervention in patients in poor clinical condition with failing right ventricles. Because of limited evidence about timing and corresponding outcome of tricuspid valve surgery, current guideline recommendations are rather conservative and show several inconsistencies. Nevertheless, there has been a trend toward a more aggressive approach in the surgical treatment of TR with improved outcomes. Moreover, emerging transcatheter options claim to provide a lower-risk alternative for selected patients. This may facilitate earlier treatment and improve the attitude toward an early treatment strategy of secondary TR, yet is not reflected in the guidelines. Future research is needed for risk stratification to determine inclusion criteria and optimal timing for intervention.

The right ventricle in tetralogy of Fallot: adaptation to sequential loading.

Right ventricular dysfunction is a major determinant of outcome in patients with complex congenital heart disease, as in tetralogy of Fallot. In these patients, right ventricular dysfunction emerges after initial pressure overload and hypoxemia, which is followed by chronic volume overload due to pulmonary regurgitation after corrective surgery. Myocardial adaptation and the transition to right ventricular failure remain poorly understood. Combining insights from clinical and experimental physiology and myocardial (tissue) data has identified a disease phenotype with important distinctions from other types of heart failure. This phenotype of the right ventricle in tetralogy of Fallot can be described as a syndrome of dysfunctional characteristics affecting both contraction and filling. These characteristics are the end result of several adaptation pathways of the cardiomyocytes, myocardial vasculature and extracellular matrix. As long as the long-term outcome of surgical correction of tetralogy of Fallot remains suboptimal, other treatment strategies need to be explored. Novel insights in failure of adaptation and the role of cardiomyocyte proliferation might provide targets for treatment of the (dysfunctional) right ventricle under stress.