Research Spotlight

Posted August 15th 2019

Response by Ailawadi et al to Letter Regarding Article, “One-Year Outcomes After MitraClip for Functional Mitral Regurgitation.”

Paul A. Grayburn M.D.

Paul A. Grayburn M.D.

Ailawadi, G., D. S. Lim and P. A. Grayburn (2019). “Response by Ailawadi et al to Letter Regarding Article, ‘One-Year Outcomes After MitraClip for Functional Mitral Regurgitation.’” Circulation 140(5): e175-e176.

Full text of this article.

We thank Gul and Haseeb for the thoughtful insights into our report that documented 1-year outcomes after MitraClip implantation for functional mitral regurgitation (FMR) for patients enrolled in the EVEREST II study (Endovascular Valve Edge-to-Edge Repair Study). Gul and Haseeb note that left ventricular dyssynchrony occurs in the setting of ventricular remodeling, which can lead to mitral regurgitation (MR). They note that cardiac resynchronization therapy (CRT) as part of an aggressive optimal medical management strategy can improve MR and should be first-line therapy. Our study spanned the early experience with MitraClip in the United States from 2007 to 2013 and included >600 patients with functional MR, many of whom were not surgical candidates. Our understanding of the role of CRT has evolved during the last decade. Therefore, our study did not capture nor did it require CRT before enrollment. With greater understanding of optimal medical therapy, the COAPT study (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) did require CRT in appropriate patients before assessment of MR severity as part of optimal medical therapy. More than 35% of patients who were in COAPT had CRT placed previously yet still had significant MR. Although the denominator of patients who were referred for treatment of their FMR in COAPT and were then treated and responded to CRT is unknown, other studies have evaluated the impact of CRT on FMR. Van der Bijl and colleagues3 reported the effect of FMR on outcomes after CRT. Of 518 patients with grade 2 to 4+ FMR, only 40% had improvement following CRT, whereas the remaining 60% had no improvement in their MR severity. Nonresponse to CRT was independently associated with mortality (hazard ratio, 1.77; P<0.001). Moreover, other studies have documented a worsening of MR severity after CRT in 10% to 15% of patients. Data such as these have called into question which therapy, MitraClip or CRT, should be first-line therapy for significant functional MR even in patients who meet criteria for CRT. According to Kienemund and colleagues, roughly one-third of patients with an indication for CRT have moderate to severe FMR, which can be caused by altered ventricular geometry/size or the dyssynchrony itself. Some have suggested that MitraClip may be a preferred approach over CRT in selected patients.4 Because current guidelines support the use of CRT as first-line treatment before evaluation for FMR, limited data remain. Unfortunately, the ongoing trial of MitraClip versus medical therapy for nonresponders to CRT to which Gul and Haseeb refer will not answer the important question of which should be first-line treatment: MitraClip or CRT for FMR. (Text of response to a comment about author’s article, Ailawadi G, Lim DS, Mack MJ, Trento A, Kar S, Grayburn PA, Glower DD, Wang A, Foster E, Qasim A, et al.; EVEREST II Investigators. One-year outcomes after MitraClip for functional mitral regurgitation. Circulation. 2019; 139:37–47.)


Posted August 15th 2019

Reconceptualization of the Molecular Mechanism by Which Sodium-Glucose Cotransporter 2 Inhibitors Reduce the Risk of Heart Failure Events.

Milton Packer M.D.

Milton Packer M.D.

Packer, M. (2019). “Reconceptualization of the Molecular Mechanism by Which Sodium-Glucose Cotransporter 2 Inhibitors Reduce the Risk of Heart Failure Events.” Circulation 140(6): 443-445.

Full text of this article.

Two sodium-glucose cotransporter 2 (SGLT2) inhibitors (ie, empagliflozin and canagliflozin) are currently approved by the Food and Drug Administration to reduce cardiovascular death or major adverse thromboembolic events in patients with type 2 diabetes mellitus. Yet, the current labeling for this class of drugs is misleading. The Food and Drug Administration indication reflects certain design features of the major cardiovascular outcome safety trials with these drugs, but it does not accurately describe the most important efficacy findings of these studies. In none of the 3 major cardiovascular trials did SGLT2 inhibitors reduce the risk of myocardial infarction and stroke.1 Instead, the primary benefit of SGLT2 inhibitors was a 25% to 35% decrease in the risk of heart failure hospitalizations, which was seen consistently across the trials. The additional benefit of empagliflozin to decrease the risk of cardiovascular death is primarily driven by an effect on pump failure deaths and sudden deaths: the 2 most common modes of death in patients with heart failure. How can inhibition of glucose transport in the proximal renal tubule lead to such a striking decrease in the risk of heart failure events? The effect of these drugs to block glucose reabsorption is accompanied by a lowering of hemoglobin A1c, body weight, and blood pressure. However, the magnitude of these effects is modest, and these changes are not well correlated with the observed decrease in the risk of heart failure deaths or hospitalizations. Furthermore, most drugs that lower blood glucose, body weight, and blood pressure do not have beneficial effects on, and they often adversely influence, the course of heart failure. Inhibition of SGLT2 in the proximal renal tubule causes a meaningful natriuresis, and the resulting decrease in plasma volume could conceivably lead to a decrease in cardiac dimensions and pressures, resulting in favorable effects on ventricular remodeling. However, it is difficult to ascribe the benefits of these drugs primarily to an increase in urinary sodium excretion, because the reduction in heart failure events was seen in patients already receiving diuretics. Intensification of diuretic therapy has not led to a dramatic decrease in cardiovascular mortality or sudden death in patients with heart failure. Similarly, the increase in hemoglobin (that is typically seen with SGLT2 inhibitors) does not lead to clinical benefits in patients with heart failure. (Excerpt from text, p. 443; no abstract available.)


Posted August 15th 2019

Nonarrhythmic Sudden Cardiac Death in Chronic Heart Failure-A Preventable Event?

Milton Packer M.D.

Milton Packer M.D.

Packer, M. (2019). “Nonarrhythmic Sudden Cardiac Death in Chronic Heart Failure-A Preventable Event?” JAMA Cardiol Jul 17. [Epub ahead of print].

Full text of this article.

Sudden cardiac death is the mode of demise in 30% to 50% of patients with chronic heart failure with reduced ejection fraction. Traditionally, physicians have assumed that the abrupt collapse of the circulation is invariably caused by sustained ventricular tachycardia or fibrillation. These arrhythmias may occur without an identifiable trigger or be precipitated by a circadian catecholamine surge, electrolyte imbalances, or the use of drugs with proarrhythmic effects. Regardless of the cause, sustained ventricular tachyarrhythmias are highly responsive to treatment with an implantable cardioverter-defibrillator (ICD). Implantable cardioverter-defibrillators are recommended for patients with heart failure who demonstrate persistent systolic dysfunction after treatment with neurohormonal antagonists and in whom nonsudden deaths are not an important competing short-term risk for demise.


Posted August 15th 2019

Dosing tuberculosis drugs in young children: the road ahead.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Pasipanodya, J. G. and T. Gumbo (2019). “Dosing tuberculosis drugs in young children: the road ahead.” Lancet Child Adolesc Health Jul 16. [Epub ahead of print].

Full text of this article.

Tuberculosis is among the ten leading causes of death in children worldwide, contributing to an estimated 239000 deaths in 2015. Machine learning methods have identified that death and therapy failure are best predicted by insufficient concentrations of isoniazid, rifampicin, and pyrazinamide; malnutrition; and being younger than 3 years. Age is an independent predictor of death, which affects pharmacokinetics of antituberculosis drugs via maturation effects, and the greater tendency for severe and disseminated tuberculosis disease, such as meningitis, increases mortality in younger children. The mortality rates in these young children as well as in older malnourished children are in the ranges of those observed during the prechemotherapy era, suggesting that the current combination regimens and doses recommended by WHO do not work well for every child. (Excerpt from text, p. 590; no abstract available.)


Posted August 15th 2019

Frequency of Left Ventricular Scars at Autopsy in Persons Dying Suddenly of Coronary Artery Disease With or Without Earlier Myocardial Infarction.

William C. Roberts M.D.

William C. Roberts M.D.

Roberts, W. C. (2019). “Frequency of Left Ventricular Scars at Autopsy in Persons Dying Suddenly of Coronary Artery Disease With or Without Earlier Myocardial Infarction.” JAMA Cardiol Jul 10. [Epub ahead of print].

Full text of this article.

In this issue of JAMA Cardiology, Vähätalo et al. investigated through clinical and autopsy records 5869 persons who had died suddenly of nontraumatic causes in northern Finland during a recent 20-year period. The deaths of 4392 individuals (74.8%) were attributed to coronary artery disease (CAD) and the deaths of 1477 individuals (25.2%) to non-CAD conditions. Of the 4392 individuals who died of CAD, 3122 (71.1%) had no prior diagnosis of CAD, per the authors, and 1026 (23.4%) had a prior CAD diagnosis. Of the 3122 with no prior CAD diagnosis, 1322 individuals (42.4%) had a left ventricular (LV) scar at autopsy, and 1798 (57.6%) did not. The article compares clinical and cardiac morphologic findings in those with vs those without an LV scar at autopsy. The scars, of course, indicate that those individuals had had an acute myocardial infarction (MI) that had healed: in 42.4%, the acute MI apparently was not recognized during life (which is called a silent MI). There were no significant differences between the 2 groups in frequency of diabetes mellitus (249 of 1322 [18.8%] vs 312 of 1798 [17.4%]), systemic hypertension (523 [39.6%] vs 688 [38.3%]), dyslipidemia (149 [11.3%] vs 200 [11.1%]), angina pectoris (81 [6.1%] vs 104 [5.8%]), or dyspnea (45 [3.4%] vs 53 [2.9%]). There were statistically different but not clinically meaningful differences between those with vs those without LV scars in mean (SD) age (66.9 [11.1] years vs 65.5 [11.6] years; P = .001) and heart weight (mean [SD]: men, 497.2 [107.0] g vs 454.7 [105.0] g; P < .001; women, 411.3 [85.7] g vs 386.1 [91.2] g; P = .001) and frequencies of total occlusion of a coronary artery (519 of 1322 [39.3%] vs 291 of 1798 [16.2%]; P < .001), occurrence of sudden death during physical activity (241 of 1322 [18.2%] vs 223 of 1798 [12.4%]; P < .001), and occurrence of the sudden death event outside (265 of 1322 [20.0%] vs 268 of 1798 [14.9%]; P = .001).