Research Spotlight

Posted January 15th 2020

HFpEF Is the Substrate for Stroke in Obesity and Diabetes Independent of Atrial Fibrillation.

Milton Packer M.D.
Milton Packer M.D.

Packer, M. (2020). “HFpEF Is the Substrate for Stroke in Obesity and Diabetes Independent of Atrial Fibrillation.” JACC Heart Fail 8(1): 35-42.

Full text of this article.

Both obesity and type 2 diabetes are important risk factors for the development of heart failure with a preserved ejection fraction (HFpEF), and both disorders increase the risk of systemic thromboembolic events. Traditionally, the risk of stroke has been explained by the strong association of these disorders with atrial fibrillation (AF). However, adiposity and diabetes are risk factors for systemic thromboembolism, even in the absence of AF, because both can lead to the development of an inflammatory and fibrotic atrial and ventricular myopathy, the 2 major elements of HFpEF. Atrial myopathy: 1) exacerbates pulmonary venous hypertension and exertional dyspnea; 2) leads to decreased flow, thrombogenesis, and systemic thromboembolization; and 3) often clinically manifests as AF; however, the relationship between AF and thromboembolism is unclear. Atrial fibrosis predisposes to thrombus formation, even in the absence of AF, and most thromboembolic events bear a poor temporal relationship to the occurrence of AF, whereas HFpEF (and the accompanying atrial disease) predicts stroke in patients with or without AF. Furthermore, rhythm control does not reduce the risk of stroke, although it reduces the burden of AF. These observations support the primacy of atrial myopathy as a critical component of HFpEF, rather than AF, as the mediator of systemic thromboembolism in obesity or diabetes. The well-established association between AF and stroke is likely explained by the fact that AF is a biomarker of more advanced inflammatory atrial disease but not necessarily a direct causal mechanism.


Posted January 15th 2020

Do amiodarone and dronedarone prevent thrombo-embolic stroke by treating the atrial myopathy of patients with atrial fibrillation? A provocative hypothesis.

Milton Packer M.D.
Milton Packer M.D.

Packer, M. (2020). “Do amiodarone and dronedarone prevent thrombo-embolic stroke by treating the atrial myopathy of patients with atrial fibrillation? A provocative hypothesis.” Europace Jan 3. [Epub ahead of print].

Full text of this article.

Aside from the relief of arrhythmia-related symptoms, the major reason to treat AF is to prevent the occurrence of systemic thromboembolism, since there remains uncertainty as to the role of AF in the progression of cardiomyopathy or heart failure. There is a growing interest in the use of catheter ablation as a first-line treatment for AF, since it is generally more effective than drug therapy in abolishing the arrhythmia, and it often spares patients from receiving potentially toxic antiarrhythmic agents. However, any preference for catheter ablation should be tempered by the possibility that certain Class III antiarrhythmic drugs may have an effect to reduce the risk of stroke because of a direct benefit on the underlying atrial myopathy. Oral anticoagulation is the most important treatment for the prevention of stroke, but many patients with AF are not prescribed these drugs or remain at risk of stroke despite receiving long-term anticoagulation. Additionally, because it exacerbates the underlying atrial myopathy, AF ablation without concomitant Class III antiarrhythmic drugs may not provide optimal protection against stroke, even in those who are prescribed oral anticoagulants. Therefore, in patients with AF who are at meaningful risk of stroke, physicians may well be advised to assess the presence and severity of an underlying atrial myopathy as a means of guiding their treatment decisions. (Excerpt from text, p. 2-3; no abstract available.)


Posted January 15th 2020

Do most patients with obesity or type 2 diabetes, and atrial fibrillation, also have undiagnosed heart failure? A critical conceptual framework for understanding mechanisms and improving diagnosis and treatment.

Milton Packer M.D.
Milton Packer M.D.

Packer, M. (2019). “Do most patients with obesity or type 2 diabetes, and atrial fibrillation, also have undiagnosed heart failure? A critical conceptual framework for understanding mechanisms and improving diagnosis and treatment.” Eur J Heart Fail Dec 17. [Epub ahead of print].

Full text of this article.

Obesity and diabetes can lead to heart failure with preserved ejection fraction (HFpEF), potentially because they both cause expansion and inflammation of epicardial adipose tissue and thus lead to microvascular dysfunction and fibrosis of the underlying left ventricle. The same process also causes an atrial myopathy, which is clinically evident as atrial fibrillation (AF); thus, AF may be the first manifestation of HFpEF. Many patients with apparently isolated AF have latent HFpEF or subsequently develop HFpEF. Most patients with obesity or diabetes who have AF and exercise intolerance have increased left atrial pressures at rest or during exercise, even in the absence of diagnosed HFpEF. Among patients with AF, those who also have latent HFpEF have increased risk for systemic thromboembolism and death. The identification of HFpEF in patients with obesity or diabetes alters the risk-to-benefit relationship of commonly prescribed treatments. Bariatric surgery and statins can ameliorate AF and reduce the risk for HFpEF. Conversely, antihyperglycaemic drugs that promote adipogenesis or cause sodium retention (insulin and thiazolidinediones) may increase the risk for heart failure in patients with an underlying ventricular myopathy. Patients with obesity and diabetes who undergo catheter ablation for AF are at increased risk for AF recurrence and for post-ablation increases in pulmonary venous pressures and worsening heart failure, especially if HFpEF coexists. Therefore, AF may be the earliest indicator of HFpEF in patients with obesity or type 2 diabetes, and recognition of HFpEF alters the management of these patients.


Posted January 15th 2020

Novel Multiphase Assessment for Predicting Left Ventricular Outflow Tract Obstruction Before Transcatheter Mitral Valve Replacement.

Michael J. Mack M.D.
Michael J. Mack M.D.

Meduri, C. U., M. J. Reardon, D. S. Lim, E. Howard, G. Dunnington, D. P. Lee, D. Liang, R. Gooley, D. O’Hair, M. K. Ng, A. Walton, K. Spargias, D. Blackman, A. Coisne, D. Hildick-Smith, M. De Gouy, S. Chenoweth, S. Kar, P. M. McCarthy, N. Piazza, A. Qasam, R. P. Martin, M. B. Leon, M. J. Mack, D. H. Adams and V. Bapat (2019). “Novel Multiphase Assessment for Predicting Left Ventricular Outflow Tract Obstruction Before Transcatheter Mitral Valve Replacement.” JACC Cardiovasc Interv 12(23): 2402-2412.

Full text of this article.

OBJECTIVES: This study proposes a physiologic assessment of left ventricular outflow tract obstruction (LVOTO) that accommodates changes in systolic flow and accounts for the dynamic neo-left ventricular outflow tract (LVOT). BACKGROUND: Patients considered for transcatheter mitral valve replacement trials often screen-fail because of the perceived risk of LVOTO. In the Intrepid Global Pilot Study, assumed risk of LVOTO was based on computed tomography estimates of the neo-LVOT area computed at end-systole. However, this may overestimate actual risk. METHODS: Retrospective analyses were performed for screen-failed patients for potential LVOTO (n = 33) and treated patients (n = 29) with available dynamic computed tomography. A multiphase assessment of the neo-LVOT area was performed and represented as: 1) multiphase average; and 2) early systolic value. Prospective evaluation was performed in 9 patients approved for enrollment with multiphase and early systole methods that would have previously screen-failed with the end-systolic approach. RESULTS: Of 166 patients screened for possible inclusion; 32 were screen-failed for nonanatomical reasons. Screen failure for assumed LVOTO risk occurred in 37 of 134 (27.6%) patients. Retrospective analysis indicated a potential enrollment increase of 11 of 33 (33.3%) and 18 of 33 (54.5%) patients using multiphase and early systolic assessment methods. In the prospective cohort, there were no clinical observations of LVOTO 30 days post-procedure, despite assumed risk based on end-systolic estimates. CONCLUSIONS: Multiphase, and specifically early systolic, assessment of the neo-LVOT may better determine risk of LVOTO with transcatheter mitral valve replacement compared with end-systolic estimates. This novel approach has the potential to significantly increase patient eligibility, with over one-half of patients previously screen-failed now eligible for treatment.


Posted January 15th 2020

A tale of two trials; chapter 2.

Michael J. Mack M.D.
Michael J. Mack M.D.

Mack, M. and P. Grayburn (2019). “A tale of two trials; chapter 2.” Eur J Heart Fail 21(12): 1635-1637.

Full text of this article.

Last year witnessed the simultaneous publication of two randomized trials attempting to determine the benefits (if any) of the correction of moderate to severe or severe secondary (functional) mitral regurgitation (MR) with the MitraClip device (Abbott Inc, Santa Clara, CA, USA) in addition to guideline‐directed medical therapy (GDMT) in patients with heart failure (HF). One trial, the COAPT trial, was unequivocally positive demonstrating clear benefit in the primary effectiveness endpoint of all HF hospitalizations within 24 months.1 Also demonstrated in this trial was a mortality benefit and the trial met all 10 of the pre‐specified and powered secondary endpoints. However, the other trial, MITRA‐FR, conducted in approximately the same time frame in a similar study cohort of patients, found a diametrically opposite result with no demonstrable benefit in the primary effectiveness endpoint of death and HF hospitalization at 12 months.2 These discordant outcomes obtained using the same device to treat the same disease at roughly the same time has led to much debate and conjecture as how to explain these seemingly irreconcilable differences. (Excerpt from text of this commentary on “Percutaneous repair or medical treatment for secondary mitral regurgitation: outcomes at 2 years’’ by B. Iung et al., published in the same issue.)