Research Spotlight

Packer, M. and P. A. Grayburn (2019). “Neurohormonal and Transcatheter Repair Strategies for Proportionate and Disproportionate Functional Mitral Regurgitation in Heart Failure.” JACC Heart Fail Jun; 7(6): 518-521. Epub 2019 May 8.

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Functional mitral regurgitation (MR) is present to varying degrees in most patients with chronic heart failure (HF) and left ventricular (LV) systolic dysfunction, and in ~30% of its magnitude is hemodynamically meaningful. A critical determinant of MR in these patients is the degree of LV dilation. Remodeling and enlargement of the LV leads to displacement of the papillary muscles and widening and flattening of the mitral annulus, which (together with a reduction in closing forces) impairs the coaptation of the mitral valve (MV) leaflets. However. independent of LV end-diastolic volume (LVEDV), ventricular dyssynchrony contributes importantly to functional MR. In patients with meaningful QRS prolongation, dyssynchrony causes unequal contraction of papillary muscle bearing walls, preventing coordinated closure of the MV leaflets; amelioration of the conduction delay by cardiac resynchronization reduces MR. Additionally, irrespective of the presence of e1ec:trfc conduction delay, localized LV remodeling can cause apical and posterior displacement of the papillary muscles and dyssynchronous contraction of the leaflet-supporting structures independent of global LV dsyfunction. These observation suggest that patients with functional MR and HF include the following: 1) those whose MR can be entirely explained by the MV distortions produced by LV enlargement: and 2) those who had regional LV dysfunction inordinately interferes with the synchronous contraction of the papillary muscle segments that support normal MV coaptation. We refer to the first group as having MR that is “proportionate'” to LV enlargement and the second group as having MR that is “disproportionate” to LVEDV (i.e., the severity of MR is greater than predicted by LV volumes). (Excerpt from introduction to article in press, p. 518.)

Stone, G. W., N. J. Weissman and M. J. Mack (2019). “Transcatheter Mitral-Valve Repair in Patients with Heart Failure. Reply.” N Engl J Med 380(20): 1980-1981.

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The authors reply: Crestanello et al. question the apparently low forward stroke volume calculated from the total left ventricular stroke volume, which was determined by applying Simpson’s method to two-dimensional biplane echocardiographic measurements and using an assumed regurgitant volume. The actual mean forward stroke volume in the COAPT trial as measured with Doppler was 51 ml, and the regurgitant volume as measured with the use of the PISA (proximal isovelocity surface area) method was 59 ml, values that are consistent with severe mitral regurgitation. There are several reasons for the discrepancies from Crestanello’s theoretical extrapolation, in which two-dimensional and Doppler data are combined, the most important being the substantial underestimation of left ventricular volume (and stroke volume), as determined by two-dimensional echocardiography with the use of Simpson’s rule, especially in patients with dilated ventricles, such as those enrolled in the COAPT trial. Drake et al. posit that a lack of imaging guidance resulted in a high rate of recurrence of mitral regurgitation after surgical repair with a downsized annuloplasty ring in the trial conducted by the Cardiothoracic Surgical Trials Network. That trial used detailed echocardiographic analysis to gauge patient suitability for inclusion. A post hoc subanalysis defined the anatomical features shown on echocardiography that were predictive of a durable surgical repair. Ongoing, detailed echocardiographic analyses in the COAPT trial will further delineate the anatomical features that predict favorable outcomes after transcatheter mitral-leaflet approximation. We do agree that image-guided assessment is essential to the identification of a responder population and that in the future it may direct patient-specific intervention (leaflet repair, annuloplasty, or valve replacement). What Garbi and Lancellotti term valvular heart failure secondary to mitral regurgitation, Grayburn et al. designate as disproportionate mitral regurgitation and Carabello calls tertiary mitral regurgitation. Regardless of the nomenclature, we agree that relative to the MITRA-FR trial, the COAPT trial investigators enrolled a greater proportion of patients in whom prognosis was dictated more by the severity of mitral regurgitation than by the degree of left ventricular dysfunction — a major reason why patients in the COAPT trial, but not those in the MITRA-FR trial, benefited from transcatheter mitral-valve repair. We further agree that reduction in left atrial pressure (and volume) was probably responsible for many of the clinical benefits associated with transcatheter mitral-valve repair in the COAPT trial. Mitral-valve replacement offers the potential for greater reduction in mitral regurgitation than transcatheter mitral-valve repair. Whether the procedure will provide sufficiently greater clinical effectiveness warranting a potentially more complex and complicated procedure is uncertain and can only be addressed by means of adequately powered randomized trials. Finally, Kalavrouziotis et al. are incorrect in stating that enrollment in the COAPT trial was “supervised” by the sponsor. Rather, investigators at each site determined whether screened patients met prespecified enrollment criteria, a determination that was then confirmed by a physician-led, sponsor-independent, central eligibility committee and echocardiographic core laboratory. We believe that practitioner fidelity to the inclusion and exclusion criteria used in the COAPT trial should lead to duplication of our results in the real world. (Text of authors’ reply to several letters in the same issue of NEJM; see also authors’ original article, Stone, G. W., J. Lindenfeld, W. T. Abraham, S. Kar, D. S. Lim, J. M. Mishell, B. Whisenant, P. A. Grayburn, M. Rinaldi, S. R. Kapadia, V. Rajagopal, I. J. Sarembock, A. Brieke, S. O. Marx, D. J. Cohen, N. J. Weissman and M. J. Mack (2018). “Transcatheter Mitral-Valve Repair in Patients with Heart Failure.” N Engl J Med 379(24): 2307-2318.)

Ryman, K. M., W. D. Pace, S. Smith and G. V. Fontaine (2019). “Alteplase Therapy for Acute Ischemic Stroke in Pregnancy: Two Case Reports and a Systematic Review of the Literature.” Pharmacotherapy May 11. [Epub ahead of print].

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Acute ischemic stroke (AIS) during pregnancy is a rare but serious complication. Intravenous alteplase is the only medication approved for hyperacute treatment of AIS; however, it has not been evaluated prospectively in pregnancy. Pregnancy was an exclusion criterion in prospective AIS studies and was only recently removed as a relative contraindication in the 2018 American Heart Association/American Stroke Association Stroke guidelines. Due to the exclusion of pregnant women from randomized controlled trials, the safety of fibrinolytic therapy in pregnant patients is not well established. In this review, we report the use of intravenous alteplase for AIS in two pregnant patients, with temporally associated clinical improvement and without complications to either the mother or fetus. Additionally, we summarize a systematic review of the literature for both intravenous and intra-arterial alteplase use for AIS in pregnant patients. A total of 31 cases met inclusion criteria for this review of assessment of safety and efficacy of alteplase use in pregnancy. Existing case reports and guidelines support the use of alteplase for AIS in pregnant patients without contraindications.

Zanoli, L., P. Lentini, M. Briet, P. Castellino, A. A. House, G. M. London, L. Malatino, P. A. McCullough, D. P. Mikhailidis and P. Boutouyrie (2019). “Arterial Stiffness in the Heart Disease of CKD.” J Am Soc Nephrol 30(6): 918-928.

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CKD frequently leads to chronic cardiac dysfunction. This complex relationship has been termed as cardiorenal syndrome type 4 or cardio-renal link. Despite numerous studies and reviews focused on the pathophysiology and therapy of this syndrome, the role of arterial stiffness has been frequently overlooked. In this regard, several pathogenic factors, including uremic toxins (i.e., uric acid, phosphates, endothelin-1, advanced glycation end-products, and asymmetric dimethylarginine), can be involved. Their effect on the arterial wall, direct or mediated by chronic inflammation and oxidative stress, results in arterial stiffening and decreased vascular compliance. The increase in aortic stiffness results in increased cardiac workload and reduced coronary artery perfusion pressure that, in turn, may lead to microvascular cardiac ischemia. Conversely, reduced arterial stiffness has been associated with increased survival. Several approaches can be considered to reduce vascular stiffness and improve vascular function in patients with CKD. This review primarily discusses current understanding of the mechanisms concerning uremic toxins, arterial stiffening, and impaired cardiac function, and the therapeutic options to reduce arterial stiffness in patients with CKD.

Webb, J. G., D. J. Murdoch, M. C. Alu, A. Cheung, A. Crowley, D. Dvir, H. C. Herrmann, S. K. Kodali, J. Leipsic, D. C. Miller, P. Pibarot, R. M. Suri, D. Wood, M. B. Leon and M. J. Mack (2019). “3-Year Outcomes After Valve-in-Valve Transcatheter Aortic Valve Replacement for Degenerated Bioprostheses: The PARTNER 2 Registry.” J Am Coll Cardiol 73(21): 2647-2655.

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BACKGROUND: Transcatheter aortic valve replacement (TAVR) for degenerated surgical bioprosthetic aortic valves is associated with favorable early outcomes. However, little is known about the durability and longer-term outcomes associated with this therapy. OBJECTIVES: The aim of this study was to examine late outcomes after valve-in-valve TAVR. METHODS: Patients with symptomatic degeneration of surgical aortic bioprostheses at high risk (>/=50% major morbidity or mortality) for reoperative surgery were prospectively enrolled in the multicenter PARTNER (Placement of Aortic Transcatheter Valves) 2 valve-in-valve and continued access registries. Three-year clinical and echocardiographic follow-up was obtained. RESULTS: Valve-in-valve procedures were performed in 365 patients. The mean age was 78.9 +/- 10.2 years, and the mean Society of Thoracic Surgeons score was 9.1 +/- 4.7%. At 3 years, the overall Kaplan-Meier estimate of all-cause mortality was 32.7%. Aortic valve re-replacement was required in 1.9%. Mean transaortic gradient was 35.0 mm Hg at baseline, decreasing to 17.8 mm Hg at 30-day follow-up and 16.6 mm Hg at 3-year follow-up. Baseline effective orifice area was 0.93 cm(2), increasing to 1.13 and 1.15 cm(2) at 30 days and 3 years, respectively. Moderate to severe aortic regurgitation was reduced from 45.1% at pre-TAVR baseline to 2.5% at 3 years. Importantly, moderate or severe mitral and tricuspid regurgitation also decreased (33.7% vs. 8.6% [p < 0.0001] and 29.7% vs. 18.8% [p = 0.002], respectively). Baseline left ventricular ejection fraction was 50.7%, increasing to 54.7% at 3 years (p < 0.0001), while left ventricular mass index was 136.4 g/m(2), decreasing to 109.1 g/m(2) at 3 years (p < 0.0001). New York Heart Association functional class improved, with 90.4% in class III or IV at baseline and 14.1% at 3 years (p < 0.0001), and Kansas City Cardiomyopathy Questionnaire overall score increased (43.1 to 73.1; p < 0.0001). CONCLUSIONS: At 3-year follow-up, TAVR for bioprosthetic aortic valve failure was associated with favorable survival, sustained improved hemodynamic status, and excellent functional and quality-of-life outcomes. (The PARTNER II Trial: Placement of Aortic Transcatheter Valves II - PARTNER II - Nested Registry 3/Valve-in-Valve [PII NR3/ViV]; NCT03225001).