Simultaneous Electrical and Mechanical Mapping Using 3D Cardiac Mapping System: Novel Approach for Optimal Cardiac Resynchronization Therapy

S16 Journal of Cardiac Failure Vol. 15 No. 6S Suppl. 2009 7, 8, 9, tissue inhibitor of MMPs (TIMPs)-1, 2, 3, 4, were performed on 446 subjects divided into 4 groups: subjects with no evidence of cardiovascular disease (CTL, n5121); hypertension but without structural or functional changes(HTN, n5120); HTN and LV hypertrophy without evidence of heart failure(LVH, n5144), and HTN, LVH, and CHF (CHF, n561). A multivariate analysis indicated a significant increase in TIMP-1 in LVH (Odds Ratio [OR]51.04, 95% Confidence interval [CI]51.02,1.05, p!0.0001) and a significant increase in TIMP-1 and -4 in CHF (OR51.03 & 2.22, 95% CI51.02,1.05 & 1.33, 3.69, p!0.003) (Table 1). The effects of medications on biomarkers were analyzed by drug class: angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB), ßblockers, calcium-channel blockers, and diuretics in 4 groups: CTL, HTN, LVH, CHF. Multivariate analysis using multiple linear regression indicated that no medication altered the CHF induced changes in TIMPs (Table 2, regression coefficient5ß). Conclusions: LVH and CHF were associated with increased TIMP expression which favors ECM accumulation. However, pharmacologic agents used to treat hypertension did not alter the expression of these proteolytic determinants of ECM composition.

Table 2. TIMP-1

Medication Class ß ACE-I/ARB ß-Blocker Ca Channel Blocker Diuretic

yes yes yes yes

(no) (no) (no) (no)

0.042 0.046 0.037 0.044

(0.042) (0.042) (0.042) (0.042)

p O O O O

0.05 0.05 0.05 0.05

initiation (or up-titration) of loop diuretics (LD). Methods: We retrospectively analyzed 325 consecutive pts (70 6 11 years) with advanced CHF admitted to our community hospital. 95 pts with anemia of specific causes or anemia of chronic disease were excluded from analysis. On admission to hospital the treatment with LD (20d120 mg furosemide daily) was started (or up-titrated) in all the pts and continued for at least 2 weeks. The rest of medications remained unchanged for at least 7d10 days. Results: The Hb levels on admission varied from 5.6 to 17.5 g/dl. The Hb levels increased from 12.6 6 2.0 g/dl on admission to 134.8 6 1.2 g/dl after 7d10 days of therapy with LD (p!0.01). Anaemia defined by WHO criteria on admission was observed in 110 of 230 (48%) pts and only 41 (18%) pts 7d10 days later. Among pts with unexplained anemia on admission in 69 (63%) Hb levels on LD increased to normal values for respective sex. The magnitude and direction of changes in Hb values on LD markedly were related to the baseline Hb levels. Among 93 pts with Hb levels below 12.0 g/dl on admission the Hb level increased from 10.7 6 1.1 to 12.4 6 1.6 g/dl (p!0.001). In contrast, there was a trend for Hb levels to decrease in pts with CHF received the LD, if they experienced Hb levels 14.5 g/dl or more on admission (15.7 6 0.8 vs 14.8 6 1.3 g/dl; p 5 NS). The increase in Hb levels of at least 1.0 g/dl was observed in 72% pts with Hb levels below 12.0 g/dl on admission but only in 5% pts with Hb levels 14.5 g/dl or more (p!0.001). Conclusion: In most of hospitalized pts with advanced CHF unexplained anemia on admission is related to hemodilution anemia and may resolve with LD. It’s unlikely to be hemodilution due to volume overload in pts with CHF, if they have Hb levels 14.5 g/dl or more. These findings raise questions about the upper limit of optimal Hb level in pts with CHF and about different approach to starting treatment with LD in pts with advanced CHF. The data obtained from CIBIS-III (2005) indicated that b-blocker-first strategy was especially useful in pts with low Hb values while ACE-inhibitor-first strategy was particularly relevant in pts with high Hb values.

042 040 LV Lead Repositioning to Apico-Lateral Position in Non Responders to Resynchronization Therapy Improves Patients Acutely and in Long Term Follow Up Dusan Z. Kocovic, Nancy Britton, Mark Heimann, Scott Cox, Steven Rothman; Cardiology, Lankenau Hospital, Wynnewood, PA Background: Up to 35% of patients with dyssynchrony do not respond to cardiac resynchronization therapy (CRT). This may result from suboptimal placement of the left ventricular (LV) pacing lead. Currently there is no consensus on the best parameter for the LV lead optimization or the optimal site for LV pacing. Methods: 27 patients, 13 with ischemic cardiomyopathy (ICM) and 14 with non-ischemic cardiomyopathy (NICM), who did not respond to CRT within twelve months, were studied. 19/27 patients had initial LV lead placement in the anterolateral and 8/27 in the lateral-basal segment of the LV. A new LV lead was placed in multiple sites in the coronary venous system. Acute measurements were performed with the conductance catheter to select the new LV pacing site. Change in LV stroke volume and dP/dtmax were used as a guide to optimal lead position, After implantation patients were followed clinically at 1, 3, 6 and 12 months. Echocardiography, the Minnesota Living with Heart Failure Questionnaire, and 6 min hall walk tests were completed at the baseline and 6 month intervals. Results: During acute measurements the biggest increase in stroke volume was seen in the apico lateral segment of the LV. The new apico lateral LV lead position significantly increased stroke volume (þ27%, P 5.01), stroke work (þ45%, P 5.04) reduced end-systolic volume (-5%, P 5.04) and did not significantly change dP/dtmax (þ5%, P 5.2) when compared to the old LV lead position in all 27 patients. Long term follow up demonstrated that the acute increase in the LV stroke volume resulted in significantly better response to therapy. After 6 months all patients showed improvement in quality of life and the 6 minute hall walk test, NICM patients had significant increase in EF (þ10%, P50.05) and 12/14 decreased ES and ED volume O15%. ICM patients had worse results EF (þ2%, P50.1) and ES and ED volumes decreased in 7/13. At 12 months 4/13 patients with ICM and 2/14 with NICM died. Conclusions: In patients who are non-responders, repositioning or adding LV lead to the original CRT system with use of hemodynamic guidance significantly improved response. Mechanism of improvement was related to the increase in LV stroke volume, not the change dP/dt max. The optimal LV pacing site was lateral towards the apex in all patients. Despite the improvements the mortality in the ICM group after 12 months was high.

041 Hemodilation Is a Main Cause of Anemia in Patients with Advanced Congestive Heart Failure Dmitry V. Preobrazhensky1, Nataliya I. Nekrasova1, Irina D. Vyshinskaya1, Irina V. Talysina1, Talantbek A. Batyraliev2; 1Department of Cardiology, Moscow Medical Academy, Moscow, Russian Federation; 2Department of Cardiology, Sani Konukoglu Medical Center, Gaziantep, Turkey Background: Hemoglobin (Hb) values were shown to fluctuate significantly in patients (pts) with congestive heart failure (CHF) over time. This study analyzed the Hb level changes in patients with CHF received standard pharmacotherapy after

Simultaneous Electrical and Mechanical Mapping Using 3D Cardiac Mapping System: Novel Approach for Optimal Cardiac Resynchronization Therapy Kyungmoo Ryu1, Andre d’Avila2, E. Kevin Heist2, Stuart P. Rosenberg1, Jessie Chou1, Michael Yang1, Jagmeet P. Singh2; 1St. Jude Medical, Inc., Sylmar, CA; 2 Medicine, Massachusetts General Hospital, Boston, MA Introduction: Left ventricular (LV) lead placement at sites of electrical and mechanical delay has been advocated to maximize response to cardiac resynchronization therapy (CRT), but there is currently no technique described to measure mechanical

delay in real-time. We tested the hypothesis that the EnSite NavX system can be used intraoperatively to assess coronary sinus (CS) mechanical activation in addition to CS electrical activation for guidance of LV pacing site optimization during CRT implantation. Methods: During CRT implantation, a right atrial (RA) lead and a 2.5Fr 16electrode EP catheter (Cardima Pathfinder) were connected to EnSite NavX system to perform electroanatomical and electromechanical mapping of two or more CS branches during sinus rhythm. The 3-dimensional motion of the catheter electrodes and sensed electrograms at each LV site were recorded over 10 cardiac cycles, generating CS electrical and mechanical activation maps. Results: Three patients (pts) undergoing CRT device implantation were studied. Anterior (AB) and lateral (LB) CS branches were mapped in all pts, and also an anterolateral branch (ALB) in pt 1. CS electrical activation patterns seemed to correlate well with the CS mechanical activation patterns in the 2 non-ischemic pts (pts 1 and 3), and less so in the ischemic pt (pt 2; Figure). The earliest electrical and mechanical activations were found in: (shown as electrical / mechanical) pt 1 - distal AB / mid AB; pt 2 - mid-basal AB / basal AB; and pt 3 - distal AB / distal AB. The latest electrical / mechanical activations were found in: pt 1 - mid-basal LB / distal ALB; pt 2 - distal LB / mid-distal LB; and pt 3 - all LB / distal LB. Conclusions: Simultaneous electrical and mechanical mapping of CS branches is feasible with the impedance based 3-dimensional cardiac mapping system. Real-time use of electrical and mechanical

The 13th Annual Scientific Meeting



HFSA

S17

mapping of the CS branches may provide insight into CRT efficacy and may reveal targets for appropriate LV lead positioning.

043 Endothelium-Independent Microvascular Dysfunction Induced by AL Amyloidosis Light Chains in Human Adipose Arterioles: Novel Mechanism of Amyloid Injury Megan Bright1, Seth Truran1, Brittany Schlundt1, David D. Gutterman1, Parameswaran Hari2, Raymond Q. Migrino1; 1Medicine (Cardiovascular Medicine), Medical College of Wisconsin, Milwaukee, WI; 2Medicine (Hematology-Oncology), Medical College of Wisconsin, Milwaukee, WI Background: Light chain amyloidosis (AL) is a plasma cell dyscrasia associated with grave prognosis and multiorgan tissue ischemic injury. The mechanism causing organ dysfunction is unknown. We previously showed impaired endothelial function in human adipose arterioles exposed to AL light chains (LC). Our aim is to determine the acute effects of LC on endothelium-independent vasodilation and induction of mitochondrial oxidative stress in human adipose arterioles. Methods: Urine LC was isolated from 2 AL patients with cardiac involvement (68 and 43 years, both males) using dialysis and size-specific filtration. Discarded adipose arterioles from 6 patients without known vascular disease, diabetes or AL undergoing routine surgery (5 females, 57 6 0.2 years) were cannulated and pressurized (60 mmHg). Vessel diameter was measured using videomicrometer. After pre-constriction with endothelin1, dilator response to sodium nitroprusside (SNP, 10-10 to 10-4 M) before and following 60 minutes of intraluminal exposure to 20 mg/mL of LC (within range of usual concentration in ALpatients) was measured as % maximum diameter. Separately, mitochondrial superoxide was measured in 25 adipose arterioles from 17 non-AL patients (10 females, 52 6 0.3years) treated with LC for 60 minutes using MitoSOX (5mM) with fluorescence microscopy. Results: see figure. Conclusions: Brief exposure to LC impairs endothelium-independent vasodilation suggesting microvascular smooth muscle dysfunction in human adipose arterioles. Increased mitochondrial superoxide in LC treated vessels suggests possible role of mitochondrial oxidative stress in this disease. This novel mechanism may be important in the pathophysiology of AL.

044 Simvastatin Attenuates Endothelial Dysfunction in Human Adipose Arterioles Exposed to AL Amyloid Light Chain Proteins Raymond Q. Migrino1, Seth Truran1, Brittany Schlundt1, Mitchell Timmons1, Megan Bright1, Parameswaran Hari2, David D. Gutterman1; 1Medicine (Cardiovascular Medicine), Medical College of Wisconsin, Milwaukee, WI; 2Medicine (Hematology-Oncology) Background: Light chain amyloidosis (AL) is a plasma cell dyscrasia associated with abnormal production of amyloidogenic light chain proteins (LC). It can often be fatal especially with heart failure. The mechanism of injury remains unknown but we have previously shown that acute ex-vivo exposure of non-AL human adipose arterioles to LC results in endothelial dysfunction. Our aim is to determine if coadministration of simvastatin will attenuate the endothelial dysfunction induced by LC. Methods: LC from the urine of 4 biopsy-proven AL subjects (57 6 11 years, all males) were isolated and purified. Arterioles were isolated from discarded adipose tissue in patients without known vascular disease, diabetes or AL undergoing routine surgery, pressure-mounted (n523) and vessel diameter measured by videomicroscopy. Following preconstriction with endothelin-1, vessels were exposed to vehicle and sequential doses of acetylcholine (endothelium-mediated dilation, 10-9 to 10-4M) then papaverine (endothelium-independent dilation 10-4M) were given and baseline dilation was measured. Dilator response was again measured after 1-hour intraluminal exposure to 20 mg/mL LC without (n514) and with (n59) simvastatin (1 mM) and compared to baseline. Separately, isolated adipose arterioles were exposed to vehicle (n514), LC 20 mg/mL without (n522) and with simvastatin (1 mM, n510) and simvastatin alone (n53) for 1 hour and nitric oxide (NO) production was assessed using 4,5-diaminofluorescein diacetate (DAF-2) fluorescence. Results: See figure. Conclusions: Brief exposure to AL LC impairs endothelium-dependent dilation in human adipose arterioles and reduces NO production, both of which are restored by simvastatin. The findings may advance understanding of the pathophysiologic mechanism and point to a novel therapeutic approach for this often-fatal disease.

045 Hypertension in Heart Failure with Normal LVEF Is Characterized by LVH, Decreased Atrial Ejection Function and Two Distinct Patterns of Abnormal LV Filling M. Rizwan Khalid1, Zaruhi V. Babayan2, Edward S. Bennett3, Fatima R. Khalid1, Frank C. Messineo4, Icilma V. Fergus5; 1Cardiology, Emory University, Atlanta, GA; 2Cardiology, Albert Einstein Montefiore Medical Ctr, Bronx, NY; 3Emergency Medicine, New York Hospital Queens, Flushing, NY; 4Cardiology, Lenox Hill Hospital, New York, NY; 5Cardiology, Harlem Hosp Ctr, New York, NY Background: Hypertension (HT) is associated with LVH, abnormal LV diastolic function and CHF with normal systolic function. Although LV size and function has been characterized in this group, left atrial (LA) size and function have not been well studied. Therefore, we characterized LA size and function in a group of patients with HT, with acute left heart failure and normal systolic function. Methods: Twenty-seven patients with HT and normal EF hospitalized with pulmonary congestion were compared to six normal individuals. LV mass index, LVEF and left atrial volumes and atrial ejection force (AEF) were measured by routine TTE methods. The ratio of peak early filling (E) and atrial filling (A) velocities was determined. Measurements were compared by unpaired t-test with a P value of !0.05 considered significant. Results: The study group consisted of eleven men and sixteen women. The HT group was older (69.5 6 14.7 years vs. 54.3 6 6.9 yrs, p!0.001) and had mean SBP, DBP and PP of 178.6 6 40.8, 90.7 6 20.4 and 58.7 6 15.5 mm Hg, respectively. Symptomatic heart failure (NYHA class II-IV) was present in 77.7% and CAD in 29.6% of the patients. In HT group the LVEF was lower (59 6 5% vs. 65 6 3%, p50.001) and LV mass index was higher (129.35 6 30.78 g/m2 vs.