Relevance of sympathetic overactivity in hypertension and heart failure Therapeutic Implications Uta C. Hoppe, MD, FESC Dep. of Internal Medicine II Paracelsus University Salzburg Austria
Disclosures Within the past 12 months, I have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company 1. Honoraria for lectures Astra, Bayer, Berlin Chemie, CVRx, Medtronic, Sanofi Aventis, Servier 2. Honoraria for advisory board activities Medtronic, Servier 3. Participation in clinical trials Ardian, Bosten Scientific, Boston, Braun, Cardiac Dimension, CVRx, Medtronic, Novartis, Remon, Sanofi- Aventis, Servier, Vessix Vascular 4. Research funding DFG, BMBF, ZMMK, Köln Fortune, Cardiac Dimension
Medical therapy in systolic heart failure Key role of sympathetic and neurohumoral blockade possibly Digitalis Aldosterone antagonist Diuretics Beta-Blockers ACE inhibitors or Angiotensine receptor blockers NYHA I NYHA II NYHA III NYHA IV ESC guidelines 212
Pentagram of antihypertensive drug combinations Diuretics Betablocker * Calcium channel blocker AT 1 -Antagonist ACE-Inhibitor Combination synergistic Combination possible * Combination for Dihydropyridine only Leitlinien zur Diagnostik und Behandlung der arteriellen Hypertonie 29; Dt. Hochdruckliga e.v. DHL - Deutsche Hypertonie Gesellschaft
Therapy-refractory arterial Hypertension - No achievement of target BP values - Exclusion of secundary hypertension - Adequate live stile modification - 3 antihypertensive drugs (including diuretics) - Approximately 8% of all hypertensive patients
Renal Denervation by catheter ablation
Reduction of systemic sympathetic Activity MSNA of patient with resistant Hypertension Baseline 1 M FU 12 M FU ECG 2 BP 15 1 5 161/17 mmhg 141/9 mmhg 127/81 mmhg MSNA 1 sec 56 bursts/min 41 bursts/min 19 bursts/min Improvement in cardiac baroreflex sensitivity after renal denervation (from 7.8 to 11.7msec/mmHg). Schlaich et al. NEJM 29;361:932
NA Spillover (ng/min) Effect of renal Denervation on renal and total Noradrenalin spillover NA Spillover (ng/min) Total renal NA spillover Total body NA spillover 1 9 8 7 6 5 4 3 2 1 Mean office BP 161/17 141/9 Baseline - 47% p=.23 3 d post bilat. Denervation Left kidney Right kidney 8 7 6 5 4 3 2 1 Baseline -28% p=.43 3 d post bilat. Denervation Schlaich et al. NEJM 29;361:932
Change of office BP after 6 months (mmhg) Renal Denervation by catheter ablation n=16; SBP 16 mmhg, 3 antihypertensive drugs, egfr of 45 ml/min/1.73m 2 Change of Office Blood Pressure after 6 months 1 - - 1-1 - -2 - P<.1-12 -3 - -4 - -5 - -32 Systolic BP Renal Denervation Control Diastolic PB Esler et al. Lancet 21;376:193
Renal Denervation: Office Blood Pressure Change Maintained Blood Pressure Reduction over Time BP change (mmhg) Krum et al., ACC 212; Krum et al., Lancet 29;373;1275
Change from baseline to 3 months (mmhg) Cardiorespiratory Response to Exercise after RD Change of Blood Pressure at rest, maximum work rate and recovery RD (n=37) Control (n=9) SBP at rest DBP at rest SBP at peak work DBP at peak work SBP at recovery DBP at recovery Increase in max. work rate by 5 ± 13 W after RD Ukena et al. JACC 211;58:1176-82
Cardiorespiratory Response to Exercise after RD % of maximum work rate Ukena et al. JACC 211;58:1176-82
Change from baseline to 3 months (bpm) Change of heart rate (bpm) Cardiorespiratory Response to Exercise after RD Change of Heart rate at rest, maximum work rate and recovery Chronotropic reserve after RD Baseline 3 months after RD RD (n=37) Control (n=9) HR at rest Peak HR HR recovery 91% of pts. on beta-blockers % of maximum work rate Ukena et al. JACC 211;58:1176-82
Sympathetic Overactivity in arterial Hypertension and Heart Failure Baroreflex Hypertrophy Heart Failure Vasoconstriction Renin Na + /Volumen GFR
Baroreflex Activation Baroreflex- Stimul.-Sonden Implantierbarer Pulsgenerator
DEBuT 4-year Blood Pressure Reduction
Baseline BP or HR (mmhg or bpm) Change in BP or HR (mmhg or bpm) Barostim neo Trial Baseline BP or HR 3-month change of BP or HR by Baroreflex Activation SBP DBP HR SBP DBP HR History of RD (n=6) No History of RD (n=24) Hoppe et al. J Am Soc Hypertens. 212;6:27-6
Cardiovasc. Events (per 1 pts. years) Total Mortality (per 1 pts. years) Left ventricular mass - Prognosis Cardiovascular Events Total Mortality 5-1.5-4 - 3-1 - 2-1 -.5 - - - 1 2 3 4 5 1 2 3 4 5 LV Mass-Index (Quintile) LV Mass-Index (Quintile) n=1925 Follow-up 4 years Schillaci et al, Hypertension 2
Effect of BP Reduction on LV Hypertrophy Dependence on treatment [%] -2-4 Meta-Analysis AT1 Receptor- Antagonist CA-Antagonist -6-8 -1-12 -11-1 -8-6 ACE-Inhibitor Diuretic Beta-Blocker -14-13 Klingbeil et al. Am J Med 23; 115: 41-46
LVMI (g/m 2.7 ) IVSTd (mm) Regression of LV Hypertrophy after RD Resistant Hypertension; on average 4.7 antihypert. drugs: 46 pts. bilateral RD vs.18 pts. control LV mass index Interventricular septum thickness 8 7 p=.1 p<.1 p=.64 p=.81 p=.7 2 18 p=.5 p=.9 6 16 p=.855 p=.337 p=.1 5-17% 14 4 12 3 1 Baseline 1 Month 6 Months RD Baseline 1 Month 6 Months Control Brandt et al. JACC 212;59:91-99
LVMI-Reduction (Δg/m 2.7 ) Regression of LV Hypertrophy after RD Resistant Hypertension; on average 4.7 antihypert. drugs: 46 pts. bilateral RD vs.18 pts. control Reduction of LV mass index 5 1 Month 6 Months -5-1 LVH no LVH -15 p=.8-2 p=.9 Brandt et al. JACC 212;59:91-99
LV Mass Index (g/m 2 ) Regression of LVH by Baroreflex Activation Reduction of LV Mass Index 12 115 11 117 p-value <.1 15 1 12 95 9 N = 6 Baseline N = 6 12 Months Bisognano et al. JACC 2112;57:1787
Mortality % Diastolic Dysfunction - Prognosis 25 - Total Mortality 2-15 - 1 - P<.1 moderate/severe diast. dysfunction mild dysfunction 5 - normal - 1 2 3 4 5 Years Schillaci et al, Hypertension 2
Mitral valve lateral E/E' Mitral valve lateral E/E' reduction Renal Denervation improves Diastolic Dysfunction Resistant Hypertension; on average 4.7 antihypert. drugs: 46 pts. bilateral RD vs.18 pts. control Intracardiac diastolic pressure 16 p<.1 p=.6 1 1 Month 6 Months 14 p=.329 p<.1 p<.1 12-1 1 8-2 -3-4 6-5 Baseline 1 Month 6 Months -6 p<.1 p=.13 RD Control Baseline lat. E/É < Median Baseline lat. E/É > Median Brandt et al. JACC 212;59:91-99
Mitral valve lateral E/E' Renal Denervation improves Cardiac Function Resistant Hypertension; on average 4.7 antihypert. drugs: 46 pts. bilateral RD vs.18 pts. control Intracardiac diastolic pressure Systolic function 16 14 12 1 p<.1 p=.6 p=.329 p<.1 p<.1 LVEDV 32.8±15.6 ml 25.6±12.5 ml @ 6 months after RD; p=.1 8 6 Baseline 1 Month 6 Months RD Control LV-EF 63.1±8.1 % 7.1±11.5 % @ 6 months after RD; p=.1 Brandt et al. JACC 212;59:91-99
Regression of LV Hypertrophy and Improvement of Cardiac Function after RD Potential Mechanisms - Blood pressure reduction per se - Direct sympatholytic effects on cardiomyocytes and fibrosis - Indirect effects on cardiomyocytes and cardiac matrix via metabolic modulation
Percentage of individuals Prevalence of Insulin Resistance in Hypertension Insulin sensitive intermediate resistant 39% 34% 47% 52% Untreated hypertension (n=56) Treated hypertension (n=7) 14% 14% <96 96-18 >18 Steady-state plasma glucose (SSPG, mg/dl) during the insulin suppression test Lima et al. Am J Hypertens 29;22:16
Change in fasting glucose (mg/dl) Change in fasting C-peptide (ng/ml) Change in fasting glucose (mg/dl) Change in fasting C-peptide (ng/ml) Effect of renal Denervation on Glucose Metabolism Change in fasting insulin (µiu/ml) Change in HOMA-IR (ng/ml) Change in fasting insulin (µiu/ml) Change in HOMA-IR (ng/ml) A A Change in fasting glucose (mg/dl) 17.5 17.5 12.5 12.5 7.5 7.5 2.5 2.5-2.5-2.5-7.5-7.5-12.5-12.5-17.5-17.5 A A Change in fasting glucose (mg/dl) 1 month 1 month 3 months 3 months 17.5 1 month 1 month 3 months 3 months Fasting glucose B 17.5 p=.589 p=.589 15 12.5 p=.589 15 p=.589 p=.177 p=.177 12.5 1 p=.177 p=.177 7.5 1 7.5 5 2.5 +4.6 +4.6 +5.1 +5.1 5 2.5 +4.6 +4.6 +5.1 +5.1-2.5-2.5-9.7-9.7-12. -12. -7.5-9.7-9.7-12. -12. -5-5 -7.5-12.5 Renal denervation Renal denervation (n=35) (n=35) -1 p=.7 Renal Control denervation (n=15) (n=35) -12.5 p=.7 Renal Control denervation (n=15) (n=35) -1 p=.7-17.5 p=.7 p=.4 p=.4 Control (n=15) Control (n=15) -15 p=.4-17.5 p=.4-15 B Change in fasting insulin (µiu/ml) B B Change in fasting insulin (µiu/ml) 1 month 1 month 3 months 3 months 1 monthp=.343 1 monthp=.343 3 months 3 months 15 p=.343 p=.343 15 1 1 5 +7.9 +7.9 p=.927 p=.927 5 +7.9 +7.9 +1.1p=.927 +1.1p=.927 +1.1 +1.1-8.7-8.7-9.2-9.2-5 -8.7-8.7-9.2-9.2-5 -1-1 p=.42 p=.42-15 -15 Insulin Renal denervation Renal denervation (n=35) (n=35) Renal Control denervation (n=15) (n=35) p=.42 Renal Control denervation (n=15) (n=35) p=.3 p=.3 p=.42 Control (n=15) Control (n=15) p=.3 p=.3 C C Change in fasting C-peptide (ng/ml) 2. 2. 1.5 1.5 1. 1..5.5.. -.5 -.5-1. -1. -1.5-1.5-2. -2. -2.5-2.5-3. -3. -3.5-3.5-4. -4. C C Change in fasting C-peptide (ng/ml) 1 month 1 month 3 months 3 months 1 monthp=.356 1 monthp=.356 3 months 3 months D 2. p=.356 C-Peptide p=.356 D 5 2. 5 1.5 4 1.5 1. p=.815 p=.815 4 +1.1 3 1. +1.1 p=.815.5 p=.815 +1.1 +1.1 +.2 +.2 3.5 2. +.2 +.2 2 -.5. 1 -.5 1-1. -1. -2.2-2.2-2.4-2.4-1.5-2.2-2.2-2.4-2.4-1 -1.5-2. -1 Renal denervation (n=35) -2-2. Renal denervation (n=35) -2.5 Renal Control denervation (n=15) Renal denervation (n=35) (n=35) -2 Control (n=15) -2.5-3 -3. Control (n=15) Control (n=15) p=.22-3 -3. p=.22 p=.5 p=.5-3.5-4 p=.22 p=.22 p=.5 p=.5-3.5-4 -4. -5-4. -5 Change in HOMA-IR (ng/ml) D D Change in HOMA-IR (ng/ml) Insulin sensitivity index 1 month 1 month 3 months 3 months 5 1 month 1 month 3 months 3 months 5 p=.246 p=.246 4 p=.246 p=.246 4 3 3 2 2 +2.1 +2.1 p=.962 p=.962 1 +2.1 +2.1 p=.962 1 +.3 +.3p=.962 +.3 +.3-3. -1-3. -3.1-3.1-3. -1-2 -3. -3.1-3.1-2 -3 Renal denervation Renal denervation (n=35) (n=35) Renal Control denervation (n=15) (n=35) -3 Renal Control denervation (n=15) (n=35) -4 Control (n=15) p=.23-4 p=.1 Control (n=15) p=.23 p=.1 p=.23-5 p=.23 p=.1 p=.1-5 Mahfoud et al. Circulation 211;123:194
Patients (%) Effect of RD on Glucose Metabolism Renal denervation (n=37) Control group (n=13) 1 9 8 7 6 5 4 3 2 1 14% 54% 32% n=3 n=4 6% 51% 43% 23% 46% 31% n=2 n=1 38% 38% 24% Diabetes IGT, IFG, or both NGT Baseline 3 months Baseline 3 months Mahfoud et al. Circulation 211;123:194
Total mortality % ASCOT-BPLA - study 19257 pts., atenolol±thiazide-based vs. amlodipine±perindopril-based therapy 1. 8. 6. 4. 2. p =.247 Total Mortality Atenolol Thiazide (82 Events) Amlodipine Perindopril (738 Events).. 1. 2. 3. 4. 5. Years Terminated prematurely Dahlöf et al., Lancet 25; 366: 895-96
Effect of Central Hemodynamics on Outcome Risk for 1 mmhg increase of central Pulse Pressure and cardiov. Events Risk for 1% increase of central Alx and total Mortality Vlachopoulos et al., Eur Heart J 21;31:1865
Pressure (mmhg) Pressure (mmhg) Conduit Artery Function Evaluation (CAFE) study 2199 pts., atenolol±thiazide-based vs. amlodipine±perindopril-based therapy Peripheral pulse waveforms Central aortic waveforms Time (sec) Time (sec) equivalent brachial blood pressure reduction Williams et al. Circulation 26;113:1213
Conduit Artery Function Evaluation (CAFE) study 2199 pts., atenolol±thiazide-based vs. amlodipine±perindopril-based therapy Effect of therapy on Systolic BP: peripheral vs. central Williams et al. Circulation 26;113:1213
Conduit Artery Function Evaluation (CAFE) study 2199 pts., atenolol±thiazide-based vs. amlodipine±perindopril-based therapy Effect of therapy on Pulse Pressure: peripheral vs. central Williams et al. Circulation 26;113:1213
Peripheral BP (mmhg) Central aortic BP (mmhg) Effect of RD on peripheral & central aortic waveforms Peripheral pulse waveforms Central aortic waveforms 18 17 16 15 14 Baseline 1 Month 16 15 14 13 AP Baseline 1 Month 13 12 11 1 9 12 11 1 9 AP 8 25 5 75 1 Time (ms) 8 25 5 75 1 Time (ms) Applanation tonometry (SphygmoCor) Brandt et al. JACC 212 in press
Central systolic BP (mmhg) Central PP (mmhg) Effect of RD on central blood pressure Resistant Hypertension; on average 4.8 antihypert. drugs: 11 pts. bilateral RD vs.1 pts. control Central systolic blood pressure Central Pulse Pressure 22 2 18 p=.773 p<.1 p<.1 p=.14 p<.1 p<.1 p<.1 12 1 p=.753 p<.1 p<.1 p=.24 p<.1 p<.1 p<.1 16 8 14 12 6 1 Baseline 1 Month 3 Months 6 Months Baseline 1 Month 3 Months 6 Months RD, n=11 Control, n=1 Brandt et al. JACC 212 in press
Augmentation pressure (mmhg) Augmentation index @75 (%) Effect of RD on Augmentation Pressure Resistant Hypertension; on average 4.8 antihypert. drugs: 11 pts. bilateral RD vs.1 pts. control Augmentation Pressure Augmentation Index 5 45 4 35 p<.1 p=.1 p=.3 p=.287 p=.3 p<.1 p<.1 4 35 3 p<.1 p<.1 p=.56 p=.41 p=.47 p=.24 p=.2 3 25 25 2 15 2 15 Baseline 1 Month 3 Months 6 Months Baseline 1 Month 3 Months 6 Months RD, n=11 Control, n=1 Brandt et al. JACC 212 in press
PWV reduction (m/s) Effect of RD on Arterial Stiffness Resistant Hypertension; on average 4.8 antihypert. drugs: 11 pts. bilateral RD vs.1 pts. control Pulse wave velocity Total RD group PWV cf > 9.6 m/s PWV cf > reference -1-2 p=.53-3 -4 p=.2 p=.1 p=.1 p<.1 p<.1-5 1 Month 3 Months 6 Months p=.2 p=.2 p=.4 Brandt et al. JACC 212 in press
Relevance of sympathetic overactivity - Beta-blockade is an established treatment in heart failure and hypertension - Renal denervation (RD) or Baroreflex activation significantly reduce peripheral BP and LV-Hypertrophy - RD has the potential to improve diastolic and systolic function - RD has benefical effects on glucose metabolism - RD improves central hemodynamics (seems to be distinct vs. Beta-blockers) - Mortality studies are warrented Therapeutic Implications
Relevance of sympathetic overactivity in hypertension and heart failure Therapeutic Implications Uta C. Hoppe, MD, FESC Dep. of Internal Medicine II Paracelsus University Salzburg Austria
Renale Denervierung Hypertonus und andere Indikationen Uta C. Hoppe Dep. of Internal Medicine II Paracelsus University Salzburg Austria