1 Basic Concepts

Clinical and Research Advances in Cardiovascular Medicine Ion Transport Studies and DynaPulse Technology Prof. Antonio Delgado-Almeida is a world known leader in hypertension research and Ion Transport studies in Cardiovascular Diseases (CVD). His group discovered a genetic defect in erythrocyte K+ uptake and content in hypertensive subjects and half of their normotensive offsprings (Bimodal distribution). In the past 15 years experience with DynaPulse technology, his group was able to describe the central aortic pulse waveform (APW) Type I-IV, PW reflection (PWr) and transit time of reflected waves (TTRW), the later with bimodal expression in healthy adults, independent of weight, height, age or race. Author of the book “Recent advances on DynaPulse Technology in Cardiovascular Diseases” (Nov. 2011), He envisions the future and ultimate goal of the hypertension treatment not only targeting “Normal Blood Pressure ” but also “Normal Hemodynamics” Part of the Research Team 2

Marey´s Sphygmogram for Radial Pulse Tracing and BP (1863) XIX CenturyXX Century Advances Methods for Measuring BP (AHA, above) From Riva-Rocci Concept (1896) to the Noninvasive Central Aortic and Cardiovascular Hemodynamics Arterial Pulse Waveform Analysis by Sphygmocor 3

4 Continuous Pulse Dynamic Recording Our Current Goal in Cardiovascular Medicine Routine Assessment of Central Aortic Pulse Waveform and Cardiovascular Hemodynamics [3] Peak central aortic systolic BP and time for dP/dT [4] Diastole PWr reflexion wave (dot), BP =93 mmHg [1] [1] SupraSystolic phase (Central Aortic PW) followed by systolic, mean and diastolic BPs (flags). Values in right figure, right upper corner [2] Subdiastolic phase for recording of brachial artery flow and hemodynamics [2] [3] [4] Aortic systolic and diastolic reflection waves XXI Century and Beyond Office DynaPulse 200M Study

5 DynaPulse Analysis 200M Healthy White Male (age 53) March 2005 Normal Central Aortic PW and PWr Equivalent Brachial BP 106/75 mmHg Central Aortic BP 114/72 mmHg Aortic Pulse Pressure 42 mmHg PWr 83 mmHg, normal TTRW Cardiovascular Hemodynamics Normal LV dP/dT max., LV Contractility Cardiac Output, SV, SVC, SVR, Brachial Artery Compliance, Distensibility, Resistance and Flow This subject remains normotensive in the next 5-years follow-up Note: The next patient descriptions do not include more complex DP Analysis 5000A for Continuous Ambulatory Hemodynamic 24-hs (CAH24) Our Goal in Cardiovascular Medicine Results: Normal Blood Pressure and CV Hemodynamics Online Pulse Dynamic Results

6 Normotensive females (age 30 year) with different central aortic PW and PWr morphology Top: Healthy white female from normotensive parents, displays normal aortic PW (Type I), end-systolic BP (130 mmHg, large first arrow), PWr in diastole (2 nd arrow) and normal time of reflection waves (248 ms). Bottom: Matched offspring from hypertensive family exhibit rapid PWr (122 ms, type IV, 2 nd arrow) at peak BP (130 mm Hg). Such severe alteration in PWr decreases LV ejection and peak aortic BP (113 mm Hg, first arrow) and coronary flow in diastole (curved arrow). This observation and our finings that nearly (52%) of the normotensive offspring of hypertensive who have PWr abnormalities and defective RBC K+ uptake and content, later develop hypertension after aged 30. This strongly support the need of reassessment of control groups of normotensives and pre-hypertension status in essential hypertension. Office central aortic PW and PWr analysis Detection of a Vascular Marker of Hypertension in Normotensive Individuals Office DynaPulse 200 Studies

7 Resting Pulse Dynamic Study Normal BP (117/74) with aortic PWr (type II) during systole and reflected wave pressure =99 mmHg, dot ) White healthy female (44 y) with previous treatment for severe hypertension DP200M Online CV Hemodynamic Normal CV Hemodynamic except higher SVR expressed by faster PW reflection above Effects of PWr in systole on aortic and CV hemodynamic

8 Same female (44 y) after IHG Test Top: 3 minutes after IHG Test, patient exhibited an extremely altered PW reflection (type IV) with severely increased aortic BPs and HR Left Side: Sharply impaired hemodynamic and severe hypertension, increased PP, LV dP/dT, CI and abrupt decrease SVC, BA Distensibility, and increased SVR. Such acute changes are probably marker of impaired vasodilation (reactive arterial disorder) indicating a stiffer artery system when compared with resting BP and CV hemodynamic Office Pulse Dynamic IHG DP 200M Online Cardiovascular Analysis Severely disturbed central aortic PW, PWr and CV hemodynamic during Isometric Hand Grip test

9 Amiloride and anti-hypertensive treatment (2-years) Same female (44 y) Medial Control Top: Graphic recording of aortic BPs, HR along with physician comments (bottom line) on drug treatment, after entering amiloride trial, from each visit in 2-year follow-up. Here, peak BP (2) corresponds to control IHG test. Excel File: Date and time of recorded aortic and brachial BP, HR along with results from 21 CV hemodynamic parameters. At office, physicians and research investigators may evaluate the statistic trends in any selected CV parameter. Further, Excel table would make easy follow-up of patients in clinical trials. Excel Cardiovascular Hemodynamics Central aortic & CV hemodynamics statistical

10 Therapeutic approach addressing aortic BP PWr and CV hemodynamics DP 200M Online Cardiovascular AnalysisResting Basal DP 200 Study (1) White female (67 y) with severe hypertension, angina, dyspnea, and markedly impaired RBC K- uptake, despite multiple drugs treatment Top: PWr type IV, restricting LV ejection & systolic aortic PW, while decreasing effective pressure for coronary perfusion Right Side: Remarkable higher brachial BP (192/96) with disturbed CV hemodynamics (LV dP/dt, low arterial compliances and high vascular resistances) at rest, despite lower HR =67.

11 Patient control in one month (2)Online Hemodynamic Results Top: Improved aortic BP and PWr (type II) and higher mean diastole pressures after the amiloride. Patient was freedom of angina, dyspnea and red blood cell K+ content improved. She required low doses of nitrates and of anti-hypertensive drugs. Right site: Clinical improvement was not a reliable index of normal CV hemodynamic. Indeed, LV dP/dT, vascular compliances and brachial distensibility were disturbed for the next 6-months (data not showed) Rapid improved erythrocyte K+ and CV hemodynamics Novel Physiological Approach with Amiloride

12 Hispanic male (64 y) hypertensive diabetic with previous inferior wall infarction, and angina (CCS class III) with serial aortic PP, PWr, BP & CV hemodynamic (not showed). Before Amiloride: Data from Feb-Sep 2000 (Row 1) had marked alteration in aortic PWr (type IV), higher BP, disturbed CV hemodynamics in IHG. After Amiloride: Row 2 (02/23/2001) No angina, low aortic BP, unchanged PWr and hemodynamic by IHG. Anginal episodes. Row 3:(03/07/2002) Patient freedom of angina, normal aortic BP and PWr type II despite no other anti-hypertensive drugs. Improved response in aortic BP and CV hemodynamics during IHG test. Row 4: (June 2003) Normal aortic BP and hemodynamic in resting and IHG, except PWr (IV) with IHG probably related to age. Asymptomatic without angina, requiring no nitrates. Office Resting Pulse Dynamic Office Pulse Dynamic after IHG3-minutes IHG Test Reversed vascular response to IHG by Amiloride Endothelial-Dependent Vasodilatation in Hypertension

HEALTHY POPULATION Normal Adolescent and Children Evaluation of vascular (aortic PWr changes) and blood (low RBC K+) phenotypes for hypertension and CVD, especially offspring of hypertensive parents or family CVD history Healthy Adult Population Recording and sustained normal central aortic BP, PWr and cardiovascular hemodynamic Epidemiological Study Redefinition of risk factors and control groups in hypertensive and cardiovascular diseases HYPERTENSION and CVD DISEASES Hypertension and CVD Routine and follow-up studies of RBC K+ along with aortic PW, PWr and CV hemodynamics Treated hypertension and CVD Serial follow-up evaluation of drug effects on RBC K+ and the isometric Hand-Grip test Pharmacology for Hypertension and CVD Novel drug or compounds addressing to improve vasodilatation and microcirculation status, since a large number of drugs may decrease high BP or improving angina, but none is able to avoid sharply increased BP episodes, or recurrence of angina, arrhythmias triggered by some vasomotor or still unknown factors. 13 Our Goals in Cardiovascular Medicine Principles for Cardiovascular Medicine in XXI Century