JACC: HEART FAILURE VOL. -, NO.

-, 2017
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 2213-1779/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jchf.2017.04.012

STATE-OF-THE-ART PAPER

The Transition From Hypertension

to Heart Failure
Contemporary Update

Franz H. Messerli, MD,a,b,c Stefano F. Rimoldi, MD,a Sripal Bangalore, MDd

ABSTRACT

Longstanding hypertension ultimately leads to heart failure (HF), and as a consequence most patients with HF have a
history of hypertension. Conversely, absence of hypertension in middle age is associated with lower risks for incident
HF across the remaining life course. Cardiac remodeling to a predominant pressure overload consists of diastolic
dysfunction and concentric left ventricular (LV) hypertrophy. When pressure overload is sustained, diastolic dysfunction
progresses, filling of the concentric remodeled LV decreases, and HF with preserved ejection fraction ensues. Diastolic
dysfunction and HF with preserved ejection fraction are the most common cardiac complications of hypertension. The end
stage of hypertensive heart disease results from pressure and volume overload and consists of dilated cardiomyopathy
with both diastolic dysfunction and reduced ejection fraction. “Decapitated hypertension” is a term used to describe the
decrease in blood pressure resulting from reduced pump function in HF. Progressive renal failure, another complication
of longstanding hypertension, gives rise to the cardiorenal syndrome (HF and renal failure). The so-called Pickering
syndrome, a clinical entity consisting of flash pulmonary edema and bilateral atheromatous renovascular disease, is a
special form of the cardiorenal syndrome. Revascularization of renal arteries is the treatment of choice. Most
antihypertensive drug classes when used as initial therapy decelerate the transition from hypertension to HF, although
not all of them are equally efficacious. Low-dose, once daily hydrochlorothiazide should be avoided, but long-acting
thiazide-like diuretics chlorthalidone and indapamide seem to have an edge over other antihypertensive drugs in
preventing HF. (J Am Coll Cardiol HF 2017;-:-–-) © 2017 by the American College of Cardiology Foundation.

M ost longstanding hypertension ultimately

leads to heart failure (HF) unless this
sequence of events is otherwise interrup-
ted by other outcome and as a consequence, patients
with HF very commonly have a history of hyperten-
sion. In the Framingham Heart Study cohort in a total
population of 5,143 subjects, hypertension antedated
the development of HF in 91% of all newly diagnosed
HF patients during up to 20 years of follow-up
(mean 14.1 years) (1). Adjusting for age and HF risk
factors, the hazard for developing HF in hypertensive
compared with normotensive subjects
Framingham Heart Study data was about 2-fold in
men and 3-fold in women. Multivariable analyses
revealed that hypertension had a high population-
attributable risk for HF, accounting for 39% of cases
in men and 59% in women. Among hypertensive sub-
jects, myocardial infarction, diabetes, left ventricular
(LV) hypertrophy, and valvular heart disease pre-
dicted an increased risk for HF in both sexes. At
80 years of age, the lifetime risk of HF was about 20%
in the Framingham cohort, and this risk doubled for
patients with blood pressure (BP) of 160/100 mm Hg
in the compared with those with 140/90 mm Hg (2).

From the aDepartment of Cardiology and Clinical Research, Inselspital, Bern University Hospital, Bern, Switzerland; bMount Sinai
Health Medical Center, Icahn School of Medicine, New York, New York; cJagiellonian University, Krakow, Poland; and the dLeon
H. Charney Division of Cardiology, New York University School of Medicine, New York, New York. Dr. Messerli has served as a
consultant for Daiichi-Sankyo, Pfizer, Servier, WebMD, Ipca, ACC, Menarini, and Sandoz. Dr. Rimoldi has served as a consultant for
Servier, Menarini, and Takeda. Dr. Bangalore has reported that he has no relationships relevant to the contents of this paper to disclose.

Manuscript received January 7, 2017; revised manuscript received April 19, 2017, accepted April 19, 2017.
2 Messerli et al.
Transition From Hypertension to HF
ABBREVIATIONS Not surprisingly, prevention of hyperten-
AND ACRONYMS sion and other HF risk factors such as obesity
and diabetes during middle age substantially
ARAS = atheromatous renal
artery stenosis
prolongs HF-free survival. Men and women
without hypertension, obesity, or diabetes at
ACE = angiotensin-converting
45 years of age lived on average 34.7 years
enzyme
and 38.0 years without incident HF, and they
ARB = angiotensin receptor
blocker lived on average an additional 3 to 15 years
BP = blood pressure longer free of HF than did those with 1, 2,
CCB = calcium-channel blocker or 3 risk factors (3). Thus, the absence of
CI = confidence interval hypertension, obesity, and diabetes by 45
CRS = cardiorenal syndrome
and 55 years of age is associated with up
to 86% lower risks for incident HF in men
CRT = cardiac
and women across the remaining life
resynchronization therapy
course. Importantly, the 22-year follow up of
HF = heart failure
the SHEP (Systolic Hypertension in the
HFpEF = heart failure with
preserved ejection fraction Elderly Program) trial documented that
compared with placebo, each month of
HFrEF = heart failure with
reduced ejection fraction active chlorthalidone-based antihypertensive
LV = left ventricular therapy during the trial period of 4.5 years
RR = risk ratio was associated with 1-day prolongation of
life expectancy free from cardiovascular
SBP = systolic blood pressure
death (4).
PATHOPHYSIOLOGY
In most hypertensive patients LV diastolic dysfunc-
tion is the first discernible manifestation of heart
disease (Figure 1). Cardiac remodeling to a predomi-
nant pressure overload consists of concentric LV
hypertrophy (increase in cardiac mass at the expense
of chamber volume). In contrast, cardiac remodeling
to a predominant volume overload (e.g., obesity,
chronic kidney disease, anemia) consists of eccentric
hypertrophy (increase in cardiac mass and chamber
volume) (5). When pressure overload is sustained,
diastolic dysfunction progresses, the concentric
remodeled LV decompensates, and hypertensive
HF with preserved ejection fraction (HFpEF) ensues.
In contrast, when volume overload is sustained,
LV dilatation progresses, the eccentric remodeled
LV decompensates, and HF with reduced ejection
fraction (HFrEF) ensues. The combination of LV
hypertrophy with increased levels of biomarkers
of subclinical myocardial injury (high-sensitivity
cardiac troponin T, N-terminal pro–B-type natriuretic
peptide) identifies patients at highest risk for devel-
oping symptomatic HF, especially HFrEF (6). The
end stage of hypertensive heart disease, usually the
result of longstanding pressure and volume overload,
consists of dilated cardiomyopathy with both dia-
stolic dysfunction and reduced ejection fraction.
From a clinical point of view hypertensive heart
disease can be divided into 4 ascending categories,
JACC: HEART FAILURE VOL. -, NO. -, 2017
- 2017:-–-
based on the pathophysiologic and clinical impact of
hypertension on the heart:
Degree I: Isolated LV diastolic dysfunction with no
LV hypertrophy
Degree II: LV diastolic dysfunction with concentric
LV hypertrophy
Degree III: Clinical HF (dyspnea and pulmonary
edema with preserved ejection fraction)
Degree IV: Dilated cardiomyopathy with HF and
reduced ejection fraction (7)
The categories would indicate that diastolic
dysfunction is a much more common complication of
longstanding hypertension than is systolic dysfunc-
tion. Patients with HFpEF have more LV hypertrophy,
epicardial coronary artery lesions, coronary micro-
vascular rarefaction, and myocardial fibrosis than do
control subjects. Coronary microvascular dysfunction
may conceivably be the result of a systemic inflam-
matory state and oxidative stress accelerated by
comorbidities of HFpEF (8,9). Importantly, isolated
diastolic dysfunction also can trigger pulmonary
edema, as was documented by Gandhi et al. (10). They
found LV ejection fraction during an episode of acute
hypertensive pulmonary edema to be similar to the
one measured after treatment, when the BP had been
controlled. In these patients systolic BP (SBP) was
200
26 mm Hg during the initial echocardiographic
examination and reduced to 139
17 mm Hg at the
time of the follow-up examination. Thus, a normal LV
ejection fraction after the treatment of a patient with
hypertensive pulmonary edema allows us to conclude
that the pulmonary congestion was due to isolated,
transient diastolic dysfunction. Transient systolic
dysfunction with or without mitral regurgitation
seemed to be infrequent during acute episodes in
these patients (10).
DECAPITATED HYPERTENSION
In advanced HF SBP is usually low, even in patients
who were previously hypertensive. This phenomenon
is termed “decapitated hypertension”: patients
who are hypertensive to begin with progressively
develop normal and even low BP as HF becomes more
severe. Severe LV dysfunction can be a powerful
antihypertensive mechanism. The decrease in SBP
results from reduced pump function and fall in
cardiac output despite the presence of compensatory
mechanisms such as peripheral vasoconstriction.
Patients with decapitated hypertension are difficult
to manage because of their inability to tolerate HF
medications, most of which tend to lower BP, such as
JACC: HEART FAILURE VOL. -, NO. -, 2017
- 2017:-–-
F I G U R E 1 Staging of Hypertensive Heart Disease
LV ¼ left ventricular.
angiotensin-converting enzyme (ACE) inhibitors or
angiotensin receptor blockers (ARBs), diuretics, and
beta-blockers.
This interplay among high BP, hypertensive HF,
and dilated cardiomyopathy (i.e., the phenomenon of
decapitated hypertension) was lucidly discussed by
Celia Oakley (11) about 4 decades ago: “The develop-
ment of left ventricular failure because of hyperten-
sion determines a decrease of the previously raised BP
to normal levels and, since the failure usually persists,
the BP remains normal (11). If the patient recovers
from HF, then the BP rises and the diagnosis is likely to
be ‘hypertension.’ In other words, the ‘diagnosis”
varies between dilated cardiomyopathy and
hypertension according to left ventricular function
and only if a patient with dilated cardiomyopathy,
HF actually recovers and develops high BP can the
causal or conditioning role of high BP be proved.”
We evaluated this hypothesis in a meta-analysis
and were able to document that in patients with HF
who underwent cardiac resynchronization therapy
(CRT) an increase in BP occurred. (12). CRT improves
cardiac function by reverting asynchronous mechan-
ical events, especially in patients with a wide QRS
complex or with echocardiographic dyssynchrony.
Messerli et al. 3
Transition From Hypertension to HF
In analyzing 18 studies we showed that CRT resulted
in an increase in SBP by about 4 mm Hg, no change in
diastolic blood pressure and an increase in pulse
pressure compared with baseline or medical therapy.
In a recent study by Tanaka et al. (13), an increase in
SBP after CRT was associated with a decrease in
the combined endpoint of HF hospitalization and
all-cause mortality.
BP IN HF PATIENTS
Although hypertension is well known to trigger inci-
dent HF, higher SBP in patients with established HF
seems to paradoxically have a protective effect on
survival. Numerous studies have shown that in pop-
ulations with HF, high SBP is associated with im-
proved, not adverse, outcomes (14–20) and this holds
true for both acute (14–17) and chronic (18,19) HF. A
retrospective study examining 2,289 patients from the
COPERNICUS (Carvedilol Prospective Randomized
Cumulative Survival) trial by Rouleau et al. (21) found
that the lower the pretreatment SBP of patients in the
cohort is, the higher the risk is of a major clinical event.
For each 10-mm Hg decrease in the pretreatment SBP
there was an 18% increase in the risk of death, 11%
4 Messerli et al.
Transition From Hypertension to HF
increase in the combined risk of death or hospitaliza-
tion for HF, and 9% increase in the combined risk of
death or hospitalization for any reason.
The increase in central BP occurring with beta-
blockade may be an additional reason for the benefi-
cial effect of this drug class in HF. McAlister et al. (22)
reported that the magnitude of heart rate reduction
(which is indirectly proportional to the increase in
central pressure) is associated with the survival
benefit of beta-blockers in HF. The same phenome-
non may be responsible for the benefits of heart rate
lowering with ivabradine in patients with HF in the
SHIFT (Systolic Heart failure treatment with the lf
inhibitor ivabradine) trial (23). As discussed, in many
patients with HF SBP is low, often critically so. In this
situation, an increase in central pressure secondary to
heart rate lowering as has been documented with
ivabradine (24) may turn out to be beneficial. The
decrease in cardiac workload with ivabradine is likely
to override a potentially detrimental effect, if any, of
a higher central systolic pressure. In contrast to
hypertension, where heart rate lowering has been
documented to progressively increase cardiovascular
mortality, in HF there is an inverse correlation
between resting heart rate and outcome (22,25).
CARDIORENAL SYNDROME
Both the heart and the kidney are target organs in
hypertension and their function and structure
becomes progressively impaired with longstanding
hypertensive cardiovascular disease. Not surpris-
ingly, therefore HF and renal failure commonly occur
in the same patient as a sequence of hypertension.
Cardiorenal interactions occur in both directions
and by a variety of mechanisms (26). The different
interactions that can take place between heart and
kidney have been thoroughly classified by Ronco
et al. (27). In HF the most common types of car-
diorenal syndrome (CRS) are:
Type 1 (acute): Acute HF leading to acute kidney
injury (renal failure)
Type 2 (chronic): Chronic HF leading to progres-
sive chronic kidney disease
Type 3: Acute, worsening of kidney function
leading to HF
Type 4: Progressive primary chronic kidney
disease leading to HF
From a clinical point of view the occurrence of
renal failure in HF, regardless of the exact CRS type,
greatly complicates all therapeutic strategies. As
chronic kidney disease progresses the prevalence of
JACC: HEART FAILURE VOL. -, NO. -, 2017
- 2017:-–-
HF increases and vice versa. The increase in comor-
bidities, as well as on the need for incremental ther-
apies, enhances the risk of hyperkalemia. From a
clinical point of view the presence of CRS drastically
limits the therapeutic armamentarium in HF patients.
Conceivably a treatment strategy with the newly
available Kþ binders in conjunction with a mineral-
ocorticoid antagonist will help to reduce CV mortality
and morbidity in HF (28).
PICKERING SYNDROME
In 1988 Pickering et al. (29) reported a series of 11
hypertensive patients with bilateral atheromatous
renal artery stenosis (ARAS) who presented with a
history of multiple episodes of flash pulmonary
edema (FPE). The clinical entity of FPE and bilateral
ARAS, now known as Pickering syndrome (30), has to
be classified as CRS type 3. Patients with Pickering
syndrome most commonly present with severely
impaired LV filling and LV hypertrophy but may have
normal or only mildly impaired LV systolic function.
This, together with defective natriuresis secondary to
bilateral ARAS, is the main pathogenetic mechanism
leading to FPE (Figure 2). The fact that flooding of the
alveolar space can occur within minutes resulting in
an acute life-threatening emergency is what distin-
guishes FPE from other forms of decompensated HF
(31). Regardless of its etiology, an acute increase of
the LV end-diastolic pressure is the common de-
nominator for the development of FPE (Figure 2). The
presence of recurrent FPE, lack of typical angina,
increased BP, and elevated creatinine should raise the
suspicion of bilateral ARAS and hence Pickering syn-
drome as a possible etiology for FPE. In the series
described by Pickering et al., FPE occurred on average
2.3 times before the diagnosis of ARAS was made, and
in our study (21) three-quarters of all patients had
more than 1 episode of FPE. Classically, these patients
have some degree of renal failure and present with
sudden onset of severe unprovoked dyspnea (“flash”
pulmonary edema). The frequent nocturnal appear-
ance of FPE may be related to reverse nocturnal BP
dipping, a phenomenon that has been well docu-
mented in patients with ARAS.
Acute management of FPE is aimed at maintaining
adequate oxygenation, diuresis, decrease of pulmo-
nary capillary pressure, and treatment of underlying
cause. However, aggressive treatment of FPE in
patients with bilateral ARAS usually will cause a
further decrease of glomerular filtration rate and
hyperkalemia may ensue. Renal revascularization is
the treatment of choice once the patient is stable
and FPE has been resolved. The American Heart
JACC: HEART FAILURE VOL. -, NO. -, 2017 Messerli et al. 5
- 2017:-–- Transition From Hypertension to HF

F I G U R E 2 Pickering Syndrome

Three main pathophysiological mechanisms contribute to the development of flash pulmonary edema: 1) defective pressure natriuresis with
sodium and fluid retention; 2) increased left ventricular end-diastolic pressure (LVEDP) associated with left ventricular hypertrophy and
stiffening; and 3) failure of the pulmonary capillary blood–gas barrier. BP ¼ blood pressure; HFpEF ¼ heart failure with preserved ejection
fraction; HFrEF ¼ heart failure with reduced ejection fraction; RAS ¼ renal artery stenosis.

Association/American College of Cardiology guide-
lines endorse revascularization as a class 1 recom-
mendation for patients with hemodynamic significant
ARAS and recurrent unexplained congestive HF or
pulmonary edema (32). In our analysis, 92% of all pa-
tients had no further FPE after revascularization. (30)
Patients with recurrent FPE after renal artery stent-
ing should have repeat Doppler ultrasound of the
kidneys to rule out recurrent ARAS due to restenosis.
ANTIHYPERTENSIVE THERAPY
FOR HF PREVENTION
By definition, all antihypertensive drugs lower BP.
However, scrutinizing the literature reveals that
not all antihypertensive drugs are created equal in
their propensity to prevent HF. b -Blockers remain a
cornerstone in the treatment of HF and recent review
concluded that “irrespective of age or sex, patients
with HFrEF in sinus rhythm should receive beta-
blockers to reduce the risk of death and admission to
hospital” (33). Most disappointing it is therefore that b-
blockers have no better preventive effect on HF than
do other antihypertensives. Among the 12 randomized
controlled trials we analyzed, evaluating 112,177 pa-
tients with hypertension, beta-blockers reduced BP by
12.6/6.1 mm Hg when compared with placebo, result-
ing in a 23% (trend) reduction in HF risk (p ¼ 0.055).
(34) Compared with other antihypertensives, beta-
blockers conferred similar but no incremental benefit
for the outcomes of all-cause mortality, cardiovascular
mortality, and myocardial infarction, but increased
stroke risk by 19% in the elderly. Given this increased
risk of stroke, beta-blockers should not be considered
as first-line agents for prevention of HF.
In a Cochrane meta-analysis, calcium-channel
blockers (CCBs) increased the risk of HF events
(risk ratio [RR]: 1.37; 95% confidence interval [CI]:
6 Messerli et al. JACC: HEART FAILURE VOL. -, NO. -, 2017
Transition From Hypertension to HF - 2017:-–-

C E N T R A L IL L U ST R A T I O N Suggested Empirical Antihypertensive Strategy in HF Patients With

Persisting Hypertension

Messerli, F.H. et al. J Am Coll Cardiol HF. 2017;-(-):-–-.

ACEi ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; Ca ¼ calcium; HF ¼ heart failure; HFpEF ¼ heart failure
with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction; LV ¼ left ventricular; LVEF ¼ left ventricular ejection
fraction; LVH ¼ left ventricular hypertrophy.

1.25 to 1.51) as compared with diuretics. Although
CCBs reduced stroke as compared with ACE inhibitors
and reduced stroke and myocardial infarction as
compared with ARBs, CCBs also increased HF events
as compared with ACE inhibitors (RR: 1.16; 95% CI:
1.06 to 1.27) and ARBs (RR: 1.20; 95% CI: 1.06 to
1.36) (35). Stroke remains the most devastating
complication of hypertension, but prima vista CCBs
are probably not the antihypertensive drug class of
choice for the prevention of HF.
However, a recent meta-analysis concluded that
BP lowering by calcium antagonists is as efficacious
as BP lowering by other antihypertensive drugs in
preventing new onset HF (36). Thomopoulos et al. (36)
reassessed the previously reported inferiority of CCBs
in preventing HF and documented that the inferiority
of CCBs may depend on, at least to a large extent, an
unequal use of accompanying drugs. The more
aggressive use of drugs known to reduce HF symp-
toms (diuretics, b -blockers, and renin-angiotensin
system blockers) in the control arms might have
masked onset of HF symptoms to a greater extent,
thereby creating a bias against CCBs.
In ALLHAT (Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial), the alpha-
blocker doxazosin arm, compared with the chlorthali-
done arm, conferred a higher risk of stroke and
combined cardiovascular disease. Importantly, HF risk
was doubled with doxazosin (4-year rates, 8.13% vs.
4.45%; RR: 2.04; 95% CI: 1.79 to 2.32; p < 0.001) (34).
This would indicate that for the treatment of
hypertension alpha-blockers should be avoided in
JACC: HEART FAILURE VOL. -, NO. -, 2017
- 2017:-–-
patients at risk or with HF. Although the data in
aggregate are less convincing for alpha-blockers than
for CCBs, specifically amlodipine, a very similar point
as was made previously for CCBs (35) could be made for
alpha-blockers. In ASCOT (Anglo-Scandinavian Car-
diac Outcomes Trial), doxazosin gastrointestinal ther-
apeutic system given as a third-line add-on drug did
not increase the risk of HF and was well tolerated (35).
Blockers of the renin-angiotensin system are effi-
cacious drugs to treat hypertension and to prevent
HF. Contrary to the common clinical notion and to
some guidelines, no meaningful difference
efficacy has been documented between
inhibitors and ARBs (37,38). Of note, the first-in-class
angiotensin II receptor neprilysin inhibitor valsartan/
sacubitril not only is a novel drug for the treatment
of HF, but also is likely to become a useful antihy-
pertensive drug. Recent data have indicated that it
may have a preferential effect on systolic pressure
(39). A meta-analysis has shown better BP lowering
with valsartan/sacubitril than with ARBs. In the
PARADIGM (Prospective Comparison of ARNI with
ACEI to Determine Impact on Global Mortality and
Morbidity in Heart Failure) trial, valsartan/sacubitril
showed a striking reduction in cardiovascular mor-
tality and morbidity in patients with HFrEF (40). Of
note, the long-term use of neprilysin inhibitors may
compromise beta-amyloid peptide degradation in
the brain, thereby possibly accelerating progression
of Alzheimer’s disease in patients at risk. Thus, it
remains to be seen whether the risk–benefit ratio of
valsartan/sacubitril confers incremental long-term
prognostic benefits in patients with hypertension.
Finally, the thiazide-like diuretics chlorthalidone
and indapamide are outstanding agents when used as
antihypertensive drugs to prevent HF. In the SHEP
trial (41) as well as in HYVET (Hypertension in the
Very Elderly Trial) (42) there was a highly significant
reduction of HF with active therapy against placebo,
amounting to an RR of 0.51 (95% CI: 0.37 to 0.71) for
chlorthalidone and 0.36 (95% CI: 0.22 to 0.58) for
indapamide (p < 0.001 for both). The HF preventive
efficacy of diuretics as a group in 10 randomized
controlled trials was clearly superior to the one of all
REFERENCES
1. Levy D, Larson MG, Vasan RS, Kannel WB, 3. Ahmad FS, Ning H, Rich JD, Yancy CW, Lloyd-
Ho KK. The progression from hypertension to Jones DM, Wilkins JT. Hypertension, obesity,
congestive heart failure. JAMA 1996;275:1557–62. diabetes, and heart failure-free survival: the Car-
diovascular Disease Lifetime Risk Pooling Project.
2. Lloyd-Jones DM, Larson MG, Leip EP, et al. J Am Coll Cardiol HF 2016;4:911–9.
Lifetime risk for developing congestive heart fail-
ure: the Framingham Heart Study. Circulation 4. Kostis JB, Cabrera J, Cheng JQ, et al. Association
2002;106:3068–72. between chlorthalidone treatment of systolic
Messerli et al. 7
Transition From Hypertension to HF
other antihypertensives (RR: 0.84; 95% CI: 0.73 to
0.98) (36). Of note, no outcome data are available for
hydrochlorothiazide, for neither HF nor any other
cardiovascular endpoint. In contrast to chlorthali-
done and indapamide, hydrochlorothiazide should be
avoided in hypertensive patients at risk for HF.
In conclusion, most antihypertensive drug classes
when used as initial therapy decelerate the transition
from hypertension to HF, although not all of them are
created equal in this regard. Low-dose, once daily
hydrochlorothiazide should be avoided, but the
in thiazide-like diuretics chlorthalidone and indapa-
ACE mide seem to have an edge over other antihyperten-
sive drugs in preventing HF.
ANTIHYPERTENSIVE THERAPY IN HF
PATIENTS WITH PERSISTING HYPERTENSION
In most HF patients too low a BP is a more common
clinical problem than is hypertension. However, some
patients with HFpEF and a few with HFrEF present
with hypertension. Because no outcome data are
available, our treatment recommendations are purely
empirical, based on clinical and pathophysiologic
considerations (Central Illustration). Also, our recom-
mendations of antihypertensive therapy are based on
the assumption that all HF patients are on baseline
triple therapy consisting of an ACE inhibitor or an
ARB, plus a b-blocker and a loop diuretic, and despite
this still exhibit residual hypertension. The proposed
antihypertensive strategy is geared at improving
diastolic and microvascular dysfunction in HFpEF
and at improving or at least preserving systolic
function in HFrEF. As a first step we suggest to in-
crease afterload reduction by switching to valsartan/
sacubitril (38) and to a vasodilating b-blocker such
as carvedilol or nebivolol. Clearly a statin should be
part of the therapeutic strategy in all patients with
HFpEF to reduce microvascular dysfunction.
ADDRESS FOR CORRESPONDENCE: Dr. Franz H.
Messerli, Department of Cardiology and Clinical Research,
University Hospital, Bern, Freiburgstrasse, CH-3010 Bern,
Switzerland. E-mail: messerli.f@gmail.com.
hypertension and long-term survival. JAMA 2011;306:
2588–93.
5. Messerli FH. Cardiovascular effects of obesity
and hypertension. Lancet 1982;1:1165–8.
6. Seliger SL, de Lemos J, Neeland IJ, et al. Older
adults, “malignant” left ventricular hypertrophy,
and associated cardiac-specific biomarker
8 Messerli et al.
Transition From Hypertension to HF
phenotypes to identify the differential risk of new-
onset reduced versus preserved ejection fraction
heart failure: CHS (Cardiovascular Health Study).
J Am Coll Cardiol HF 2015;3:445–55.
7. Iriarte M, Murga N, Sagastagoitia D, et al.
Classification of hypertensive cardiomyopathy. Eur
Heart J 1993;14 Suppl J:95–101.
8. Paulus WJ, Tschope C. A novel paradigm for
heart failure with preserved ejection fraction:
comorbidities drive myocardial dysfunction and
remodeling through coronary microvascular
endothelial inflammation. J Am Coll Cardiol 2013;
62:263–71.
9. Mohammed SF, Hussain S, Mirzoyev SA,
Edwards WD, Maleszewski JJ, Redfield MM. Cor-
onary microvascular rarefaction and myocardial
fibrosis in heart failure with preserved ejection
fraction. Circulation 2015;131:550–9.
10. Gandhi SK, Powers JC, Nomeir AM, et al. The
pathogenesis of acute pulmonary edema associ-
ated with hypertension. N Engl J Med 2001;344:
17–22.
11. Oakley C. Diagnosis and natural history of
congested (dilated) cardiomyopathies. Postgrad
Med J 1978;54:440–50.
12. Ather S, Bangalore S, Vemuri S, Cao LB,
Bozkurt B, Messerli FH. Trials on the effect of
cardiac resynchronization on arterial blood pres-
sure in patients with heart failure. Am J Cardiol
2011;107:561–8.
13. Tanaka Y, Tada H, Yamashita E, et al. Change in
blood pressure just after initiation of cardiac
resynchronization therapy predicts long-term
clinical outcome in patients with advanced heart
failure. Circ J 2009;73:288–94.
14. Adamopoulos C, Zannad F, Fay R, et al. Ejec-
tion fraction and blood pressure are important and
interactive predictors of 4-week mortality in se-
vere acute heart failure. Eur J Heart Fail 2007;9:
935–41.
15. Bhatia RS, Tu JV, Lee DS, et al. Outcome of
heart failure with preserved ejection fraction in a
population-based study. N Engl J Med 2006;355:
260–9.
16. Fonarow GC, Adams KF Jr., Abraham WT, et al.
Risk stratification for in-hospital mortality in
acutely decompensated heart failure: classification
and regression tree analysis. JAMA 2005;293:
572–80.
17. Gheorghiade M, Abraham WT, Albert NM, et al.
Systolic blood pressure at admission, clinical
characteristics, and outcomes in patients hospi-
talized with acute heart failure. JAMA 2006;296:
2217–26.
18. Lee TT, Chen J, Cohen DJ, Tsao L. The asso-
ciation between blood pressure and mortality in
patients with heart failure. Am Heart J 2006;151:
76–83.
19. Pulignano G, Del Sindaco D, Tavazzi L, et al.
Clinical features and outcomes of elderly out-
patients with heart failure followed up in hospital
cardiology units: data from a large nationwide
JACC: HEART FAILURE VOL.
cardiology database (IN-CHF Registry). Am Heart J
2002;143:45–55.
20. Schrier RW, Abraham WT. Hormones and he-
modynamics in heart failure. N Engl J Med 1999;
341:577–85.
21. Rouleau JL, Roecker EB, Tendera M, et al. In-
fluence of pretreatment systolic blood pressure on
the effect of carvedilol in patients with severe
chronic heart failure: the Carvedilol Prospective
Randomized Cumulative Survival (COPERNICUS)
study. J Am Coll Cardiol 2004;43:1423–9.
22. McAlister FA, Wiebe N, Ezekowitz JA,
Leung AA, Armstrong PW. Meta-analysis: beta-
blocker dose, heart rate reduction, and death in
patients with heart failure. Ann Intern Med 2009;
150:784–94.
23. Swedberg K, Komajda M, Bohm M, et al.
Ivabradine and outcomes in chronic heart failure
(SHIFT): a randomised placebo-controlled study.
Lancet 2010;376:875–85.
24. Rimoldi SF, Messerli FH, Cerny D, et al. Se-
lective heart rate reduction with ivabradine in-
creases central blood pressure in stable coronary
artery disease. Hypertension 2016;67:1205–10.
25. Messerli FH, Rimoldi SF, Bangalore S,
Bavishi C, Laurent S. When an increase in central
systolic pressure overrides the benefits of heart
rate lowering. J Am Coll Cardiol 2016;68:754–62.
26. Bock JS, Gottlieb SS. Cardiorenal syndrome:
new perspectives. Circulation 2010;121:
2592–600.
27. Ronco C, Cicoira M, McCullough PA. Car-
diorenal syndrome type 1: pathophysiological
crosstalk leading to combined heart and kidney
dysfunction in the setting of acutely decom-
pensated heart failure. J Am Coll Cardiol 2012;60:
1031–42.
28. Epstein M, Pitt BC. A propitious time for
initiating clinical trials in patients with heart failure
with reduced ejection fraction and an estimated
glomerular filtration rate <30 mL/min with an
mineralocorticoid receptor antagonist and a Kþ
binder: ’the forbidden fruit’. Eur Heart J 2016;37:
3130–4.
29. Pickering TG, Herman L, Devereux RB, et al.
Recurrent pulmonary oedema in hypertension due
to bilateral renal artery stenosis: treatment by
angioplasty or surgical revascularisation. Lancet
1988;2:551–2.
30. Messerli FH, Bangalore S, Makani H, et al.
Flash pulmonary oedema and bilateral renal artery
stenosis: the Pickering syndrome. Eur Heart J
2011;32:2231–5.
31. Rimoldi SF, Yuzefpolskaya M, Allemann Y,
Messerli F. Flash pulmonary edema. Prog Car-
diovasc Dis 2009;52:249–59.
32. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/
AHA 2005 guidelines for the management of
patients with peripheral arterial disease (lower
extremity, renal, mesenteric, and abdominal
aortic): executive summary a collaborative report
from the American Association for Vascular
-, NO. -, 2017
- 2017:-–-
Surgery/Society for Vascular Surgery, Society for
Cardiovascular Angiography and Interventions,
Society for Vascular Medicine and Biology, Society
of Interventional Radiology, and the ACC/AHA
Task Force on Practice Guidelines (Writing Com-
mittee to Develop Guidelines for the Management
of Patients With Peripheral Arterial Disease)
endorsed by the American Association of Cardio-
vascular and Pulmonary Rehabilitation; National
Heart, Lung, and Blood Institute; Society for
Vascular Nursing; TransAtlantic Inter-Society
Consensus; and Vascular Disease Foundation.
J Am Coll Cardiol 2006;47:1239–312.
33. Kotecha D, Manzano L, Krum H, et al. Effect of
age and sex on efficacy and tolerability of beta
blockers in patients with heart failure with
reduced ejection fraction: individual patient data
meta-analysis. BMJ 2016;353:i1855.
34. Bangalore S, Wild D, Parkar S, Kukin M,
Messerli FH. Beta-blockers for primary prevention
of heart failure in patients with hypertension in-
sights from a meta-analysis. J Am Coll Cardiol
2008;52:1062–72.
35. Chen N, Zhou M, Yang M, et al. Calcium
channel blockers versus other classes of drugs for
hypertension. Cochrane Database Syst Rev 2010;
8:CD003654.
36. Thomopoulos C, Parati G, Zanchetti A. Effects
of blood pressure-lowering treatment: 6. Preven-
tion of heart failure and new-onset heart failure–
meta-analyses of randomized trials. J Hypertens
2016;34:373–84, discussion 384.
37. Bangalore S, Fakheri R, Toklu B, Ogedegbe G,
Weintraub H, Messerli FH. Angiotensin-converting
enzyme inhibitors or angiotensin receptor blockers
in patients without heart failure? Insights from
254,301 patients from randomized trials. Mayo
Clinic Proc 2016;91:51–60.
38. Messerli FH. Angiotensin receptor blockers
reduce cardiovascular events, including the risk of
myocardial infarction. Circulation 2016. In press.
39. Bavishi C, Messerli FH, Kadosh B, Ruilope LM,
Kario K. Role of neprilysin inhibitor combinations
in hypertension: insights from hypertension and
heart failure trials. Eur Heart J 2015;36:1967–73.
40. McMurray JJ, Packer M, Desai AS, et al.
Angiotensin-neprilysin inhibition versus enalapril
in heart failure. N Engl J Med 2014;371:993–1004.
41. Prevention of stroke by antihypertensive drug
treatment in older persons with isolated systolic
hypertension. Final results of the Systolic Hyper-
tension in the Elderly Program (SHEP). SHEP
Cooperative Research Group. JAMA 1991;265:
3255–64.
42. Beckett NS, Peters R, Fletcher AE, et al.
Treatment of hypertension in patients 80 years of
age or older. N Engl J Med 2008;358:1887–98.
KEY WORDS antihypertensive therapy,
cardio-renal syndrome, HFpEF, hypertensive
heart disease, left ventricular hypertrophy,
Pickering syndrome